Adrenalectomy for advanced breast cancer: a reappraisal.
The introduction of strict criteria of treatment response for advanced breast cancer facilitates comparison of treatment modalities. Recent studies of pharmacological measures are usually recorded according to UICC criteria but this has not been the case with regard to adrenalectomy. An analysis of 41 patients undergoing adrenalectomy for advanced breast cancer was undertaken to assess response according to UICC criteria. There were no complete objective responses but 12.2% had Partial Remission and 12.2% Static Disease, the remainder showing disease progression. These figures are lower than in most reported series which have used less clearly defined criteria of response. The Partial Response and No Change groups were similar in terms of symptomatic improvement and survival but superior to the treatment failure group. Adrenalectomy was associated with significant morbidity (46.7%) and operative mortality (6.7%). Only 1 patient of 11 previously treated with tamoxifen had a subsequent response to adrenalectomy. The low response rate when assessed on UICC criteria and high morbidity when compared with alternative treatment suggest that adrenalectomy will be less widely used in the future.


Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria.
Although a classification for mastocytosis and diagnostic criteria are available, there remains a need to define standards for the application of diagnostic tests, clinical evaluations, and treatment responses. To address these demands, leading experts discussed current issues and standards in mastocytosis in a Working Conference. The present article provides the resulting outcome with consensus statements, which focus on the appropriate application of clinical and laboratory tests, patient selection for interventional therapy, and the selection of appropriate drugs. In addition, treatment response criteria for the various clinical conditions, disease-specific symptoms, and specific pathologies are provided. Resulting recommendations and algorithms should greatly facilitate the management of patients with mastocytosis in clinical practice, selection of patients for therapies, and the conduct of clinical trials.


Energy landscape of a small peptide revealed by dihedral angle principal component analysis.
A 100 ns molecular dynamics simulation of penta-alanine in explicit water is performed to study the reversible folding and unfolding of the peptide. Employing a standard principal component analysis (PCA) using Cartesian coordinates, the resulting free-energy landscape is found to have a single minimum, thus suggesting a simple, relatively smooth free-energy landscape. Introducing a novel PCA based on a transformation of the peptide dihedral angles, it is found, however, that there are numerous free energy minima of comparable energy (less than or approximately 1 kcal/mol), which correspond to well-defined structures with characteristic hydrogen-bonding patterns. That is, the true free-energy landscape is actually quite rugged and its smooth appearance in the Cartesian PCA represents an artifact of the mixing of internal and overall motion. Well-separated minima corresponding to specific conformational structures are also found in the unfolded part of the free energy landscape, revealing that the unfolded state of penta-alanine is structured rather than random. Performing a connectivity analysis, it is shown that neighboring states are connected by low barriers of similar height and that each state typically makes transitions to three or four neighbor states. Several principal pathways for helix nucleation are identified and discussed in some detail.


General solution of the coupled-wave equations of acousto-optics.
The basic problem of the diffraction of an optical plane wave by an acoustic plane wave in an anisotropic homogeneous medium is considered. The acousto-optical interaction is considered indifferently of the isotropic or of the birefringent type. Coupled-wave equations are obtained rigorously and cast into an eigenvalue value problem. A general solution is obtained for the diffraction efficiency of diffracted orders, for any interaction length and diffraction regime. The theory includes the Bragg regime, the Raman-Nath regime, and all intermediate situations in the same formulation. The method of solution is both exact and computationally efficient. It is similar in character to the rigorous coupled-wave analysis of Moharam and Gaylord but differs by the choice of basis functions adapted to propagating rather than static gratings. Examples are given for acousto-optical interaction in paratellurite, TeO2.


Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.
This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.


Identification of DeltaNp63alpha protein interactions by mass spectrometry.
p63, a transcription factor related to the p53 tumor suppressor, plays a key role in epidermal differentiation and limb development. The gene has two distinct promoters that allow the formation of proteins that either contain (TA) or lack (DeltaN) a transactivation domain. DeltaNp63alpha is the most widely expressed isoform, at all stages of development and in adult tissues. It supports the regenerative capacity of basal keratinocytes and its upregulation is a hallmark of human squamous carcinomas. To get insight into the complex biology of DeltaNp63alpha, we set out to identify DeltaNp63alpha interacting proteins by co-immunoprecipitation in mammalian cells and mass spectrometry analysis. A total of 49 potential DeltaNp63alpha binding proteins, including several heterogeneous ribonucleoproteins (hnRNPs), were identified. Integration of the proteomic data with a Human Coexpression Network highlighted 5 putative p63 protein interactors whose expression is significantly comodulated with p63: hnRNPA/B, hnRNPK, hnRNPQ, FUS/TLS and Keratin 5. hnRNPA/B was already described as a p63 partner, but the others were novel. Interaction of DeltaNp63alpha with hnRNPQ, hnRNPK and FUS/TLS was confirmed by reciprocal co-immunoprecipitations in human keratinocytes. The finding that DeltaNp63alpha exists in complexes with several RNA-binding proteins lays the premises for the analysis of the role of DeltaNp63alpha in mRNA metabolism and transport.


Cultural and contextual influences in mental health help seeking: a focus on ethnic minority youth.
In this article, a mental health help-seeking model is offered as a framework for understanding cultural and contextual factors that affect ethnic minority adolescents' pathways into mental health services. The effects of culture and context are profound across the entire help-seeking pathway, from problem identification to choice of treatment providers. The authors argue that an understanding of these help-seeking pathways provides insights into ethnic group differences in mental health care utilization and that further research in this area is needed.


Loss of DAB2IP in RCC cells enhances their growth and resistance to mTOR-targeted therapies.
Targeted therapies using small-molecule inhibitors (SMIs) are commonly used in metastatic renal cell cancer (mRCC) patients; patients often develop drug resistance and eventually succumb to disease. Currently, understanding of mechanisms leading to SMIs resistance and any identifiable predictive marker(s) are still lacking. We discovered that DAB2IP, a novel Ras-GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. Loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin (mTOR) inhibitors). Mechanistically, loss of DAB2IP results in the activation of extracellular signal-regulated kinase/RSK1 and phosphoinositide-3 kinase/mTOR pathway, which synergizes the induction of hypoxia-inducible factor (HIF)-2α expression. Consequently, elevated HIF-2α suppresses p21/WAF1 expression that is associated with resistance to mTOR inhibitors. Thus combinatorial targeting both pathways resulted in a synergistic tumor inhibition. DAB2IP appears to be a new prognostic/predictive marker for mRCC patients, and its function provides a new insight into the molecular mechanisms of drug resistance to mTOR inhibitors, which also can be used to develop new strategies to overcome drug-resistant mRCC.


Vaccines to prevent hepatitis B and hepatitis A virus infections.
Vaccines to prevent hepatitis B infection became available in 1982, and were recommended primarily for adults considered at high risk because of exposure in the workplace or lifestyles that lead to sexual or parenteral exposure to the virus. Plasma-derived and recombinant vaccines produced in yeast are highly immunogenic, safe, and effective for all age groups. Decreased response and protection by vaccine occur in older persons and in persons with immunosuppressive illnesses. The main issues concerning current vaccination programs include the possible use of lower doses to reduce the cost of the vaccine, the duration of protection and need for vaccine booster doses, and the need for postvaccination testing in hospitals. The failure of current vaccination programs to decrease disease incidence, a matter of great concern nationally, can be ascribed to failure to deliver vaccine to the groups at highest risk. More effective strategies for control, including the universal vaccination of infants or adolescents, must now be examined. Newer vaccines that incorporate other viral antigens and that may offer increased efficacy are being developed. Vaccines to prevent hepatitis A--both killed and live attenuated vaccines--are undergoing clinical trials and may become available in the next 5 years.


Transitions to work for persons with serious mental illness in northeastern Ontario, Canada: examining barriers to employment.
This paper considers the importance of place in the conceptualization of transitions to work for persons with serious mental illness (SMI). A qualitative case study was conducted to explore the influence of place on access to employment for persons with SMI. In-depth interviews, focus groups, and demographic data collected from urban and rural residing individuals who experience SMI, mental health and vocational service providers, and decision makers across northeastern Ontario inform this paper. The results highlight the primary theme, stuck in the mud, which explains how people with SMI, service providers and decision makers are stuck regarding employment. Ultimately, their being stuck creates a variety of place-related tensions and a tendency to settle for less in the area of employment for persons with SMI. The condition of being stuck in the mud is expressed as a metaphor depicting the existing tensions between ideas which govern provincial employment policy for persons with SMI and the mainstream or dominant discourse governing local organizations, programs and practices in the case communities and supports the need to consider place in policy implementation.


Role of antibodies against biotype-specific Vibrio cholerae pili in protection against experimental classical and El Tor cholera.
Vibrio cholerae O1, which exists as two biotypes, classical and El Tor, expresses fimbrial antigens called toxin-coregulated pili (TCP) and mannose-sensitive hemagglutinin (MSHA) pili, respectively. We have raised rabbit antisera and monoclonal antibodies against these fimbrial antigens and prepared Fab fragments which possess specific antibodies directed against the respective fimbrial antigens from these antisera. The protective effect of these antibody preparations was studied in the infant mouse cholera model. Antibodies against TCP were able to protect baby mice against challenge with V. cholerae O1 of the classical but not of the El Tor biotype. Similar but reverse biotype differences in protection against challenge with classical and El Tor vibrios were observed when antibodies against MSHA pili were used. The protective effect of V. cholerae O1 antilipopolysaccharide (anti-LPS) antibodies, both alone and in combination with antifimbrial antibodies, was also evaluated. We showed that antibodies to the LPS component also prevented infections with V. cholerae O1. Moreover, our results indicate that antibodies against TCP or MSHA pili and against LPS cooperate at least additively, and possible even synergistically, in protecting baby mice against challenge with group O1 vibrios. These results indicate that TCP and MSHA pili as well as LPS play an important role in the pathogenesis of experimental cholera. We could also demonstrate that antibacterial immunity preventing colonization is biotype specific. Our results might be used for the generation of new oral cholera vaccines including both TCP and MSHA fimbrial antigens.


Influence of oxygen concentration on the metabolism of Penicillium chrysogenum.
In large-scale bioreactors, there is often insufficient mixing and as a consequence, cells experience uneven substrate and oxygen levels that influence product formation. In this study, the influence of dissolved oxygen (DO) gradients on the primary and secondary metabolism of a high producing industrial strain of Penicillium chrysogenum was investigated. Within a wide range of DO concentrations, obtained under chemostat conditions, we observed different responses from P. chrysogenum: (i) no influence on growth or penicillin production (>0.025 mmol L-1); (ii) reduced penicillin production, but no growth limitation (0.013-0.025 mmol L-1); and (iii) growth and penicillin production limitations (<0.013 mmol L-1). In addition, scale down experiments were performed by oscillating the DO concentration in the bioreactor. We found that during DO oscillation, the penicillin production rate decreased below the value observed when a constant DO equal to the average oscillating DO value was used. To understand and predict the influence of oxygen levels on primary metabolism and penicillin production, we developed a black box model that was linked to a detailed kinetic model of the penicillin pathway. The model simulations represented the experimental data during the step experiments; however, during the oscillation experiments the predictions deviated, indicating the involvement of the central metabolism in penicillin production.


Proteasome inhibition in myelodysplastic syndromes and acute myelogenous leukemia cell lines.
In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.


[A method of closed iridoplasty in transparent crystalline lens].
The operation is performed through two punctures of the cornea with the normal depth of the anterior chamber artificially maintained with physiologic saline supplied via a flat cannula. Through a corneal puncture this cannula is brought under the contralateral edge of iridal defect, elevating this defect beyond the lens, and a needle brought via the other puncture pricks the iris and the needle tip enters the cannula canal. The needle and cannula joined together are brought to the second edge of iridal defect, similarly pricking it, and brought out of the anterior chamber, still joined together. Then the needle is brought back through the same corneal puncture, so that it joins the cannula brought through the other corneal puncture, and brought from the anterior chamber. The stitch is tied on the cornea, with the iris being tightened.


Studies on the physiology of macrophage receptors for alpha-macroglobulin X protease complexes.
Alveolar macrophages exhibit high-affinity receptors that effect the binding and internalization of alpha-macroglobulin X protease complexes (alpha M X P). Studies were designed to probe the mechanism of internalization of alpha M X P complexes. Macrophages also exhibit receptors capable of clearing other injurious agents such as mannose-terminal glycoproteins. We have demonstrated that uptake of mannose-terminal glycoproteins does not affect the rate of internalization of alpha M X P complexes, suggesting that "scavenger" receptors function independently, and that the machinery for endocytosis is not rate limiting. We have also demonstrated that the rate of internalization of receptor-bound alpha M X P is independent of receptor occupancy. During the internalization of alpha M X P there is a decrease in the number of surface receptors consistent with the internalization of ligand-receptor complexes. Using photoaffinity-labeled alpha M X P to inactivate surface receptors, we have demonstrated that even in the absence of ligand accumulation, pools of intracellular receptors exist which are capable of being exteriorized to the cell surface. These results suggest that concomitant with internalization of occupied receptors is the appearance of unoccupied receptors on the cell surface from an internal pool.


Comparison of Guided and Unguided Ocriplasmin Injection for the Treatment of Vitreomacular Traction: A Preliminary Study.
This retrospective quality control study aimed at comparing resolution in patients treated with intravitreal ocriplasmin (IVO) using two injection techniques, classical injection procedure (unguided) and targeted injection using a surgical microscope with a 30-gauge 1-inch needle (guided) for the treatment of focal VMT without macular hole. The two groups presented a statistically significant difference in terms of resolution of VMT within the first month following treatment: 1/7 for the unguided group versus 6/7 for the guided group (p = 0.0291). The majority of the guided group presented an earlier resolution than the single resolved case in the unguided group. The results of this preliminary study indicate that the injection of ocriplasmin closer to the site of VMT results in the resolution in a higher number of cases and that this resolution occurs in a short time interval.


Exergaming in older adults: the effects of game characteristics on brain activity and physical activity.
Exergames are increasingly used in rehabilitation settings for older adults to train physical and cognitive abilities. To meet the potential that exergames hold, they need to be adapted to the individual abilities of the player and their training objectives. Therefore, it is important to know whether and how game characteristics affect their playing. The aim of this study is to investigate the effect of two different kinds of exergame (step game and balance game) played at two difficulty levels on brain activity and physical activity. Twenty-eight older independently living adults played two different exergames at two difficulty levels each. In addition, the same movements as during gaming (leaning sideways with feet in place and stepping sideways) were performed as reference movements. Brain activity was recorded using a 64-channel EEG system to assess brain activity, while physical activity was recorded using an accelerometer at the lower back and a heart rate sensor. Source-space analysis was applied to analyze the power spectral density in theta (4 Hz-7 Hz) and alpha-2 (10 Hz-12 Hz) frequency bands. Vector magnitude was applied to the acceleration data. Friedman ANOVA revealed significantly higher theta power for the exergaming conditions compared to the reference movement for both games. Alpha-2 power showed a more diverse pattern which might be attributed to task-specific conditions. Acceleration decreased significantly from the reference movement to the easy condition to the hard condition for both games. The results indicate that exergaming increases frontal theta activity irrespective of type of game or difficulty level, while physical activity decreases with increasing difficulty level. Heart rate was found to be an inappropriate measure in this population older adults. These findings contribute to understanding of how game characteristics affect physical and cognitive activity and consequently need to be taken into account when choosing appropriate games and game settings for exergame interventions.


In search of the ideal method in perforator mapping: noncontrast magnetic resonance imaging.
A reliable method for precise identification of the dominant perforator would be extremely valuable in perforator flap surgery. During the past 5 years, multidetector-row computed tomography has demonstrated excellent results in preoperative planning of abdominal free flap breast reconstruction, significantly reducing operative time and complications. The main drawbacks of computed tomography are unnecessary radiation to the patient and possible allergic reactions to intravenous contrast material. To circumvent these limitations, we performed noncontrast magnetic resonance imaging for abdominal perforator mapping. The aim of our study was to assess the accuracy and reliability of this technique in preoperative planning of breast reconstruction with deep inferior epigastric artery perforator flaps. From October 2007 to February 2009, noncontrast magnetic resonance preoperative mapping was performed in 56 female patients who underwent breast reconstruction after mastectomy with deep inferior epigastric artery perforator flaps. Imaging results were compared with the intraoperative clinical findings in all patients. Preoperative magnetic resonance imaging without the contrast showed no false-positive or false-negative results. In all cases, the perforator chosen as dominant according to magnetic resonance images corresponded with the perforator chosen intraoperatively (100% predictive value). Preoperative imaging techniques make perforator flap surgery safer for the patient. Noncontrast magnetic resonance imaging provides reliable information on the vascular anatomy of the abdominal wall, facilitating selection of the most appropriate deep inferior epigastric artery dominant perforator. It avoids radiation to the patient and also the need for intravenous contrast medium as required for the multidetector-row computed tomography. In our opinion, noncontrast magnetic resonance imaging is an ideal method for preoperative planning of breast reconstruction with deep inferior epigastric artery perforator flaps.


Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer.
The oncogenic human papilloma viruses (HPVs) are associated with precancerous cervical lesions and development of cervical cancer. The DNA methylation signatures of the host genome in normal, precancerous and cervical cancer tissue may indicate tissue-specific perturbation in carcinogenesis. The aim of this study was to identify new candidate genes that are differentially methylated in squamous cell carcinoma compared with DNA samples from cervical intraepithelial neoplasia grade 3 (CIN3) and normal cervical scrapes. The Illumina Infinium HumanMethylation450 BeadChip method identifies genome-wide DNA methylation changes in CpG islands, CpG shores and shelves. Our findings showed an extensive differential methylation signature in cervical cancer compared with the CIN3 or normal cervical tissues. The identified candidate biomarker genes for cervical cancer represent several types of mechanisms in the cellular machinery that are epigenetically deregulated by hypermethylation, such as membrane receptors, intracellular signaling and gene transcription. The results also confirm extensive hypomethylation of genes in the immune system in cancer tissues. These insights into the functional role of DNA methylome alterations in cervical cancer could be clinically applicable in diagnostics and prognostics, and may guide the development of new epigenetic therapies.


Cellular proliferation and activation of NF kappa B are induced by autocrine production of tumor necrosis factor alpha in the human T lymphoma line HuT 78.
Tumor necrosis factor (TNF) is a pleiotropic cytokine which has both cytotoxic and proliferative effects. HuT 78, a T-cell line derived from a Sezary lymphoma, is resistant to the cytotoxic effects of TNF, suggesting that TNF may be a growth factor for this cell line. The aim of this study was to determine whether autocrine TNF production could function as a growth factor for HuT 78. Resting HuT 78 and K-4 cells, a protein kinase C-beta-deficient clone of HuT 78, both produced significant amounts of TNF compared with Jurkat cells. Thymidine incorporation by HuT 78 and K-4 cells was inhibited by 90.5 and 73.2%, respectively, with addition of a neutralizing monoclonal antibody to TNF alpha, suggesting that TNF is an autocrine growth factor for these cells. HuT 78 and K-4 cells also expressed high levels of constitutively active NF kappa B, unlike Jurkat cells, which expressed high levels only upon activation with TNF or phorbol 12-myristate 13-acetate. p50 was the major component in the NF kappa B complexes in HuT 78 and K-4 cells. Anti-TNF alpha antibody dramatically decreased levels of NF kappa B in both HuT 78 and K-4 cells. As the TNF gene has an NF kappa B binding motif, an autocrine loop involving TNF induction of NF kappa B is therefore likely in these cells. These findings in a neoplastic T-cell line suggest that therapy directed against TNF could be effective in a subset of T-cell lymphomas.


One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid-susceptible tuberculosis in Eastern Europe, Western Europe, and Latin America.
The high mortality among HIV/tuberculosis (TB) coinfected patients in Eastern Europe is partly explained by the high prevalence of drug-resistant TB. It remains unclear whether outcomes of HIV/TB patients with rifampicin/isoniazid-susceptible TB in Eastern Europe differ from those in Western Europe or Latin America. One-year mortality of HIV-positive patients with rifampicin/isoniazid-susceptible TB in Eastern Europe, Western Europe, and Latin America was analysed and compared in a prospective observational cohort study. Factors associated with death were analysed using Cox regression modelsRESULTS:: Three hundred and forty-one patients were included (Eastern Europe 127, Western Europe 165, Latin America 49). Proportions of patients with disseminated TB (50, 58, 59%) and initiating rifampicin + isoniazid + pyrazinamide-based treatment (93, 94, 94%) were similar in Eastern Europe, Western Europe, and Latin America respectively, whereas receipt of antiretroviral therapy at baseline and after 12 months was lower in Eastern Europe (17, 39, 39%, and 69, 94, 89%). The 1-year probability of death was 16% (95% confidence interval 11-24%) in Eastern Europe, vs. 4% (2-9%) in Western Europe and 9% (3-21%) in Latin America; P < 0.0001. After adjustment for IDU, CD4 cell count and receipt of antiretroviral therapy, those residing in Eastern Europe were at nearly 3-fold increased risk of death compared with those in Western Europe/Latin America (aHR 2.79 (1.15-6.76); P = 0.023). Despite comparable use of recommended anti-TB treatment, mortality of patients with rifampicin/isoniazid-susceptible TB remained higher in Eastern Europe when compared with Western Europe/Latin America. The high mortality in Eastern Europe was only partially explained by IDU, use of ART and CD4 cell count. These results call for improvement of care for TB/HIV patients in Eastern Europe.


Core Size does not Affect Blinking Behavior of Dye-Doped Ag@SiO2 Core-Shell Nanoparticles for Super-Resolution Microscopy.
Dye-doped nanoparticles have been investigated as bright, luminescent labels for super -resolution microscopy via localization methods. One key factor in super-resolution is the size of the luminescent label, which in some cases results in a frame shift between the label target and the label itself. Ag@SiO2 core-shell nanoparticles, doped with organic fluorophores, have shown promise as super-resolution labels. One key aspect of these nanoparticles is that they blink under certain conditions, allowing super-resolution localization with a single excitation source in aqueous solution. In this work, we investigated the effects of both the Ag core and the silica (SiO2) shell on the self-blinking properties of these nanoparticles. Both core size and shell thickness were manipulated by altering the reaction time to determine core and shell effects on photoblinking. Size and shell thickness were investigated individually under both dry and hydrated conditions and were then doped with a 1 mM solution of Rhodamine 110 for analysis. We observed that the cores themselves are weakly luminescent and are responsible for the blinking observed in the fully-synthesized metal-enhanced fluorescence nanoparticles. There was no statistically significant difference in photoblinking behavior-both intensity and duty cycle-with decreasing core size. This observation was used to synthesize smaller nanoparticles ranging from approximately 93 nm to 110 nm as measured using dynamic light scattering. The blinking particles were localized via super-resolution microscopy and show single particle self-blinking behavior. As the core size did not impact blinking performance or intensity, the nanoparticles can instead be tuned for optimal size without sacrificing luminescence properties.


Impaired measles virus-specific cytotoxic T cell responses in multiple sclerosis.
To assess whether an virus-specific immune defect may be associated with multiple sclerosis (MS), we have examined the ability to generate measles virus-and influenza virus-specific cytotoxic T cells (CTL) in patients with MS, normal individuals, and other disease controls (ODC). The mean (+/- SEM) measles virus-specific CTL response for normal individuals and ODC was 26.9 +/- 2.9% (N = 17) and 26.7 +/- 2.8% (N = 13) specific lysis, respectively. In contrast, the capacity of MS patients to generate measles virus-specific CTL was markedly diminished. Peripheral blood lymphocytes from MS patients stimulated with measles virus lysed their measles virus-infected autologous B cell line at a group mean level of 6.0 +/- 1.4% (N = 16) specific lysis. MS patients had significantly lower measles virus-specific CTL responses than normal individuals (p less than 0.00001) or ODC (p less than 0.0001). Importantly, this lowered response did not reflect a generalized depressed cytolytic activity of MS patients, since influenza virus-specific CTL and NK activity from these patients were comparable to normals and ODC. Thus, in MS there is a significant depression of measles virus-specific CTL which suggests that this virus-specific immune dysfunction may play a role in the pathogenesis of this disorder.


[Intermediate plateaux in kinetics of the reaction catalyzed by biodegradative L-threonine dehydratase from Escherichia coli].
It has been shown that for the reaction catalyzed by "biodegradative" L-threonine dehydratase from E. coli strains K-12 and 980 in 0.5 M phosphate-carbonate buffer, pH 8.4 and pH 9.5, the plots of initial reaction rate (v) versus the initial substrate concentration ([S]0 are characterized by several inflection points, i. e. an intermediate plateau. The plot of v versus the allosteric activator (AMP) concentration have very complicated shapes: there are several inflection points, and also the maximum at L-threonine concentration equal to 3-10(2) and 5-10(-2) M. High AMP concentrations inhibit the enzyme at high substrate concentrations. The reduced glutathion dose not influence the enzyme and does not alter the activating effect of AMP. On the basis of the data obtained it is proposed that the substrate and AMP shift the equilibrium between multiple oligomeric enzyme forms differing in catalytic activity and kinetic manifestations of allosteric interactions between the active and allosteric AMP-binding sites towards polymerization. Thus, the functioning the enzyme under study is discussed in the frames of the model of dissociating regulatory enzymes with multiple intermediate oligomeric forms.


Cellular and molecular neurosurgery: pathways from concept to reality--part II: vector systems and delivery methodologies for gene therapy of the central nervous system.
Different vector systems that have been used and/or specifically developed for central nervous system (CNS) gene transfer studies are briefly discussed along with their advantages and disadvantages with respect to potential clinical application. These include retroviruses, recombinant herpes simplex virus, adenoviruses, adenoassociated viruses, encapsulation of plasmid deoxyribonucleic acid into cationic liposomes, and neural and oliogodendroglial stem cells. Particular attention has been paid to relate the modality of a specific CNS gene therapy to the strategy for adequate delivery of genetic material to the brain for either global or localized CNS neurodegenerative chronic disorder, as well as for CNS tumors and stroke. Techniques to circumvent the "impermeable" blood-brain barrier and how to breach the more versatile blood-brain-tumor barrier to deliver the genetic material to the target CNS cells are reviewed and include the following: 1) local stereotactic CNS injection/infusion of viral vectors, administration of vector producer cells, or cell replacement; 2) local administration of genetic material into the cerebrospinal fluid ventriculocisternal system; 3) osmotic opening of the blood-brain barrier; 4) local intra-arterial infusion; and 5) administration of blood-brain-tumor barrier permeabilizers, such as a bradykinin B2 agonist RMP-7. It is concluded that gene therapy for several brain disorders holds great potential, as suggested mainly by in vitro experiments and, to some extent, by a limited number of animal experiments. However, several drawbacks currently hamper the application of gene therapy under the clinical setting. The problems associated with gene therapy that still present major obstacles are as follows: 1) inefficient transfection of host cells by viral vectors; 2) restricted delivery of genetic material across vascular barriers of the CNS and brain tumors; 3) nonselective expression of the transgene; and 4) in situ CNS regulation of the transgene expression in a therapeutically controlled manner, as imposed by the course and phenotype of the CNS disease.


Upward ant distribution shift corresponds with minimum, not maximum, temperature tolerance.
Rapid climate change may prompt species distribution shifts upward and poleward, but species movement in itself is not sufficient to establish climate causation. Other dynamics, such as disturbance history, may prompt species distribution shifts resembling those expected from rapid climate change. Links between species distributions, regional climate trends and physiological mechanism are needed to convincingly establish climate-induced species shifts. We examine a 38-year shift (1974-2012) in an elevation ecotone between two closely related ant species, Aphaenogaster picea and A. rudis. Even though A. picea and A. rudis are closely related with North American distributions that sometimes overlap, they also exhibit local- and regional-scale differences in temperature requirements so that A. rudis is more southerly and inhabits lower elevations whereas A. picea is more northerly and inhabits high elevations. We find considerable movement by the warm-habitat species upward in elevation between 1974 and 2012 with A. rudis, replacing the cold-habitat species, A. picea, along the southern edge of the Appalachian Mountain chain in north Georgia, USA. Concomitant with the distribution shifts, regional mean and maximum temperatures remain steady (1974-2012), but minimum temperatures increase. We collect individuals from the study sites and subject them to thermal tolerance testing in a controlled setting and find that maximum and minimum temperature acclimatization occurs along the elevation gradient in both species, but A. rudis consistently becomes physiologically incapacitated at minimum and maximum temperatures 2 °C higher than A. picea. These results indicate that rising minimum temperatures allow A. rudis to move upward in elevation and displace A. picea. Given that Aphaenogaster ants are the dominant woodland seed dispersers in eastern deciduous forests, and that their thermal tolerances drive distinct differences in temperature-cued synchrony with early blooming plants, these climate responses not only impact ant-ant interactions, but might have wide implications for ant-plant interactions.


TP53BP2 locus is associated with gastric cancer susceptibility.
We investigated the association of the TP53BP2 locus with gastric cancer susceptibility in a Korean population. We assayed 9 single nucleotide polymorphisms (SNP) in an 82.5 kb region that included the TP53BP2 locus in 233 male gastric cancer patients and 390 unaffected healthy male controls. The allelic frequencies of 4 SNP within TP53BP2, g.206692C>T, g.198267A>T, g.164895G>A and g.152389A>T, differed significantly between cases and controls (p < or = 0.0376). When compared to carriers of non-risk alleles, individuals homozygotic for each of the risk alleles had a 50% increase in risk of gastric cancer (age-adjusted odds ratio [OR] > or = 1.48; p < or = 0.0371). Furthermore, these 4 significantly associated SNP were in strong linkage disequilibrium (r2 > or = 0.51). Haplotype analysis showed that individuals with the CAGA haplotype, consisting of the risk alleles at each SNP, had a 1.55-fold higher risk for gastric cancer than individuals with the haplotype TTAT, consisting of the non-risk alleles at each SNP (OR = 1.55; 95% confidence interval [CI] = 1.13-2.14; p = 0.00705). Two other SNP were not polymorphic in the study subjects, whereas the other 3 SNP, located toward the outside of the TP53BP2 locus, were not associated with gastric cancer susceptibility. Although the location of the pathogenic variant is not yet known, our results suggest that the TP53BP2 locus is associated with susceptibility to gastric cancer in the Korean population.


Antifungal activity of puroindoline protein from soft wheat against grain molds and its potential as a biocontrol agent.
Mold growth reduces the quality of stored grains, besides producing toxins that pose a potential threat to human health. Therefore, prevention of grain mold growth during storage is important to ensure a safe and high-quality product, preferably using an eco-friendly antifungal agent. The puroindoline (PIN) protein was extracted by Triton X-114 and identified by QE mass spectrometry. Aspergillus flavus has attracted much attention because of its toxic secondary metabolites, and PIN protein showed a significant inhibition on A. flavus growth. Scanning electron microscopy revealed altered spore morphology of A. flavus following PIN protein treatment, and propidium iodide staining showed incomplete spore cell membranes. The disruption and deformation of A. flavus spores suggest that the cell walls and cell membranes were compromised. Decreased mitochondrial membrane potential and increased levels of intracellular reactive oxygen specieswere detected using JC-1 and 2,7-dichlorodihydrofluorescein diacetate staining, respectively. PIN protein could effectively inhibit the growth and aflatoxins B1 production of A. flavus in stored grains, such as wheat and rice. PIN proteins can inhibit the growth of many common grain storage molds, including Penicillium, Aspergillus spp. (A. flavus, A. glaucus, A. kawachii, A. ochraceus and A. niger), Alternaria and Fusarium graminearum, in a dose-dependent manner. PIN protein has a significant inhibitory effect on the growth of grain molds, with a stronger inhibitory effect noted in wheat and rice. Our study provides a novel and simple theoretical basis for the selection and storage of mold resistance in grains and food during storage.


Metabolic Adjustment of High Intertidal Alga Pelvetia canaliculata to the Tidal Cycle Includes Oscillations of Soluble Carbohydrates, Phlorotannins, and Citric Acid Content.
The brown alga Pelvetia canaliculata is one of the species successfully adapted to intertidal conditions. Inhabiting the high intertidal zone, Pelvetia spends most of its life exposed to air, where it is subjected to desiccation, light, and temperature stresses. However, the physiological and biochemical mechanisms allowing this alga to tolerate such extreme conditions are still largely unknown. The objective of our study is to compare the biochemical composition of Pelvetia during the different phases of the tidal cycle. To our knowledge, this study is the first attempt to draft a detailed biochemical network underneath the complex physiological processes, conferring the successful survival of this organism in the harsh conditions of the high intertidal zone of the polar seas. We considered the tide-induced changes in relative water content, stress markers, titratable acidity, pigment, and phlorotannin content, as well as the low molecular weight metabolite profiles (GC-MS-based approach) in Pelvetia thalli. Thallus desiccation was not accompanied by considerable increase in reactive oxygen species content. Metabolic adjustment of P. canaliculata to emersion included accumulation of soluble carbohydrates, various phenolic compounds, including intracellular phlorotannins, and fatty acids. Changes in titratable acidity accompanied by the oscillations of citric acid content imply that some processes related to the crassulacean acid metabolism (CAM) may be involved in Pelvetia adaptation to the tidal cycle.


[Identification of mycobacteria in sputum by determining antigens in the culture medium].
Antigens to M. tuberculosis in culture fluid of sputum samples were compared to bacterioscopy and inoculation results for 64 new-onset cases of tuberculosis and 60 chronics with bronchitis. The authors used diagnostic preparations of monoclonal and polyclonal antibodies to M. tuberculosis. The use of the above preparations in the enzyme immunoassay reduced the time of M. tuberculosis detection in the patients' sputum and increased the frequency of the bacteria registration against standard methods of bacterioscopy and inoculation.


Acute cerebellar ataxia after immunisation with recombinant hepatitis B vaccine.
We report one woman with acute cerebellar ataxia (ACA), a well-defined clinical syndrome, which occurred 10 days after the second vaccination with recombinant hepatitis B vaccine. The patient had no previous symptoms or signs of neurological disease and there was no evidence of neurologic disease in the family history. Within nine months the symptoms remitted completely according to other reports of ACA. As there was a close temporal connection and no noticeable other cause we assume a causal link between the vaccination and the disease. As far as we known this is the first case of ACA after hepatitis B vaccination.


Genotyping of Pneumocystis jirovecii in colonized patients with various pulmonary diseases.
Pneumocystis jirovecii is an opportunistic fungus causing Pneumocystis pneumonia primarily in immunosuppressed patients. However, immunocompetent individuals may become colonized and, as asymptomatic carriers, serve as reservoirs of the pathogen. Moreover, these asymptomatic carriers are at higher risk of developing pneumonia if favorable conditions occur. This study aimed to determine the prevalence of P. jirovecii in patients with various pulmonary diseases and to characterize the genetic diversity of organisms circulating in the studied population. Bronchial washing specimens from 105 patients were tested for presence of P. jirovecii using nested polymerase chain reaction (PCR) targeting the mtLSU rRNA gene, as well as immunofluorescence microscopy. Multilocus sequence typing involving analysis of three loci-mtLSU rRNA, CYB, and SOD-was used for genotyping analysis. P. jirovecii DNA was detected in 17 (16.2%) patients. Amplification of the SOD locus was successful only in five cases (29.4% of the positive patients), while mtLSU rRNA and CYB were genotyped in all positive samples. Therefore, combined genotypes were identified based only on mtLSU rRNA and CYB loci. Eight different genotypes were identified, with Pj 1 and Pj 2 being the most prevalent (29.4% of patients each). There was no statistical correlation between these genotypes and demographic or clinical data; however, we found that infection with mutant CYB strains occurred only in patients diagnosed with lung cancer. Of the potential predictors examined, only immunosuppressive treatment was significantly associated with colonization. In conclusion, patients with various respiratory diseases, especially when immunosuppressed, are at risk of Pneumocystis colonization.


A systematic review of qualitative evidence: Perspectives of fathers whose partner experienced postpartum psychosis.
This study aimed to systematically identify, appraise and synthesize qualitative evidence which explored fathers' experiences and perspectives of their partners' postpartum psychosis. Qualitative evidence synthesis (QES). Seven databases (CINAHL, PsycINFO, Medline, Scopus, Google Scholar, ProQuest Dissertations and Open Grey) were systematically searched for qualitative studies from each database's inception to the 17th of February 2022. Studies that utilized a qualitative research design to explore fathers' experiences and perspectives of their partners' postpartum psychosis were included. Studies were appraised using the Critical Appraisal Skills Programme to determine their methodological quality. Qualitative data were extracted and synthesized using the process of thematic synthesis to form analytical themes. Eleven reports (seven journal articles and four theses), representing six unique qualitative studies were included in the review. Two analytical themes and eight subthemes were identified. The analytical themes were 'a sense of loss across multiple domains of their lives', and 'informational and emotional support needs'. Postpartum psychosis is a severe mental health condition which also impacts the woman's partner. Fathers experienced an array of emotions which they attributed to a lack of knowledge and understanding of postpartum psychosis. The development of appropriate support structures is needed to better support fathers in supporting their partners. This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement and ENTREQ reporting guidelines. There was no patient or public contribution. WHAT PROBLEM DID THIS STUDY ADDRESS?: Fathers play a pivotal role in supporting their partner who has postpartum psychosis, and a supportive father has a positive impact on the mental health of the mother. Several qualitative studies have explored fathers' experiences of their partners' psychosis. This QES integrated findings from these studies to gain a deeper understanding and knowledge of the father's experience. WHAT ARE THE MAIN FINDINGS?: Fathers reported a significant sense of loss across multiple domains of their lives, from a perceived loss of their relationship with their partner to a loss of the future they had planned together. Fathers experienced an array of emotions, such as fear and shock which they attributed to their lack of knowledge and awareness of postpartum psychosis. WHERE AND ON WHOM WILL THIS RESEARCH HAVE AN IMPACT?: This review provides a deeper insight and understanding into the father's experiences and perspectives of their partners' postpartum psychosis. This insight can inform healthcare professionals and policymakers in the development of appropriate support structures which meet the needs of this population. The provision of appropriate support structures could have a positive impact on the father's well-being and ability to support their partner.


THEORY AND MEASUREMENT OF VISUAL MECHANISMS : VI. WAVE-LENGTH AND FLASH DURATION IN FLICKER.
For spectral regions associated with violet, blue, green, and red the relation between mean critical flash intensity I(m) for visual flicker and the flash frequency F is modified as already found with white light when the light time fraction t(L) in the flash cycle is changed. For a square image 6.13 degrees on a side, foveally fixated, the "rod" and "cone" contributions to the duplex contour are analyzed in the way already used for white. It is pointed out that several customary qualitative criteria for cone functioning do not necessarily give concordant results. The analysis shows that the three parameters of the probability summations giving the "rod" and "cone" curves are changed independently as a function of wave-length composition of the light, and of the light time fraction. The correlation of these changes, and of those found in the associated variability functions, can be understood in terms of differences in (1) the numbers of neural units potentially excitable and (2) in the numbers of elements of neural effect obtained from them. In a multivariate situation of this kind it is necessary to compare intensities of luminous flux required to activate half the total population of potentially available elements when this total size is held constant for the different conditions. The results of this comparison, for the filtered lights used, are discussed in relation to certain aspects of excitation vs. wave-length. The problem is a general one, arising where the effects produced as a function of a particular variable are concerned. In the distinction between (1) units excited and (2) the actions they produce may be found the clue for the curious fact that with certain wave-lengths the critical intensities are lower than for white. The extension of the observations to other parts of the retina may be expected to further this analysis.


Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study.
Several risk factors for the development of hepatotoxicity during short course antituberculosis therapy have been suggested. A case-control study was undertaken to assess the role of age, sex, disease extent, nutritional status, past history of liver disease, infection with hepatitis viruses, acetylator status, and high alcohol intake as risk factors in the development of hepatotoxicity in patients with pulmonary tuberculosis receiving antituberculosis treatment. The cases comprised 86 consecutive patients who were diagnosed as having hepatitis induced by antituberculosis drugs and who were negative for any of the hepatitis markers (HAV-IgM, HBsAg, HBc-IgM, and anti-HCV). The control group comprised 406 consecutive patients attending the chest clinic who completed antituberculosis treatment without developing hepatitis. The variables analysed were age, sex, body mass index (BMI), history of high alcohol intake, radiological extent of the disease, acetylator status, and serum proteins. The cases were older and their serum albumin levels were lower than in the control group. High alcohol intake was more common among the cases, they had more extensive disease radiologically, and the proportion of slow acetylators was higher. No differences were observed between the two groups in the other risk factors analysed. Of the various risk factors analysed, only advanced age, hypoalbuminaemia, high alcohol intake, slow acetylator phenotype, and extensive disease were risk factors for the development of hepatotoxicity. The risk of hepatitis in the presence of one or more of these risk factors may be increased.


Wildlife roadkill patterns in a fragmented landscape of the Western Amazon.
One of the most evident and direct effects of roads on wildlife is the death of animals by vehicle collision. Understanding the spatial patterns behind roadkill helps to plan mitigation measures to reduce the impacts of roads on animal populations. However, although roadkill patterns have been extensively studied in temperate zones, the potential impacts of roads on wildlife in the Neotropics have received less attention and are particularly poorly understood in the Western Amazon. Here, we present the results of a study on roadkill in the Amazon region of Ecuador; a region that is affected by a rapidly increasing development of road infrastructure. Over the course of 50 days, in the wet season between September and November 2017, we searched for road-killed vertebrates on 15.9 km of roads near the city of Tena, Napo province, for a total of 1,590 surveyed kilometers. We recorded 593 dead specimens, predominantly reptiles (237 specimens, 40%) and amphibians (190, 32%), with birds (102, 17%) and mammals (64, 11%) being less common. Recorded species were assigned to three functional groups, based on their movement behavior and habitat use ("slow," "intermediate," and "fast"). Using Ripley's K statistical analyses and 2D HotSpot Identification Analysis, we found multiple distinct spatial clusters or hotspots, where roadkill was particularly frequent. Factors that potentially determined these clusters, and the prevalence of roadkill along road segments in general, differed between functional groups, but often included land cover variables such as native forest and waterbodies, and road characteristics such as speed limit (i.e., positive effect on roadkill frequency). Our study, which provides a first summary of species that are commonly found as roadkill in this part of the Amazon region, contributes to a better understanding of the negative impacts of roads on wildlife and is an important first step toward conservation efforts to mitigate these impacts.


Distance/near differences in intermittent exotropia.
Burian's classification of exotropia based on the difference between the distance deviation and near deviation (distance/near differences) leaves some questions unanswered. Controversy exists concerning whether the divergence excess pattern is caused by an excess of divergence or by excessive accommodative convergence. Much of the literature on this subject has been confusing because investigators did not eliminate tenacious proximal fusion as an artifact in calculating the ratio of accommodative convergence to accommodation (AC/A ratio). Previously, one of us (B.J.K.) proposed a classification system that respected this artifact and subdivided the classification system proposed by Burian. A total of 202 consecutive patients with an exotropia underwent a series of measurements to determine the respective role of accommodative convergence and tenacious proximal fusion as a cause for their distance/near differences. In addition, the value obtained by a rapid prism adaptation test as a possible substitute for 1 hour of monocular occlusion was studied. In 98 patients, the initial distance deviation exceeded the near deviation. In 10 patients, the distance/near differences were caused by a high AC/A ratio, which would have been mislabeled by Burian's classification system. Brown's recommendation of using +3.00-diopter lenses at near to diagnose simulated divergence excess would have led to the misdiagnosis of a high AC/A ratio in 61 of these patients. In 26 patients, the near deviation exceeded the distance deviation. Burian's classification would have incorrectly labeled 2 patients as having convergence insufficiency when, in fact, they had pseudoconvergence insufficiency. The new proposed classification system proved 100% sensitive and 100% specific (6 of 6 patients for both parameters) for identifying preoperatively exotropic patients who postoperatively developed an esotropia at near with a high AC/A ratio. Rapid prism adaptation tests at near proved useful for identifying the presence of tenacious proximal fusion, but were not accurate in its quantification. The validity and utility of the new classification system was confirmed. Identification of exotropic patients with a high AC/A ratio and consideration of nonsurgical treatment is important. The rapid prism adaptation test is qualitatively, but not quantitatively, the same as 1 hour of monocular occlusion.


Cavity-based architecture to preserve quantum coherence and entanglement.
Quantum technology relies on the utilization of resources, like quantum coherence and entanglement, which allow quantum information and computation processing. This achievement is however jeopardized by the detrimental effects of the environment surrounding any quantum system, so that finding strategies to protect quantum resources is essential. Non-Markovian and structured environments are useful tools to this aim. Here we show how a simple environmental architecture made of two coupled lossy cavities enables a switch between Markovian and non-Markovian regimes for the dynamics of a qubit embedded in one of the cavity. Furthermore, qubit coherence can be indefinitely preserved if the cavity without qubit is perfect. We then focus on entanglement control of two independent qubits locally subject to such an engineered environment and discuss its feasibility in the framework of circuit quantum electrodynamics. With up-to-date experimental parameters, we show that our architecture allows entanglement lifetimes orders of magnitude longer than the spontaneous lifetime without local cavity couplings. This cavity-based architecture is straightforwardly extendable to many qubits for scalability.


Improvement of Smoking Abstinence Rates With Increased Varenicline Dosage: A Propensity Score-Matched Analysis.
It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence. We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling. At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, χ = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4-3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6-3.9) and 9-month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4-3.3). A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d.


SMAD7 antagonizes key TGFβ superfamily signaling in mouse granulosa cells in vitro.
Transforming growth factor β (TGFβ) superfamily signaling is essential for female reproduction. Dysregulation of the TGFβ signaling pathway can cause reproductive diseases. SMA and MAD (mothers against decapentaplegic) (SMAD) proteins are downstream signaling transducers of the TGFβ superfamily. SMAD7 is an inhibitory SMAD that regulates TGFβ signaling in vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to regulation by intraovarian growth factors from the TGFβ superfamily. TGFB1 (TGFβ1), bone morphogenetic protein 4, and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducing Smad7 expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA approach, we further demonstrated that SMAD7 was a negative regulator of TGFB1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte-granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGFβ superfamily signaling, which is involved in the regulation of oocyte-somatic cell interaction and granulosa cell function.


Comparative study of piroxicam and nitroglycerin on prostaglandin-modulated blood and electrolyte indices during di-estrous in female Wistar Rats.
Endogenous prostaglandins are involved in hemostasis, renal excretion of electrolytes, and implicated in dysmenorrhea. Piroxicam and Nitroglycerin are common drugs used in treating dysmenorrhea by inhibiting the cyclooxygenase pathway involved in prostaglandin production. However, studies comparing the effects of these drugs on prostaglandin-modulated hemostasis and renal function are lacking. Fifteen female rats (120-160g) were divided into 3 groups (20 per group), namely Control (distilled water, 0.3 mL), Piroxicam treated (3mg/kg) and Nitroglycerin treated (1 mg/kg). Di-estrous phase was confirmed in animals in each group using the Pipette smear method. Treatment was administered for 4 days covering the estrous cycle. Bleeding and clotting time were assessed and blood concentrations of sodium, potassium, urea and platelet counts were evaluated in all phases. Data were analyzed using one-way ANOVA and Newman-Keuls post-hoc test. Statistical significance was considered at p<0.0. The nitroglycerin-treated group showed significant increases in blood potassium during di-estrous while the piroxicam-treated group showed significant increases in blood potassium, urea and clotting time with a significant decrease in sodium levels during di-estrous compared to controls. Results obtained in other phases were not significant compared to controls. The study showed that Nitroglycerin produces minimum alteration of blood and electrolyte indices compared to piroxicam during di-estrous.


Canine platelets express functional Toll-like receptor-4: lipopolysaccharide-triggered platelet activation is dependent on adenosine diphosphate and thromboxane A2 in dogs.
Functional Toll-like receptor 4 (TLR4) has been characterized in human and murine platelets indicating that platelets play a role in inflammation and hemostasis during sepsis. It is unclear whether canine platelets could express functional TLR4 by responding to its ligand, lipopolysaccharide (LPS). We sought to determine if dogs express functional TLR4 and if LPS-induced platelet activation requires co-stimulation with ADP or thromboxane A2 (TxA2). Canine platelets were unstimulated (resting) or activated with thrombin or ADP prior to flow cytometric or microscopic analyses for TLR4 expression. We treated resting or ADP-primed platelets with LPS in the absence or presence of acetylsalicylic acid (ASA) and inhibited TLR4 with function blocking antibody or LPS from Rhodobacter sphaeroides (LPS-RS). We discovered that dog platelets have variable TLR4 expression, which was upregulated following thrombin or ADP activation. LPS augmented P-selectin expression and thromboxane B2 secretion in ADP-primed platelets via TLR4. Inhibition of cyclooxygenase by ASA attenuated LPS-mediated P-selectin expression demonstrating that TLR4 signaling in platelets is partially dependent on TxA2 pathway. Expression of functional TLR4 on canine platelets may contribute to hypercoagulability in clinical septic dogs. Cyclooxygenase and TxA2 pathways in TLR4-mediated platelet activation may present novel therapeutic targets in dogs with sepsis.


The future of family planning programs.
National family planning programs have been an important instrument in accelerating global fertility decline and in restricting ultimate world population to a level probably below ten billion. They began to come into being after 1950 and will probably go out of existence in most of the world's regions by 2050. The archetypal programs were instituted in Asia and North Africa. The end of the twentieth century is an appropriate half-way mark at which to evaluate the twentieth-century programs and to assess what changes in them will be needed for the twenty-first century. Some changes are necessary because dramatic events have occurred: (1) long-term replacement-level fertility has been attained in most of East Asia and some of Southeast Asia, and accordingly, some programs there are being phased out; (2) mainland South Asian fertility has been slower to decline; (3) international donor funding is diminishing and may not be significant during much of the twenty-first century; (4) the 1994 International Conference on Population and Development held in Cairo called for a radical change in programs away from demographic aims and toward reproductive health and the improvement of the situation of women; and (5) the future family planning frontier will be sub-Saharan Africa, for which radically new types of programs may have to be developed. These issues were discussed in January 2000 at a conference held in Dhaka, Bangladesh. A selection of contributions to the conference is published here. This article provides an overview of the issues based partly on this selection and partly on the discussions that took place at the conference.


Modified Fasting Compared to True Fasting Improves Blood Glucose Levels and Subjective Experiences of Hunger, Food Cravings and Mental Fatigue, But Not Cognitive Function: Results of an Acute Randomised Cross-Over Trial.
Recent dietary trends have prompted growing support for a variety of fasting paradigms involving extreme restriction or nil-caloric intake on fasting days. Some studies indicate that fasting may negatively influence factors including cognitive function through inducing fatigue, which may prove problematic in the context of completing a range of cognitively demanding activities required by daily obligations such as work. This randomised within-subjects cross-over trial explored the effects of true fasting (i.e., nil-caloric intake) versus modified fasting, the latter of which involved two sub-conditions: (1) extended distribution (three small meals distributed across the day; 522 kcal total); and (2) bulking (two meals eaten early in the day; 512 kcal total) over a period of 7.5 h on a single day with a 7-day washout period between conditions. Participants were n = 17 females (Body Mass Index (BMI) Mean (M) = 25.80, Standard Deviation (SD) = 2.30) aged 21-49 years. Outcomes included cognitive function, subjective mental fatigue, satiety, food cravings and blood glucose. Results showed that there were no differences in cognitive test performance between conditions;however, both modified fasting sub-conditions had improved blood glucose levels, cravings, hunger and fullness compared to true fasting. Moreover, subjective mental fatigue was significantly reduced in the modified fasting conditions relative to true fasting. Overall, results indicated that the subjective experience of true fasting and modified fasting is different, but that cognition does not appear to be impaired.


Convex mixture regression for quantitative risk assessment.
There is wide interest in studying how the distribution of a continuous response changes with a predictor. We are motivated by environmental applications in which the predictor is the dose of an exposure and the response is a health outcome. A main focus in these studies is inference on dose levels associated with a given increase in risk relative to a baseline. In addressing this goal, popular methods either dichotomize the continuous response or focus on modeling changes with the dose in the expectation of the outcome. Such choices may lead to information loss and provide inaccurate inference on dose-response relationships. We instead propose a Bayesian convex mixture regression model that allows the entire distribution of the health outcome to be unknown and changing with the dose. To balance flexibility and parsimony, we rely on a mixture model for the density at the extreme doses, and express the conditional density at each intermediate dose via a convex combination of these extremal densities. This representation generalizes classical dose-response models for quantitative outcomes, and provides a more parsimonious, but still powerful, formulation compared to nonparametric methods, thereby improving interpretability and efficiency in inference on risk functions. A Markov chain Monte Carlo algorithm for posterior inference is developed, and the benefits of our methods are outlined in simulations, along with a study on the impact of dde exposure on gestational age.


Engineering C-C Bond Cleavage Activity into a P450 Monooxygenase Enzyme.
The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.


Cyclists' helmet usage and characteristics in central and southern Malawi: a cross-sectional study.
The objective of this study was to determine the prevalence of, and factors associated with, bicycle helmet usage in southern and central Malawi. This study was across-sectional observation of public behaviour. The urban and rural roadways in southern and central Malawi were studied during the dry season. In total, 1900 bicyclists were observed along the roadways of southern and central Malawi over a four-day period. Observer ascertainment of cyclists' helmet status, approximate age, sex and bicycle operator or passenger status were measured. Of the 1900 cyclists observed, no cyclist was identified as wearing a helmet (exact 95% CI: 0.0-0.2%). There was no variation by age, sex or operator/passenger status. Nearly, 91.5% of observed cyclists were males and 87.7% were operating the bicycle. The sizeable majority of male cyclists were classified as young adults from adolescence to 25 years old (47.2%) or adults over age 25 (44.9%); 7.9% of male cyclists were pre-adolescent. Passengers were more likely to be female than operators (39.1% versus 4.2%), though, even for passengers, a higher proportion were males than females (p < 0.001). In Malawi, helmet usage is so rare as to be non-existent. This suggests an opportunity for significant improvement. Based on the observed cyclists' characteristics, interventions should be targeted to adult and young adult males.


Activity-Based Therapy: From Basic Science to Clinical Application for Recovery After Spinal Cord Injury.
Collaboration between scientists and clinicians effectively accelerated translation of scientific evidence for activity-based therapies (ABTs) into rehabilitation. This article addresses the basic scientific findings of activity-dependent plasticity that led to locomotor training, an ABT, and its principles to advance recovery in adult and pediatric populations with spinal cord injury (SCI). Expansion to new therapies based on these common principles is highlighted, for example, epidural stimulation. The article also describes a recently developed measure, the Neuromuscular Recovery Scale (NRS), and its psychometric properties. Locomotor training has led to recovery of walking in some individuals with motor-incomplete SCI even years after injury. Recent studies resulted in individuals with motor-complete SCI regaining some voluntary movements and standing in the presence of epidural stimulation. The level of success for locomotor training and epidural stimulation appears dependent on spinal networks maintaining the appropriate central state of excitability for the desired task. As these new advances in restorative therapies required an outcome measure that measured performance without compensation, the NRS was developed. The NRS has strong psychometric properties in adults, and a pediatric version is under development. Application of locomotor training in children is still novel. Preliminary evidence suggests that locomotor training can improve trunk control and also foster participation in children with chronic SCI. ABTs may effectively promote neuromuscular recovery and improve function and participation in adults and children post-SCI. Evaluation of outcomes with valid measures, such as the NRS, is necessary to document the ability to perform functional tasks and to assess progress as function improves.


Early detection of prostate cancer by routine screening.
In an attempt to detect prostate cancer when the disease was still localized, a free screening clinic was established for men over the age of 45 years. Digital rectal examinations were performed for 811 men. Prostate biopsy was recommended to 43 in whom abnormalities were found by digital rectal examination; only 38 complied. Prostate cancer was detected in 11 men. The patients with cancer ranged in age from 60 to 79 years, with the highest incidence of cancer in the group aged 70 to 79 years. The overall incidence in men between 51 and 80 years old was 1.7%. Staging evaluation revealed that none of the patients with prostate cancer had metastases to the bone or elevated serum acid phosphatase levels. Five men (45%) were found by clinical or pathological methods to have stage B disease. Two others (18%) showed radiographic evidence of lymph node metastases (stage D1). The cost of detecting each cancerous prostate tumor was approximately +6,300. Routine screening can be a cost-effective method for diagnosing prostate cancer in patients with less extensive disease. The ability of early detection to prolong survival of patients with this disease will require further investigation.


Leptin as immune mediator: Interaction between neuroendocrine and immune system.
Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates.


Biological variation of high sensitivity cardiac troponin-T in stable dialysis patients: implications for clinical practice.
Changes in high sensitivity cardiac troponin-T (hs-cTnT) concentrations may reflect either acute myocardial injury or biological variation. Distinguishing between these entities is essential to accurate diagnosis, however, the biological variation of hs-cTnT in dialysis population is currently unknown. We sought to estimate the within- and between-person coefficients of variation of hs-cTnT in stable dialysis patients, and derive the critical difference between measurements needed to exclude biological variation with 99% confidence. Fifty-five prevalent haemo- and peritoneal-dialysis patients attending two metropolitan hospitals were assessed on 10 consecutive occasions; weekly for 5 weeks then monthly for 4 months. Assessments were conducted at the same dialysis cycle time-point and entailed hs-cTnT testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they developed clinical or physiological instability. In total 137 weekly and 114 monthly hs-cTnT measurements from 42 stable patients were analysed. Respective between- and within-person coefficients of variation were 83% and 7.9% for weekly measurements, and 79% and 12.6% for monthly measurements. Within-person variation was unaffected by dialysis modality or cardiac co-morbidity. The bidirectional 99% reference change value was -25% and +33% for weekly measurements, and -37% and +58% for monthly measurements. The between-person variation of hs-cTnT in the dialysis population is markedly greater than within-person variation indicating that hs-cTnT testing is best applied in this population using a relative change strategy. An increase of 33% or a reduction of 25% in serial hs-cTnT concentrations measured at weekly intervals excludes change due to analytical and biological variation alone with 99% confidence.


Expression level of pre-B-cell leukemia transcription factor 2 (PBX2) as a prognostic marker for gingival squamous cell carcinoma.
In this study, we investigated the interrelationship between clinicopathologic findings and pre-B-cell leukemia transcription factor 2 (PBX2) expression in gingival squamous cell carcinoma (GSCC). Expression level of PBX2 was immunohistochemically examined in 66 GSCC subjects (30 men and 36 women) with ages ranging from 42 to 85 (median 64.5) years, in which staining intensity in tumor cells was categorized as either weaker (level 1) or equal to/stronger (level 2) than that in the endothelial cells. PBX2 expression is correlated with valosin-containing protein (VCP) expression. Univariate and multivariate analyses revealed a high level of PBX2 expression to be a poor prognosticator for disease-free survival (DFS) and overall survival (OS), and PBX2 expression was an independent prognostic factor for both DFS and OS in GSCC. PBX2 expression level in GSCC is prognostic. PBX2 may be a useful marker to identify the potential for progression in GSCC.


Evaluation of Quadrox-i and Capiox FX neonatal oxygenators with integrated arterial filters in eliminating gaseous microemboli and retaining hemodynamic properties during simulated cardiopulmonary bypass.
Perfusion quality during cardiopulmonary bypass (CPB) procedures can contribute to postoperative neurological complications and influence patient recovery and outcome. Gaseous microemboli generated in the circuit and hemodynamic properties of blood reaching the patient can be monitored during CPB to optimize perfusion. Oxygenators that oxygenate the blood during CPB can significantly influence the quality of blood reaching the patient by their manufacturing designs. New hollow-fiber membrane oxygenators are developed with integrated arterial filters to reduce priming volume and eliminate a separate arterial filter in the circuit. To evaluate the performance of these new oxygenators, we used a simulated model to compare the Quadrox-i Neonatal and the Capiox Baby FX05 neonatal oxygenators and to provide a review of these oxygenators with their respective counterparts which have separate arterial filters. We found that microemboli counts for the new Quadrox-i and Capiox FX05 oxygenators are similar in the arterial line, but different across the oxygenator for all experimental conditions. The arterial purge line diverting blood from the patient reduces microemboli count for the Capiox FX05, but is inconsistent for the Quadrox-i Neonatal. While hemodynamic energy delivered to the patient is similar for both oxygenators, shunted blood flow for the Quadrox-i Neonatal oxygenator is three times higher than the Capiox FX05 (103.6 mL/min vs 33.0 mL/min at 400 mL/min and 35°C) (p<0.001).


Photofunctionalization enhances bone-implant contact, dynamics of interfacial osteogenesis, marginal bone seal, and removal torque value of implants: a dog jawbone study.
Ultraviolet (UV) light treatment of titanium, ie, photofunctionalization, has been extensively reported to enhance the osteoconductivity of titanium in animal and in vitro studies. This is the first study to examine whether photofunctionalization is effective on commercial dental implants in vivo. Dental implants with a microroughened surface were placed into dog jawbones. Photofunctionalization was performed by treating implants with UV light for 15 minutes using a photo device immediately before placement. Four weeks after placement, bone-implant integration was evaluated using a removable torque test and static and dynamic histology. Implant surfaces were converted from hydrophobic to super-hydrophilic after photofunctionalization. Removable torque for photofunctionalized implants was significantly higher by 50% than that for untreated implants. Bone-implant contact (BIC) was significantly higher for photofunctionalized implants in all zones examined: marginal, cortical, and bone marrow zones. An intensive mineralized layer was exclusively present in marginal bone at photofunctionalized interface. Dynamic histology identified early-onset, long-lasting robust bone deposition at photofunctionalized interface. Photofunctionalization enhanced the morphology, quality, and behavior of periimplant osteogenesis, including the increased BIC, expedited robust interfacial bone deposition, and improved marginal bone seal and support.


ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein-Barr virus infection and microsatellite instability.
The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.


Experimental investigation of an RNA sequence space.
Modern rRNAs are the historic consequence of an ongoing evolutionary exploration of a sequence space. These extant sequences belong to a special subset of the sequence space that is comprised only of those primary sequences that can validly perform the biological function(s) required of the particular RNA. If it were possible to readily identify all such valid sequences, stochastic predictions could be made about the relative likelihood of various evolutionary pathways available to an RNA. Herein an experimental system which can assess whether a particular sequence is likely to have validity as a eubacterial 5S rRNA is described. A total of ten naturally occurring and hence known to be valid, sequences and two point mutants of unknown validity were used to test the usefulness of the approach. Nine of the ten valid sequences tested positive whereas both mutants tested as clearly defective. The tenth valid sequence gave results that would be interpreted as reflecting a borderline status were the answer not known. These results demonstrate that it is possible to experimentally determine which sequences in local regions of the sequence space are potentially valid 5S rRNAs. This approach will allow direct study of the constraints governing RNA evolution and allow inquiry into how the last common ancestor of extant life apparently came to have very complex ribosomal RNAs that subsequently were very conserved.


Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS.
CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibit leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models. Here we showed that Gp1a, a highly selective CB2 agonist, with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In addition, the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation.


Application of lipases in kinetic resolution of racemates.
Lipases have been well established as valuable catalysts in organic synthesis. This review article focuses on some of the recent developments in the rapidly growing field of lipase-catalyzed kinetic resolution of racemates as a versatile method for the separation of enantiomers. The literature search dates back to the last five years and covers some comprehensive examples. The main emphasis is on the use of lipases in organic solvents.


Association of placental inflammation with fetomaternal hemorrhage and loss of placental mucin-1.
Fetomaternal hemorrhage (FMH) poses an immediate risk to the fetus and, in case of Rhesus-immunization, to future pregnancies. Given that altered endothelial permeability is part of the pathophysiology of inflammation, in this study we investigated whether placental inflammatory processes like chorioamnionitis (ChoA) or preeclampsia (PE) lead to increased rates of FMH compared to the established risk factor of placenta previa (PP). Putative accompanying markers of trophoblastic damage were also explored. 40 patients (14 PE; 6 ChoA; 9 PP; 11 normal controls) were evaluated for FMH using a flowcytometric test kit, which is able to quantify FMH of 0.06% fetal cells. Placental tissue samples were immunostained for human placental lactogen (hPL), human chorionic gonadotropin (hCG), and mucin-1 (MUC1). MUC1 was evaluated as a potential serum marker of FMH. Patients with ChoA had a mean calculated FMH volume of 29 ml, compared to 4 ml in PE and 1 ml in PP and controls. MUC1 staining was reduced in PE and ChoA placenta samples, while elevated MUC1 serum concentration correlated positively with FMH. Diseases of placental inflammation are associated with FMH. Placental MUC1 staining is reduced and serum concentrations are increased in cases of FMH.


Neoadjuvant photodynamic therapy as a therapeutic alternative in multiple basal cell carcinoma induced by radiotherapy.
Non-melanoma skin cancer within previously irradiated areas presents a common challenge, requiring innovative therapies. Complex scenarios, like XRT-induced basal cell carcinoma (BCC) or Gorlin's syndrome, often involve multiple synchronous tumor lesions where photodynamic therapy (PDT) offers a viable therapeutic alternative. We present the case of a 49-year-old male with a history of XRT for brain tumors. The patient was undergoing treatment for recurrent basal cell carcinomas (BCCs) in the right temporal irradiated area, unresponsive to conventional treatments. In the latest evaluation, the patient presented a nodular tumor and several peripheral superficial foci. Photodynamic therapy (PDT) was administered using methyl aminolevulinate 160 mg/g in cream (Metvix®) in two sessions spaced 7 days apart before surgery. The photosensitizer was applied 3 h before initiating PDT, and red light exposure was performed with the Aktilite© lamp (wavelength 630 nm, 100 mm distance, voltage 100 to 240 V, frequency 50 Hz, power 180 W) for 7 min. CONCLUSIóN: PDT with methyl aminolevulinate demonstrated efficacy as a neoadjuvant treatment in a case of multiple XRT-induced BCCs before surgery. PDT emerges as a valuable therapeutic alternative for multiple BCCs, particularly in non-responsive cases.


Intraoperative coronary excimer laser angioplasty: preliminary clinical experience.
Diffuse coronary artery atherosclerosis is generally recognized as a deterrent to successful revascularization if it cannot be adequately treated. Mechanical endarterectomy can be useful, but it is not the optimal solution owing to the associated higher incidences of perioperative infarction and mortality. The use of laser energy as an endarterectomy tool appears promising. To investigate the application of excimer laser radiation to intraoperative coronary artery endarterectomy, 15 stenotic lesions in 13 patients were treated with excimer irradiation during coronary artery bypass grafting. Eleven (73%) of the lesions were enlarged by the excimer probe (6 of the successes were in calcified lesions). The 4 arteries not enlarged by the excimer laser all demonstrated calcified lesions. There were 3 perforations and 2 dissections, all but 1 in heavily calcified arteries. The results of this phase 1 safety and efficacy study indicate that excimer irradiation can recanalize most arteries, including total and subtotal occlusions and some calcified lesions. Further evaluation with better delivery systems is needed to determine whether the perforation rate can be reduced.


RanGTP is required for meiotic spindle organization and the initiation of embryonic development in Drosophila.
RanGTP is important for chromosome-dependent spindle assembly in Xenopus extracts. Here we report on experiments to determine the role of the Ran pathway on microtubule dynamics in Drosophila oocytes and embryos. Females expressing a dominant-negative form of Ran have fertility defects, suggesting that RanGTP is required for normal fertility. This is not, however, because of a defect in acentrosomal meiotic spindle assembly. Therefore, RanGTP does not appear to be essential or sufficient for the formation of the acentrosomal spindle. Instead, the most important function of the Ran pathway in spindle assembly appears to be in the tapering of microtubules at the spindle poles, which might be through regulation of proteins such as TACC and the HURP homolog, Mars. One consequence of this spindle organization defect is an increase in the nondisjunction of achiasmate chromosomes. However, the meiotic defects are not severe enough to cause the decreased fertility. Reductions in fertility occur because RanGTP has a role in microtubule assembly that is not directly nucleated by the chromosomes. This includes microtubules nucleated from the sperm aster, which are required for pronuclear fusion. We propose that following nuclear envelope breakdown, RanGTP is released from the nucleus and creates a cytoplasm that is activated for assembling microtubules, which is important for processes such as pronuclear fusion. Around the chromosomes, however, RanGTP might be redundant with other factors such as the chromosome passenger complex.


Motivating High School Students From Rural Areas to Attend College and Pursue Careers as Osteopathic Physicians.
One potential way to address critical current and future projected health care workforce shortages is through comprehensive programs that could potentially inspire high school students to pursue osteopathic medical careers in underserved areas. To determine whether a comprehensive, 5-week enrichment program could promote interest among rural high-school students in careers osteopathic medicine. In May 2018, 116 high school students with a grade point average of 2.8 or higher from rural areas, including New Mexico and its surrounding rural areas in the US-Mexico border region, enrolled in а 5-week program offering American College Testing (ACT) preparation and biomedical sciences enrichment at Burrell College of Osteopathic Medicine (BCOM). During the program, students were offered more than 150 hours of interactive in-class lectures and hands-on activities with laboratories focusing on college preparedness, health sciences, and motivating students to pursue osteopathic medical career and practice medicine in rural areas. Clinically-oriented sessions covering osteopathic philosophy and osteopathic manipulative medicine were included. After completion, a voluntary and anonymous survey was sent to students who completed the program students through QualtricsXM©. Blinded ACT scores were collected from participants' schools, along with college enrollment status information. Of 116 enrolled students, 106 (91.4%) completed the program successfully. In their postcompletion survey responses, students reported that they had gained a realistic perception of the field of medicine and were motivated to attend college (mean [standard error, SE] score on 5-point Likert scale over 2 questions, 4.8 [0.06]) and osteopathic medical school (mean [SE], 4.7 [0.1]). Participants also felt more informed about physician shortage in rural areas (mean [SE], 4.7 [0.07]) and appeared to be inspired to practice medicine in rural areas (mean [SE], 4.6 [0.09]). Students also reported feeling better prepared to take the ACT after finishing this program (mean [SE], 4.9 [0.04]). Finally, we were able to collect the ACT scores of 51 participants (48.1%) who completed the program; the mean ACT score was 24.3, compared with a reported national mean of 20.7 on a scoring scale of 1-36. We also performed a follow-up inquiry showing that 78 of the 81 participating students (96%) who had graduated from high school were enrolled in college or university and 59 (73%) had elected in science, technology, engineering, mathematics, or health majors. Rural high school pipeline programs could be a tool to motivate high school students to attend college and ultimately to develop physicians who are interested to practice in medically underserved areas.