Developmental Maturation and Alpha-1 Adrenergic Receptors-Mediated Gene Expression Changes in Ovine Middle Cerebral Arteries.
The Alpha Adrenergic Signaling Pathway is one of the chief regulators of cerebrovascular tone and cerebral blood flow (CBF), mediating its effects in the arteries through alpha1-adrenergic receptors (Alpha1AR). In the ovine middle cerebral artery (MCA), with development from a fetus to an adult, others and we have shown that Alpha1AR play a key role in contractile responses, vascular development, remodeling, and angiogenesis. Importantly, Alpha1AR play a significant role in CBF autoregulation, which is incompletely developed in a premature fetus as compared to a near-term fetus. However, the mechanistic pathways are not completely known. Thus, we tested the hypothesis that as a function of maturation and in response to Alpha1AR stimulation there is a differential gene expression in the ovine MCA. We conducted microarray analysis on transcripts from MCAs of premature fetuses (96-day), near-term fetuses (145-day), newborn lambs, and non-pregnant adult sheep (2-year) following stimulation of Alpha1AR with phenylephrine (a specific agonist). We observed several genes which belonged to pro-inflammatory and vascular development/angiogenesis pathway significantly altered in all of the four age groups. We also observed age-specific changes in gene expression-mediated by Alpha1AR stimulation in the different developmental age groups. These findings imply complex regulatory mechanisms of cerebrovascular development.


The burden of illness of severe nausea and vomiting of pregnancy in the United States.
Our purpose was to determine the extent to which nausea and vomiting of pregnancy affects a woman's quality of life (QOL), ability to function, and health care resource use. We conducted an observational, multicenter, prospective cohort study by gathering data on the symptoms, QOL, and health care resource use from women who have nausea and vomiting of pregnancy. All 8 domains of health measured by the Short Form-36 QOL survey were limited by patient symptoms. This limitation manifested itself as patient-time loss from work and other normal activities, unpaid caregiver-time loss from work, and use of health care resources (eg, hospitalization). All types of time loss were correlated to severity of symptoms. Nausea and vomiting of pregnancy can severely reduce a woman's QOL and ability to function. The degree of limitation is associated with the severity of symptoms.


Analytical expression of the purine/pyrimidine autocorrelation function after and before random mutations.
The mutation process is a classical evolutionary genetic process. The type of mutations studied here is the random substitutions of a purine base R (adenine or guanine) by a pyrimidine base Y (cytosine or thymine) and reciprocally (transversions). The analytical expressions derived allow us to analyze in genes the occurrence probabilities of motifs and d-motifs (two motifs separated by any d bases) on the R/Y alphabet under transversions. These motif probabilities can be obtained after transversions (in the evolutionary sense; from the past to the present) and, unexpectedly, also before transversions (after back transversions, in the inverse evolutionary sense, from the present to the past). This theoretical part in Section 2 is a first generalization of a particular formula recently derived. The application in Section 3 is based on the analytical expression giving the autocorrelation function (the d-motif probabilities) before transversions. It allows us to study primitive genes from actual genes. This approach solves a biological problem. The protein coding genes of chloroplasts and mitochondria have a preferential occurrence of the 6-motif YRY(N)6YRY (maximum of the autocorrelation function for d = 6, N = R or Y) with a periodicity modulo 3. The YRY(N)6YRY preferential occurrence without the periodicity modulo 3 is also observed in the RNA coding genes (ribosomal, transfer, and small nuclear RNA genes) and in the noncoding genes (introns and 5' regions of eukaryotic nuclei). However, there are two exceptions to this YRY(N)6YRY rule: the protein coding genes of eukaryotic nuclei, and prokaryotes, where YRY(N)6YRY has the second highest value after YRY(N)0YRY (YRYYRY) with a periodicity modulo 3. When we go backward in time with the analytical expression, the protein coding genes of both eukaryotic nuclei and prokaryotes retrieve the YRY(N)6YRY preferential occurrence with a periodicity modulo 3 after 0.2 back transversions per base. In other words, the actual protein coding genes of chloroplasts and mitochondria are similar to the primitive protein coding genes of eukaryotic nuclei and prokaryotes. On the other hand, this application represents the first result concerning the mutation process in the model of DNA sequence evolution we recently proposed. According to this model, the actual genes on the R/Y alphabet derive from two successive evolutionary genetic processes: an independent mixing of a few nonrandom types of oligonucleotides leading to genes called primitive followed by a mutation process in these primitive genes.(ABSTRACT TRUNCATED AT 400 WORDS)


A nationwide survey of nonspeech oral motor exercise use: implications for evidence-based practice.
A nationwide survey was conducted to determine if speech-language pathologists (SLPs) use nonspeech oral motor exercises (NSOMEs) to address children's speech sound problems. For those SLPs who used NSOMEs, the survey also identified (a) the types of NSOMEs used by the SLPs, (b) the SLPs' underlying beliefs about why they use NSOMEs, (c) clinicians' training for these exercises, (d) the application of NSOMEs across various clinical populations, and (e) specific tasks/procedures/tools that are used for intervention. A total of 2,000 surveys were mailed to a randomly selected subgroup of SLPs, obtained from the American Speech-Language-Hearing Association (ASHA) membership roster, who self-identified that they worked in various settings with children who have speech sound problems. The questions required answers that used both a forced choice and Likert-type scales. The response rate was 27.5% (537 out of 2,000). Of these respondents, 85% reported using NSOMEs to deal with children's speech sound production problems. Those SLPs reported that the research literature supports the use of NSOMEs, and that they learned to use these techniques from continuing education events. They also stated that NSOMEs can help improve the speech of children from disparate etiologies, and "warming up" and strengthening the articulators are important components of speech sound therapy. There are theoretical and research data that challenge both the use of NSOMEs and the efficacy of such exercises in resolving speech sound problems. SLPs need to follow the concepts of evidence-based practice in order to determine if these exercises are actually effective in bringing about changes in speech productions.


Bananas decrease acetaminophen potency in in vitro assays.
Edible portions of bananas contain high levels of polyphenol oxidase, which catalyzes reactions in the melanin formation pathway. Tyrosine, a physiological substrate of polyphenol oxidase, has an analogous structure to acetaminophen. We investigated whether banana extract causes structural changes in acetaminophen and a decrease in its potency. Acetaminophen concentration in banana extract was measured under different conditions to characterize incompatibility. Reaction products in solution were identified using liquid chromatography/electrospray ionization/mass spectrometry (LC/ESI/MS). Acetaminophen potency decreased with time in the presence of banana extract. The reaction proceeded most efficiently in temperatures 30-37°C and neutral to weakly acidic conditions. Molecular ion peaks derived from the oxidized catechol moiety of acetaminophen were identified in LC/ESI/MS spectra. Our findings suggest that incorporation or simultaneous administration of acetaminophen medication and banana juice may result in decreased efficacy of the clinically important drug. This interaction is likely due to the oxidation of acetaminophen by polyphenol oxidase activity in banana pulp. Therefore, we investigated and characterized a novel interaction between bananas and acetaminophen. To establish a safe and effective antipyretic analgesic regimen using acetaminophen, future studies of this interaction are expected to be performed in humans.


Foreign Body Reaction to Biomaterial Nanotubular Surface and the Influence of Silver Loading.
The impacts of biomaterial surface properties (i.e., surface nanotopography) and dopants (i.e., silver (Ag)) on the biomaterial-associated foreign body reaction (FBR) remain unclear. In this study, an in vivo FBR that was induced by a titania nanotube array (NT) on titanium was examined with and without Ag loading. An NT with an 80 nm diameter that was fabricated by anodization, and the NT samples that were loaded with two Ag concentrations (NT-AgH and NT-AgL) and formed by electrodeposition exhibited high hydrophilicities. A relatively rapid initial Ag+ release with a subsequent gradual reduction was observed for NT-AgH and NT-AgL; the Ag+ release was higher for NT-AgH than for NT-AgL. We found that the NT decreased the biomaterial-associated FBR, evidenced by a decreased fibrous capsule thickness and a number of recruited macrophages. The effect of Ag loading on the FBR was considered acceptable because the FBR induced by the NT-Ag samples was still less severe than that of the PT control. Additionally, the temporary increases in the blood, brain, liver and kidney Ag+ concentrations did not produce general side effects and were considered to be in the safe range. This study demonstrates the ability of nanotopography to alleviate the biomaterial-associated FBR and provides further evidence for future clinical applications of biomaterials with nanostructures and Ag loading.


Cellular localization of the bcl-2 protein and response to glucocorticoid stress.
We performed immunoelectronmicroscopy, immunofluorescence and subcellular fractionation studies of insect cells (Spodopetra frugiperda or SF9) infected with recombinant baculovirus containing bcl-2 cDNA to determine the cellular localization of the bcl-2 product. Similar studies were also undertaken in pre-B cells carrying a bcl-2 gene activated by t(14;18) chromosomal translocation. By immunogold electron microscopy, bcl-2 was localized at several intracellular sites including the nuclear membrane, endoplasmic reticulum, mitochondria and plasma membrane. Immunofluorescence studies revealed the presence of the bcl-2 product throughout the cytoplasm, whereas biochemical fractionation studies indicated a similar pattern to that observed on electron microscopy. Our investigation clearly indicates that the bcl-2 product is expressed at several intracellular sites. Studies were also undertaken to determine any changes in the subcellular distribution of bcl-2 protein following glucocorticoid exposure of immature B lymphocytes. Although no major changes in the distribution of bcl-2 protein were observed, more aggregated patches of gold labelled bcl-2 particles were found under glucocorticoid stress. Aggregation of bcl-2 molecules might represent dimerization necessary to prevent apoptosis.


Oral somatosensory factors in dietary self-selection in rats.
For studying the mechanisms of the control of protein intake, rats were subjected to partial trigeminal deafferentation. Oral somatosensory afferents from the lower anterior portion of the oral cavity were selectively sectioned, but somatosensation of the other parts of the mouth as well as gustatory and olfactory afferents were left intact. Animals were allowed to choose from two diets, only one of which contained protein. Before deafferentation, the rats chose a constant portion of their daily intake in the form of protein (12.2%; SE = 0.5). After deafferentation, protein intake was all but eliminated at first but was resumed later; carbohydrate intake was reduced. When total intake had recovered to nearly preoperative values, the protein/total-intake ratio remained impaired, with deficits that ranged from seemingly random selection to extreme preferences. The variability of dietary selection between days was considerably higher than before surgery. The discussion considers the involvement of learning processes in homeostasis.


Effects of organic phosphate systemic insecticides on bovine embryonic survival and development.
Experiments were conducted to determine effects of 2 organic phosphate systemic insecticides on embryonic survival and possible teratogenesis in cattle. A total of 726 heifers at 3 locations were treated with either crufomate (4-tert-butyl-2-chlorophenyl methyl methylphos-phoramidate) or coumaphos (O,O-diethyl O-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) phosphorothioate). The compounds were administered to pregnant bovine females at various stages of gestation by pouring along the dorsal midline. None of the treatments, including those at recommended one-time doses, one-time doses at double or triple the recommended dose levels, or doses at recommended one-time dose levels repeated each day for 10 days, gave evidence of increasing embryonic death rates or of teratogenic effects. In one experiment, the crufomate compound had apparent erratic effects on serum ace5ylcholinesterase activities, but no effects on electrocardiographic patterns, heart rate, or respiration rate. Rectal palpation for pregnancy determination during the 35- to 44-day stages of pregnancy is discussed as a possible, but unsubstantiated, cause of congenital malformation of the caudal portion of the intestinal tract in 1 calf born during these studies and in other calves previously observed.


Changes in lipid composition of plasma lipoproteins after total hepatectomy in the rat.
Lipidic composition of plasma lipoproteins were determined at different times after total hepatectomy in the rat and compared with those in sham-operated animals. After hepatectomy there was a progressive decrease in the plasma triglycerides amounts corresponding to changes in the content of very low density lipoproteins (VLDL) triglycerides. Phospholipid concentrations in both low density lipoproteins (LDL) and VLDL decreased after hepatectomy but theses lipids were unchanged in high density lipoproteins (HDL) which are the main contributors to plasma phospholipid content. Contrary to the other lipid components, plasma cholesterol levels increased after hepatectomy, due mainly to the increment in HDL-esterified cholesterol. Modifications in plasma triglyceride levels after hepatectomy are interpreted as the result of total reduced synthesis and the effect of extrahepatic lipoprotein lipase activity on VLDL-triglycerides. Changes in cholesterol are considered due to its enhanced production by extrahepatic tissues.


Nanostructured lipid carriers for incorporation of copper(II) complexes to be used against Mycobacterium tuberculosis.
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis. Cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. The aim of this study was to develop nanostructured lipid carriers (NLCs) for use in the treatment of M. tuberculosis. The NLCs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50% poloxamer 407 (F1-F6), and 0.50% cetyltrimethylammonium bromide (F7-F12); and incorporated the copper(II) complexes [CuCl2(INH)2]·H2O (1), [Cu(NCS)2(INH)2]·5H2O (2), and [Cu(NCO)2(INH)2]·4H2O (3) to form compounds F11.1, F11.2, and F11.3, respectively. The mean diameter of F11, F11.1, F11.2, and F11.3 ranged from 111.27±21.86 to 134.25±22.72 nm, 90.27±12.97 to 116.46±9.17 nm, 112.4±10.22 to 149.3±15.82 nm, and 78.65±6.00 to 122.00±8.70 nm, respectively. The polydispersity index values for the NLCs ranged from 0.13±0.01 to 0.30±0.09. The NLCs showed significant changes in zeta potential, except for F11.2, with F11, F11.1, F11.2, and F11.3 ranging from 18.87±4.04 to 23.25±1.13 mV, 17.03±1.77 to 21.42±1.87 mV, 20.51±1.88 to 22.60±3.44 mV, and 17.80±1.96 to 25.25±7.78 mV, respectively. Atomic force microscopy confirmed the formation of nanoscale spherical particle dispersions by the NLCs. Differential scanning calorimetry determined the melting points of the constituents of the NLCs. The in vitro activity of copper(II) complex-loaded NLCs against M. tuberculosis H37Rv showed an improvement in the anti-TB activity of 55.4, 27.1, and 41.1 times the activity for complexes 1, 2, and 3, respectively. An in vivo acute toxicity study of complex-loaded NLCs demonstrated their reduced toxicity. The results suggest that NLCs may be a powerful tool to optimize the activity of copper(II) complexes against M. tuberculosis.


Role of Senescence in Tumorigenesis and Anticancer Therapy.
Although the role of senescence in many physiological and pathological processes is becoming more identifiable, many aspects of senescence are still enigmatic. A special attention is paid to the role of this phenomenon in tumor development and therapy. This review mainly deals with a large spectrum of oncological issues, beginning with therapy-induced senescence and ending with oncogene-induced senescence. Moreover, the role of senescence in experimental approaches, such as primary cancer cell culture or reprogramming into stem cells, is also beginning to receive further consideration. Additional focus is made on senescence resulting from mitotic catastrophe processes triggered by events occurring during mitosis and jeopardizing chromosomal stability. It has to be also realized that based on recent findings, the basics of senescent cell property interpretation, such as irreversibility of proliferation blockade, can be undermined. It shows that the definition of senescence probably requires updating. Finally, the role of senescence is lately more understandable in the immune system, especially since senescence can diminish the effectiveness of the chimeric antigen receptor T-cell (CAR-T) therapy. In this review, we summarize the current knowledge regarding all these issues.


Diurnal cortisol rhythms, fatigue and psychosocial factors in five-year survivors of ovarian cancer.
Fatigue is a challenge in ovarian cancer survivorship and greatly impacts quality of life. In other cancer populations, fatigue has been associated with abnormal diurnal cortisol patterns. However, little is known about biological and behavioral factors in 5+-year ovarian cancer survivors and potential mechanisms underlying persistent fatigue have not been investigated in this population. Moreover, relationships between neuroendocrine and psychosocial factors in 5+-year ovarian cancer survivors have not been studied. We addressed these issues by examining relationships between diurnal cortisol rhythms, fatigue, life stress, and social support in 30 survivors of ovarian cancer who were assessed at least 5 years (mean=6.20years) following their primary diagnosis. Flatter diurnal cortisol slopes were associated with higher levels of fatigue, suggesting a role for HPA-axis dysregulation in sustained fatigue experienced by survivors. Moreover, greater cumulative lifetime stressor exposure (p=0.023) and stressor severity (p=0.004) were associated with flatter diurnal cortisol slopes, while higher social attachment (p=0.001) was associated with steeper diurnal cortisol slopes. These findings suggest that ovarian cancer survivors with greater lifetime stress exposure or lower social attachment may be at increased risk for circadian rhythm disruption, which in turn is associated with fatigue. Future research should examine relationships of clinical stage and inflammatory cytokines to cortisol rhythms and fatigue in long-term ovarian cancer survivors, as well as investigating the clinical significance of abnormal diurnal cortisol profiles in this population.


Bupivacaine 0.5% versus ropivacaine 0.75% wound infiltration to decrease postoperative pain in total thyroidectomy, a prospective controlled study.
Control of postoperative pain is one of the most important concerns for both the patients and the surgical team. In this regard the efficacy of wound infiltration with local analgesia and the most proper drugs to be used are not settled. We conducted our study trying to investigate this point in a prospective randomized double blinded manner. With inclusion criteria of: age (18-65 y), volume <90 mL, first time, no lymph node enlargement and exclusion criteria of: duration >90 min, incision length >10 cm, neck dissection decided during surgery and a postoperative complication within the first 24 hours. Sixty patients planned for total thyroidectomy under general anesthesia were enrolled in the study in three groups with twenty patients assigned randomly to each one: group (A) a control group in which no wound infiltration was done, group (B) in which preoperative wound infiltration with 10 mL bupivacaine 0.5% was done, and group (C) in which preoperative wound infiltration with 10 mL ropivacaine 0.75% was done. Postoperative pain was evaluated by Visual Analogue Score (VAS) with a scale of (0-10) at 1 hour, 4 hours, 8 hours and 16 hours. The postoperative pain experienced by all the patients reached a maximum point at 1 hour postoperatively then started to decrease to be minimal at 8 hours and almost negligible at 16 hours. Ropivacaine group showed a statistically significant decrease in pain perception at 1 hour postoperatively (P=0.028), bupivacaine group showed also a decrease in pain perception at 1 hour but it was not statistically significant. At 4 hours of operation and after; neither ropivacaine nor bupivacaine showed an effect on pain perception. The benefit of local wound infiltration with local analgesia in decreasing postoperative pain is limited to a short period after surgery in which the use of ropivacaine 0.75% is recommended over pubivaccaine 0.5%.


In Situ Activation of Pituitary-Infiltrating T Lymphocytes in Autoimmune Hypophysitis.
Autoimmune hypophysitis (AH) is a chronic inflammatory disease characterized by infiltration of T and B lymphocytes in the pituitary gland. The mechanisms through which infiltrating lymphocytes cause disease remain unknown. Using a mouse model of AH we assessed whether T lymphocytes undergo activation in the pituitary gland. Infiltrating T cells co-localized with dendritic cells in the pituitary and produced increased levels of interferon-γ and interleukin-17 upon stimulation in vitro. Assessing proliferation of CD3- and B220-postive lymphocytes by double immunohistochemistry (PCNA-staining) and flow cytometry (BrdU incorporation) revealed that a discrete proportion of infiltrating T cells and B cells underwent proliferation within the pituitary parenchyma. This proliferation persisted into the late disease stage (day 56 post-immunization), indicating the presence of a continuous generation of autoreactive T and B cells within the pituitary gland. T cell proliferation in the pituitary was confirmed in patients affected by autoimmune hypophysitis. In conclusion, we show that pituitary-infiltrating lymphocytes proliferate in situ during AH, providing a previously unknown pathogenic mechanism and new avenues for treatment.


Coupling between the TRPC3 ion channel and the NCX1 transporter contributed to VEGF-induced ERK1/2 activation and angiogenesis in human primary endothelial cells.
It has been previously demonstrated that the bi-directional transporter Na+/Ca2+ exchanger (NCX) working in the reverse (Ca2+-influx) - mode promotes the activation of ERK1/2 in response to the key pro-angiogenic cytokine VEGF in human endothelial cells (ECs). However, the molecular event(s) that elicit NCX reversal in VEGF-stimulated ECs remain unclear. Here we investigated whether Na+ influx via the diacylglycerol (DAG) - activated non-selective cation channel TRPC3 was functionally associated with NCX and whether its activity was required for VEGF-induced ERK1/2 activation and angiogenesis. We provide evidence that TRPC3 inhibitors and siRNA attenuated ERK1/2 phosphorylation, reduced PKCα activity and partially suppressed Ca2+ transients in response to VEGF. Additionally, TRPC3 inhibitors and siRNA significantly suppressed endothelial tubular differentiation, an in vitro indicator of angiogenesis. We also report that simulating PLCγ activation downstream of VEGF receptor 2 by application of the cell-permeable DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) was sufficient to activate ERK1/2 and enhance tubular differentiation. OAG-induced ERK1/2 activation and tubulogenesis were significantly suppressed by TRPC3 and reverse-mode NCX inhibitors and siRNA. Moreover, whilst both reverse-mode NCX and TRPC3 inhibitors attenuated OAG-induced Ca2+ transients, only TRPC3 antagonists blunted Na+ influx in response to OAG. Importantly, when Na+ was increased in ECs by inhibiting the Na+-K+-ATPase, TRPC3 activity was dispensable for OAG-induced ERK1/2 phosphorylation. Collectively, our research suggests that DAG generation downstream of VEGF receptors activatesTRPC3 causing Na+ influx with subsequent reversal of NCX, ERK1/2 activation and ultimately contributes to enhanced angiogenesis. Targeting reverse-mode NCX and its upstream initiator TRPC3 could be clinically relevant in conditions characterised by abnormal VEGF signalling.


Supernumerary lumbar ribs: a rare occurrence on an adult African male skeleton.
Supernumerary lumbar ribs are usually asymptomatic and discovered incidentally during routine diagnostic radiography. During a routine inventory of the research skeletal repository at the University of the Witwatersrand, a rare case of bilateral supernumerary ribs on the first lumbar vertebra was observed. The skeletal specimen belonged to a 70-year-old African male whose recorded cause of death was esophageal carcinoma. Plain radiography revealed bilateral joint cavities between the transverse processes of the first lumbar vertebra and the supernumerary ribs. Clinically, supernumerary lumbar ribs may present with pain of the renal angle, cause confusion during enumeration of the vertebral levels on radiographs, and may be misinterpreted as fractures, kissing osteophytes, and/or calcification of abdominal vasculature.


Periodontitis and systemic lupus erythematosus.
A large number of studies have shown a potential association between periodontal and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE). Similar mechanisms of tissue destruction concerning periodontitis and other autoimmune diseases have stimulated the study of a possible relationship between these conditions. This study aims to review the literature about this potential association and their different pathogenic mechanisms. Considering that periodontal disease is a disease characterized by inflammation influenced by infectious factors, such as SLE, it is plausible to suggest that SLE would influence periodontal disease and vice versa. However, this issue is not yet fully elucidated and several mechanisms have been proposed to explain this association, as deregulation mainly in innate immune system, with action of phagocytic cells and proinflammatory cytokines such as IL-1β and IL-18 in both conditions' pathogenesis, leading to tissue destruction. However, studies assessing the relationship between these diseases are scarce, and more studies focused on common immunological mechanisms should be conducted to further understanding.


Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects.
A method for stereotactic high-dose radiotherapy of malignancies in the abdomen has been developed. A stereotactic frame for the body has been developed and a method for fixation of the patient in the frame is described. The reproducibility in the stereotactic system of tumours in the liver and the lung was found to be within 5-8 mm for 90% of the patient set-ups. The diaphragmatic movements were reduced to 5-10 mm, by applying a pressure on the abdomen. An analytical method is used to calculate dose distributions for a continuum of beams in an isocentric treatment technique. The advantage of a heterogeneous target dose is demonstrated and proposed for the present application. A non-coplanar treatment technique, using eight individually shaped beams is proposed and has been used for patient treatments. The dose distribution for a patient with a metastasis in the liver is shown as well as dose volume histograms for the target and the liver.


Enhancing diversity in science: is teaching science process skills the answer?
The Biology Fellows Program at the University of Washington aims to enhance diversity in science by helping students succeed in the rigorous introductory biology classes and motivating them to engage in undergraduate research. The composite Scholastic Achievement Test scores and high school grade point averages of the Biology Fellows are comparable to those of students who are not in the program; however, they earn, on average, higher grades in introductory biology classes than non-Biology Fellows. Underrepresented minorities and disadvantaged students in the program also earn higher grades in the introductory biology classes than do their non-Biology Fellows counterparts. Analysis of the performance of Biology Fellows shows that the program assists students who are not proficient in certain science process skills and that students who lack these skills are at risk for failing introductory biology. This evaluation provides insight for designing programs that aim to enhance the performance of beginning students of biology, particularly for underrepresented minorities, who want to obtain a life science degree.


Renalase is removed by kidneys and during dialysis - excess related to CKD complications?
The most common complications of chronic kidney disease (CKD) are hypertension and cardiovascular (CV) disorders. Renalase is produced and released by the kidney and also cardiomyocytes. Renalase deficiency was claimed to be responsible for hypertension and CV complication in CKD. There are contradictory data about serum renalase because of low activity and high levels revealed in hypertensive patients with CKD. We assessed serum renalase concentration in objects with CKD after one-side and both-side nephrectomy (on haemodialysis [HD]), or hemodiafiltration (HDF), in urine and ultrafiltrate in hemodialysis objects. We also evaluated the influence of hemodialysis sessions on renalase concentrations. The concentration of renalase in plasma, ultrafiltrate and urine of 100 hemodialysis patients was assessed by commercially accessible test. We evaluated renalase in 17 HDF objects and 24 healthy controls. Western Blot test was also used to assess renalase concentration. Ultrafiltrate in hemodialysis objects contained renalase and there was no impact of dialysers' type (high-flux and low-flux). Renalase concentration of urine in control group was higher than in hemodialysis objects (n=60). The anuric group had higher renalase concentration comparing to those with remaining diuresis (p<0.001). Univariate analysis revealed the correlation between renalase concentration in plasma and in urine (r=-0.28, p<0.05) and ultrafiltrate renalase in hemodialysis group and between renalase in urine in the control group (r=0.61, p<0.01). There was a correlation between urinary renalase and residual diuresis, hemodialysis sessions non-significantly lowered renalase, the type of heparin had no effect on serum renalase levels. HDF patients had significantly lower renalase than HD patients. In Western blot analysis we found that patients after bilateral nephrectomy had the highest renalase, followed by unilateral nephrectomy. Kidneys eliminate renalase and it is possible that the increased renalase has the impact on cardiovascular diseases in chronic kidney disease.


[Strangulated hernia and eventration].
Incarcerated hernia or wound dehiscence are responsible for more than 10% of small bowel obstructions. The complication is easily recognized when hernia or wound dehiscence was previously diagnosed. Difficulties occur when mass is deeply located in a thick abdominal wall or inside the inguinal canal. Femoral hernias and direct inguinal hernias are those which strangulate the most. Strangulation in wound dehiscence is the most severe. Strangulated hernia should be routinely excluded in patient with intestinal obstruction, to avoid inappropriate surgical approach.


How seasons, weather, and part of day influence baseline affective valence in laboratory research participants?
Many people believe that weather influences their emotional state. Along similar lines, some researchers in affective science are concerned whether testing individuals at a different time of year, a different part of the day, or in different weather conditions (e.g., in a cold and rainy morning vs. a hot evening) influences how research participants feel upon entering a study; thus inflating the measurement error. Few studies have investigated the link between baseline affective levels and the research context, such as seasonal and daily weather fluctuation in temperature, air pressure, and sunshine duration. We examined whether individuals felt more positive or negative upon entering a study by clustering data across seven laboratory experiments (total N = 1108), three seasons, and daily times ranging from 9 AM to 7 PM. We accounted for ambient temperature, air pressure, humidity, cloud cover, precipitation, wind speed, and sunshine duration. We found that only ambient temperature was a significant predictor of valence. Individuals felt more positive valence on days when it was cooler outside. However, the effect was psychologically negligible with differences between participants above c.a. 30 degrees Celsius in ambient temperature needed to generate a difference in affective valence surpassing one standard deviation. Our findings have methodological implications for studying emotions by suggesting that seasons and part of the day do not matter for baseline affective valence reported by participants, and the effects of ambient temperature are unlikely to influence most research.


Seminoma presented as testicular rupture: Case report and literature review.
Rupture of the testis as a result of blunt trauma is rarely seen in daily urological practice. We report an unusual case of incidental seminoma diagnosed after surgical exploration and subsequent orchidectomy of a severed testis following testicular injury as a result of trivial blunt trauma. This case highlights the inability of investigative tools, such as a scrotal ultrasound, in distinguishing an underlying tumour in the presence of testicular parenchymal damage. We therefore advocate a high index of clinical suspicion for co-existing pathology in cases of testicular rupture secondary to an insignificant blunt trauma to the scrotum.


Simultaneous determination of purity and potency of the components of gentamycin using high-performance liquid chromatography.
The quality of some earlier developed antibiotics is usually ensured by the combination of HPLC purity and microbiological potency measurement in the pharmacopoeias of various countries because the relationship between their purity and potency is not clearly quantified. Due to potency is assessed using certain units of measurement, it can not be directly traced to the international system of units (SI unit). This has become a hotspot in the study of the quantitative relationship between purity and potency of antibiotics. It would be quite an achievement to simultaneously determine both purity and potency using HPLC methods during quality control. This study evaluated a multicomponent antibiotic product, gentamycin, as a test sample. First, pure samples of the C components of gentamycin: C1a, C2, C2a and C1 were prepared, separately. Second, quantitative relationship (theoretical potency) between the purity and potency of each C component of gentamycin were determined using 1H NMR, HPLC-ELSD and microbiological assay method. One milligram of gentamycin C1a, C2, C2a and C1 was equal to 1 286.98, 1 095.74, 1 079.52 and 739.61 gentamycin units, respectively. Finally, a method for the determination of gentamycin potency was established based on the proportion and content of C components of gentamycin. The unification of purity and potency for gentamycin was achieved using only HPLC-ELSD. It is also demonstrated that C components of gentamycin and micronomicin produce the same responses under ELSD, which means that it is not necessary to prepare separate reference standards for each C component of gentamycin and that quantitative testing can be performed accurately using only one micronomicin reference standard. This study simplified the previous method for the determination of the content of C components of gentamycin using HPLC-ELSD. The developed method is suitable for regular use as a part of quality control and can simplify the rigmarole quality control procedures provided in current pharmacopeias.


Plant-animal interactions mediate climatic effects on selection on flowering time.
Selection on flowering time in plants is often mediated by multiple agents, including climatic conditions and the intensity of mutualistic and antagonistic interactions with animals. These selective agents can have both direct and indirect effects. For example, climate might not only influence phenotypic selection on flowering time directly by affecting plant physiology, but it can also alter selection indirectly by modifying the seasonal activity and relative timing of animals interacting with plants. We used 21 yr of data to identify the drivers of selection on flowering time in the perennial herb Lathyrus vernus, and to examine if antagonistic plant-animal interactions mediate effects of climate on selection. We examined the fitness consequences of vertebrate grazing and predispersal seed predation, and how these effects varied among years and among individuals within years. Although both antagonistic plant-animal interactions had important negative effects on plant fitness, only grazing intensity was consistently related to plant phenology, being higher in early-flowering individuals. Spring temperature influenced the intensity of both plant-animal interactions, as well as the covariance between seed predation and plant phenology. However, only differences in grazing intensity among years were associated with differences in selection on flowering time; the strength of selection for early flowering being stronger in years with lower mean intensity of grazing. Our results illustrate how climatic conditions can influence plant-animal interactions that are important selective agents for plant traits. A broader implication of our findings is that both ecological and evolutionary responses to climatic changes might be indirect, and largely mediated by species interactions.


β-Bracelets: Macrocyclic Cross-β Epitope Mimics Based on a Tau Conformational Strain.
The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression of Alzheimer's disease (AD) and related tauopathies. Disease-associated conformations of filamentous tau are characterized by hydrophobic interactions between side chains on unique and distant β-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of β-arch peptide macrocycles composed of the aggregation-prone PHF6 hexapeptide of tau and the cross-β module specific to the AD tau fold. Termed "β-bracelets", these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel β-sheet structure. Backbone N-amination of a selected β-bracelet affords soluble inhibitors of tau aggregation. We further demonstrate that the N-aminated macrocycles block the prion-like cellular seeding activity of recombinant tau as well as mature fibrils from AD patient extracts. These studies establish β-bracelets as a new class of cross-β epitope mimics and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.


Blueberry treatment decreased D-galactose-induced oxidative stress and brain damage in rats.
D-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB) (Vaccinium corymbosum L.) treatment on oxidative stress in age-related brain damage model. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with 5 % (BB1) and 10 % (BB2) BB containing chow for two months. Malondialdehyde (MDA),protein carbonyl (PC) and glutathione (GSH) levels, and Cu Zn-superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities as well as acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brain by immunohistochemistry. MDA and PC levels and AChE activity increased, but GSH levels, SOD and GSH-Px activities decreased together with histopathological structural damage in the brain of GAL-treated rats. BB treatments, especially BB2 reduced MDA and PC levels and AChE activity and elevated GSH levels and GSH-Px activity. BB1 and BB2 treatments diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. These results indicate that BB partially prevented the shift towards an imbalanced prooxidative status and apoptosis together with histopathological amelioration by acting as an antioxidant (radical scavenger) itself in GAL-treated rats.


Comparison of native matrix metalloproteinases and their recombinant catalytic domains using a novel radiometric assay.
A novel radiometric assay was developed for human fibroblast collagenase (matrix metalloproteinase-1, MMP-1), stromelysin (MMP-3), and their recombinant catalytic domains. Using this assay we were able to compare the native MMPs with the respective catalytic domains in terms of inhibitor affinities and peptide hydrolysis. The assay works on the same principle as an assay developed for carboxypeptidase (Rossier et al., Anal. Biochem. 1989, 178, 27-31) and is based on a synthetic peptide substrate, [1-benzoyl-14C]benzoyl-Pro-Leu-Ala-Leu-Trp- NH(CH2)4N(CH3)2(bnzPLALW-NX). The generation of product is measured by selective solvent extraction of radioactive product directly into scintillation cocktail; the entire assay, including the radioactivity measurement, is completed in a single 1-ml tube (96-well format) without removal or transfer of phases. Results of steady-state measurements demonstrated that peptide hydrolysis follows Michaelis-Menten kinetics with the fibroblast MMPs and their C-terminal deleted forms. The kinetic constants for hydrolysis of bnz-PLALW-NX, and for inhibition by actinonin, a natural peptide-hydroxamate, are essentially the same for the native and the C-terminally deleted MMPs.


Association of the PGC-1α rs8192678 variant with microalbuminuria in subjects with type 2 diabetes mellitus.
PPAR-γ co-activator-1α (PGC-1α) is a tissue-specific transcriptional co-activator involved in the regulation of antioxidant enzymes. The A-allele of the rs8192678 PGC-1 α} (G>A) gene variant has previously been associated with nephropathy in Korean and Indian-Asian type 2 diabetes mellitus (T2DM) samples. Our aim was to examine the association between this variant and urine albumin exccretion in European subjects with T2DM. Genotyping was performed on 583 European subjects with T2DM and examined in relation to urinary albumin, plasma oxidized-LDL and small dense-LDL percentage. We observed a significant association between genotype (GG/GA/AA) and urinary albumin (normoalbuminuria v micro/macroalbuminuria: 48.6/39.7/11.7% v 38.2/51.2/10.5%, p=0.02; for GG v GA/AA, p=0.01). The odds ratio for micro/macroalbuminuria in GA and AA subjects relative to GG were 1.70 [1.15-2.50], p=0.008 and 1.20 [0.66-2.16], p=0.56 respectively (for GA/AA v GG: 1.58 [95% CI: 1.09-2.27], p=0.02). There was a significant association between the A allele and a higher percentage of small dense-LDL particles (GG v GA v AA: 70.8 [58.01-81.06] % v 72.8 [56.18-81.19] % v 78.9 [67.16-85.33] %, p=0.03). In European subjects with T2DM the GA relative to the GG genotype is associated with a 70% increase in the risk of micro/microalbuminuria. Furthermore, homozygosity for the A-allele is also associated with a preponderance of small dense-LDL particles.


Time-varying correlations between delta EEG power and heart rate variability in midlife women: the SWAN Sleep Study.
No studies have evaluated the dynamic, time-varying relationship between delta electroencephalographic (EEG) sleep and high frequency heart rate variability (HF-HRV) in women. Delta EEG and HF-HRV were measured during sleep in 197 midlife women (M(age) = 52.1, SD = 2.2). Delta EEG-HF-HRV correlations in nonrapid eye movement (NREM) sleep were modeled as whole-night averages and as continuous functions of time. The whole-night delta EEG-HF-HRV correlation was positive. The strongest correlations were observed during the first NREM sleep period preceding and following peak delta power. Time-varying correlations between delta EEG-HF-HRV were stronger in participants with sleep-disordered breathing and self-reported insomnia compared to healthy controls. The dynamic interplay between sleep and autonomic activity can be modeled across the night to examine within- and between-participant differences including individuals with and without sleep disorders.


[Frequency and phase correlations of the biorhythms of metabolic indices in mice during their postnatal ontogeny].
In laboratory mice the daily rhythms of feeding, plasma insulin, blood glucose and liver glycogen were investigated beginning from an age of 1 week to 52 weeks. For all parameters circadian and ultradian rhythms changing in the course of development could be quantified. During juvenile phase and inversion of all patterns connected with temporary increasing ultradian components takes place. The beginning and the end of this inversion are specific for various parameters, to that changing frequency and phase correlations could be obtained. The lowest degree of phase correspondence is found at weaning, it reaches its maximum in adults and decreases again in older mice. The possible consequences of demonstrated phenomena for the stability of the functional system and the existence of sensitive phases during postnatal ontogeny are discussed.


Speech arrest in partial seizures: evidence of an associated language disorder.
Recurrent episodes of speech arrest were observed in a man as the primary manifestation of a partial seizure disorder. To determine whether speech arrest was associated with a language disorder, the Syntactic Comprehension test was administered during and after speech arrest. This test does not depend upon speech production, but evaluates ability to comprehend sentences in which meaning depends on syntactic relationships. Using this test, we were able to show that speech arrest was associated with a language disturbance.


Investigation of factors related to healthy eating behavior based on the developed theory of planned behavior in adolescents.
Adolescence is a complicated and sensitive period, and proper nutrition in this period of life can influence the quality and quantity of growth and maturity. The aim of the present study is to determine the factors associated with healthy eating behavior based on the developed theory of planned behavior in adolescents. This is a descriptive-correlational study in which 400 female students of the first grade of high school in Bandar Anzali participated. Among the junior high schools in this city, two schools were randomly selected and sampling was done using census method. Data collection tool was Healthy Eating Behavior questionnaire based on Theory of Planned Behavior, which includes three sections of demographic information, constructs of Theory of Planned Behavior, including attitude toward behavior, subjective norms, perceived behavioral control, and behavioral intention, and food behavior, and food habits questionnaire. The scale was evaluated and confirmed by content validity ratio, content validity index, and alpha coefficient. P value was considered significant at less than 5%. Data analysis was performed using SPSS software 24, through linear regression and Pearson's correlation. As shown by linear regression analysis, the developed theory of planned behavior is able to predict 26% of the variance of healthy eating behavior, and this predictive power is related to the constructs of behavioral intention, attitude, and habits. In the present study, adding the variable of habits to the theory of planned behavior showed that this variable is very effective in predicting healthy eating behavior in adolescents, just like the constructs of behavioral intention and attitude. Therefore, it is suggested to carry out educational interventions based on the developed theory of planned behavior with the focus of the mentioned structures.


Submandibular venous hemangioma: Case report and review of the literature.
Hemangiomas of the submandibular space are very rare. Only 11 cases have been reported in the English literature, all of which were cavernous hemangiomas. In this report, we describe the case of a venous hemangioma in a 70-year-old woman. Ultrasound examination revealed a lobulated, homogeneous, hypoechoic mass, and minimal flow was detected on power Doppler evaluation. The mass and the submandibular gland were surgically excised, and the endothelium was found to be positive for CD31 and D2-40 markers, consistent with venous hemangioma. To our knowledge, this is the first reported case of a venous hemangioma in the submandibular space.


Relation between serum fibroblast growth factor-23 level and mortality in incident dialysis patients: are gender and cardiovascular disease confounding the relationship?
Circulating fibroblast growth factor-23 (FGF23) promotes renal phosphate excretion and is markedly increased in patients with chronic kidney disease. High serum FGF23 is associated with cardiovascular risk factors and was recently identified as a predictor of total mortality in haemodialysis patients. Herein, our aim was to evaluate the relation between FGF23 and mortality, including the impact of gender and cardiovascular disease (CVD), in a Swedish cohort of 'incident' dialysis patients. Two hundred and twenty-nine incident dialysis patients (149 males; mean age 55 years) were included. Serum intact FGF23, calcium, phosphate, S-albumin, parathyroid hormone, high-sensitivity C-reactive protein and interleukin-6 were measured at baseline. Cardiovascular disease was defined as clinical symptoms and/or a history of CVD. During a median follow-up time of 23 months, 66 patients (29%) died. FGF23 levels positively correlated to calcium (r = 0.27, P < 0.0001), phosphate (r = 0.40, P < 0.0001), calcium x phosphate product (r = 0.52, P < 0.0001) and creatinine (r = 0.18, P = 0.007). In Cox proportional hazard models, FGF23 was not associated with increased mortality risk, neither in crude nor in multivariate adjusted models. However, in a subgroup analysis of men with prevalent CVD, FGF23 level above median was associated with higher mortality risk in crude models [hazard ratio 2.19, 95% confidence interval 1.04-4.60, P = 0.04]. In primary analysis, serum FGF23 was not associated with increased mortality risk in this cohort of 'incident' dialysis patients. Our data support that the impact of FGF23 on mortality may be modified by gender and CVD and, as previously shown, is blunted in the setting of pronounced hyperphosphatemia.


Human bone marrow CD34- cells engraft in vivo and undergo multilineage expression that includes giving rise to CD34+ cells.
We used the human/sheep competitive engraft model to investigate the in vivo engraftment potential of human CD34-, Lin- cells. In three separate studies, transplantation of CD34+, Lin- and CD34-, Lin- cells from the same normal human donors into preimmune fetal sheep resulted in long-term engraftment and multilineage hematopoietic cell/progenitor expression. Human cell/progenitor activities of the CD34+ group were CD3, 0.52%; CD13, 0.36%; CD45, 1.02%; glyA, 1.78%; HLA-DR, 0.99%; colony-forming units (CFU)-Mix, 7.1%; and granulocyte-macrophage CFU (CFU-GM), 13.7%; those of the CD34- group were CD3, 0.24%; CD45, 2.49%; glyA, 0.75%; HLA-DR, 0.3%; CFU-Mix, 7.1%; and CFU-GM, 4.3%. Of special interest was the detection of highly significant numbers (1 x 10[9] cells) of human CD34+ cells in animals transplanted with CD34- cells. Secondary transplantation and limiting dilution studies confirmed the presence of cells with long-term engraftment potential in CD34- populations. The results presented here demonstrate that the CD34- fraction of normal human bone marrow contains cells capable of engraftment and differentiation into CD34+ progenitors and multiple lymphohematopoietic lineages in primary and secondary hosts.


Brachial artery compression by the lacertus fibrosus.
Five patients presented with classic symptoms diagnostic of intermittent claudication that were exacerbated by strenuous activity. Examination demonstrated localized tenderness over the lacertus fibrosus (bicipital aponeurosis), as well as increased pain and an obliterated radial pulse with forearm pronation and resisted elbow flexion. All 5 were athletes who had hypertrophied forearm muscles. Patients were diagnosed with brachial artery compression by the lacertus fibrosus. Release of the lacertus fibrosus restored normal pulses in all cases. Followup ranged from 6 months to 25 years. Full clinical recovery was achieved in 3 patients. One patient had a good result and 1 a fair result. Although the lacertus fibrosus has been well described as a cause of neural compression and compartment syndrome, it has been reported only once to cause intermittent arterial compromise. Hypertrophy of the muscles and the lacertus fibrosus related to excessive use is an important factor in the development of isolated vascular, neural, or combined neurovascular lesions.


SPOC domain proteins in health and disease.
Since it was first described >20 yr ago, the SPOC domain (Spen paralog and ortholog C-terminal domain) has been identified in many proteins all across eukaryotic species. SPOC-containing proteins regulate gene expression on various levels ranging from transcription to RNA processing, modification, export, and stability, as well as X-chromosome inactivation. Their manifold roles in controlling transcriptional output implicate them in a plethora of developmental processes, and their misregulation is often associated with cancer. Here, we provide an overview of the biophysical properties of the SPOC domain and its interaction with phosphorylated binding partners, the phylogenetic origin of SPOC domain proteins, the diverse functions of mammalian SPOC proteins and their homologs, the mechanisms by which they regulate differentiation and development, and their roles in cancer.


Optimizing the use of blood products in trauma care.
Blood transfusion has been used to treat the injured since the US Civil War. Now, it saves the lives of tens of thousands of injured patients each year. However, not everyone who receives blood benefits, and some recipients are injured by the transfusion itself. Effective blood therapy in trauma management requires an integration of information from diverse sources, including data relating to trauma and blood use epidemiology, medical systems management, and clinical care. Issues of current clinical concern in highly developed trauma systems include how to manage massive transfusion events, how to limit blood use and so minimize exposure to transfusion risks, how to integrate new hemorrhage control modalities, and how to deal with blood shortages. Less developed trauma systems are primarily concerned with speeding transport to specialized facilities and assembling trauma center resources. This article reviews the factors that effect blood use in urgent trauma care.


[Clinical spectrum and management of congenital pulmonary cystic lesions].
Congenital cystic lesions of the lung in children are uncommon but potentially life-threatening and warrant an urgent diagnostic work-up. Pulmonary sequestration (PS), congenital cystic adenomatoid malformation (CCAM), congenital lobar emphysema (CLE), and bronchogenic cyst (BC) are the four major congenital cystic lesions, but they share similar embryologic and clinical characteristics. The purpose of this study is to review our institutional experience with congenital cystic lung disease emphasizing on diagnosis and management. Between January 1975 and October 2007, 109 patients have been treated, of which 57 males and 52 females, the age ranged from the birth to 13 years. 104 patients presented solitary lesions: CCAM (47), CLE (16), PS (22), BC (19). The remainders 5 patients presented two simultaneous lesions: intralobar PS and CCAM (2), CLE and CCAM (3). All the lesions have been treated surgically: in the first cases, only symptomatic patients underwent surgery, while in the last years, patients have systematically been submitted operated. A meaningful percentage of CCAM joins to PS and CLE; instead the BC are generally isolated, probably deriving by a more precocious embryogenetic defect. The treatment of these lesions is surgical: CCAM (type I-II) and CLE should be treated promptly in newborns for respiratory distress and pneumothorax; CCAM (type II) and BC generally become symptomatic gradually and expose to degenerative risk; intralobar PS generally becomes symptomatic and surgery prevents the risk of infections. Extralobar PS and the asymptomatic BC are not exempted by surgical approach whenever accidentally described as masses of uncertain nature. Asymptomatic cysts in children should be resected, to avoid later complications of the cysts, which could make operation more difficult. Conservative anatomic resections should be attempted to preserve functional lung tissue. Careful histologic examination of the resection specimen is mandatory to identify occult malignancy. In conclusion a correct embryogenetic organization and a clinical evaluation of the congenital cystic lung diseases allow a precocious and effective surgical timing.


Down-regulation of key virulence factors makes the Salmonella enterica serovar Typhimurium rfaH mutant a promising live-attenuated vaccine candidate.
Mutants of Salmonella enterica serovar Typhimurium that lack the transcriptional regulator RfaH are efficient as live oral vaccines against salmonellosis in mice. We show that the attenuation of the vaccine candidate strain is associated with reduced net growth in epithelial and macrophage cells. In order to identify the relevant RfaH-dependent genes, the RfaH regulon was determined with S. enterica serovars Enteritidis and Typhimurium using whole-genome Salmonella microarrays. As well as impacting the expression of genes involved in lipopolysaccharide (LPS) core and O-antigen synthesis, the loss of RfaH results in a marked down-regulation of SPI-4 genes, the flagellum/chemotaxis system, and type III secretion system 1. However, a proportion of these effects could have been the indirect consequence of the altered expression of genes required for LPS biosynthesis. Direct and indirect effects of the rfaH mutation were dissociated by genome-wide transcriptional profiling of a structural deep-rough LPS mutant (waaG). We show that truncation of LPS itself is responsible for the decreased intracellular yield observed for DeltarfaH strains. LPS mutants do not differ in replication ability; rather, they show increased susceptibility to antimicrobial peptides in the intracellular milieu. On the other hand, evidence that deletion of rfaH, as well as some other genes involved in LPS biosynthesis, results in enhanced invasion of various mammalian cells is shown. Exposure of common minor antigens in the absence of serovar-specific antigens might be responsible for the observed cross-reactive nature of the elicited immune response upon vaccination. Increased invasiveness of the Salmonella rfaH mutant into antigen-presenting cells, combined with increased intracellular killing and the potential for raising a cross-protective immune response, renders the rfaH mutant an ideal vaccine candidate.


Partial anomalous pulmonary venous return in patients with pulmonary hypertension.
Anomalous pulmonary venous return is an uncommon congenital malformation, and may be partial or total. Partial anomalous pulmonary venous return (PAPVR) is more common than total anomalous pulmonary venous return, and is often associated with other congenital cardiac anomalies. Whilst many patients with PAPVR remain asymptomatic, some may present in later age with symptoms related to left-to-right shunt, right heart failure and pulmonary hypertension. We report two cases of PAPVR detected on Computed Tomography Pulmonary Angiogram (CTPA) for the work up of pulmonary hypertension. The cases demonstrate that, although uncommon, partial anomalous pulmonary venous return can be a contributing factor to pulmonary hypertension and pulmonary veins should be carefully examined when reading a CTPA study.


Androgen deprivation therapy toxicity and management for men receiving radiation therapy.
Androgen deprivation therapy is commonly used in combination with radiotherapy as part of the definitive treatment for men with clinically localized and locally advanced prostate cancer. Androgen deprivation has been associated with a wide range of iatrogenic effects impacting a variety of body systems including metabolic, musculoskeletal, cardiovascular, neurocognitive, and sexual. This review aims to provide the radiation oncology community with the knowledge to monitor and manage androgen deprivation therapy toxicity in an effort to provide the highest level of care for patients and to minimize the iatrogenic effects of androgen deprivation as much as possible.


Pharmacist recognition of and adherence to medication-use policies and safety practices.
Pharmacist recognition of and adherence to medication-use policies and safety practices were assessed. Simulation testing was used to assess the performance of pharmacists in hypothetical scenarios simulating real-life situations. Fifty test case medication orders were developed, some requiring specific intervention and some requiring no special action. Orders were classified into four categories: those posing safety concerns n ( = 16), those with formulary and product standardization issues (n = 4), those with pharmacy and therapeutics (P&T) committee restrictions (n = 4), and those requiring no special action (n = 26). Potential barriers to compliance were identified by the project team and the orders categorized accordingly. The orders were processed by 25 pharmacists using a simulation testing procedure. Data were analyzed by pharmacists' demographics, order category, and perceived barriers to compliance. Pharmacists were correctly able to recognize 77.3% of test orders: 67.3% with safety concerns, 98.9% with formulary issues, and 98.5% with restrictions. Appropriate action was taken with 74.2% of test orders: 64.5% of safety orders, 96.6% of formulary orders, and 92.4% of restriction orders. There was no correlation between pharmacists' performance and demographic characteristics. The two barriers to correct response identified most often were ambiguous responsibility and low perceived level of importance. Pharmacists generally recognized and took appropriate action with simulated medication orders that contained problems related to formulary or P&T committee restrictions. They were less able to recognize and act appropriately on orders with safety-related problems. Ambiguous responsibility and low perceived importance were the most significant factors contributing to noncompliance with P&T committee policies and guidelines.


Interaction of fibrinogen and muramidase-released protein promotes the development of Streptococcus suis meningitis.
Muramidase-released protein (MRP) is as an important virulence marker of Streptococcus suis (S. suis) serotype 2. Our previous works have shown that MRP can bind human fibrinogen (hFg); however, the function of this interaction in S. suis meningitis is not known. In this study, we found that the deletion of mrp significantly impairs the hFg-mediated adherence and traversal ability of S. suis across human cerebral microvascular endothelial cells (hCMEC/D3). Measurement of the permeability to Lucifer yellow in vitro and Evans blue extravasation in vivo show that the MRP-hFg interaction significantly increases the permeability of the blood-brain barrier (BBB). In the mouse meningitis model, wild type S. suis caused higher bacterial loads in the brain and more severe histopathological signs of meningitis than the mrp mutant at day 3 post-infection. Western blot analysis and immunofluorescence observations reveal that the MRP-hFg interaction can destroy the cell adherens junction protein p120-catenin of hCMEC/D3. These results indicate that the MRP-hFg interaction is important in the development of S. suis meningitis.


Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target.
The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs. TrxR was overexpressed approximately 10-fold in G. lamblia WB C6 cells by placing the trxR gene behind the arginine deiminase (ADI) promoter on a plasmid. Likewise, a mutant TrxR with a defective disulphide reductase catalytic site was strongly expressed in another G. lamblia WB C6 cell line. Susceptibilities to five antigiardial drugs, i.e. metronidazole, furazolidone, nitazoxanide, albendazole and auranofin were determined in both transfectant cell lines and compared to wildtype. Further, the impact of all five drugs on TrxR activity in vivo was measured. Overexpression of TrxR rendered G. lamblia WB C6 more susceptible to metronidazole and furazolidone but not to nitazoxanide, albendazole, and auranofin. Of all five drugs tested, only auranofin had an appreciably negative effect on TrxR activity in vivo, albeit to a much smaller extent than expected. Overexpression of TrxR and mutant TrxR had hardly any impact on growth of G. lamblia WB C6, although the enzyme also exerts a strong NADPH oxidase activity which is a source of oxidative stress. Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs.


Serum Gastrin and Pepsinogen Levels after Administration of Acid Secretion Inhibitors for Ulcers due to Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer.
Acid secretion inhibitors, such as proton pump inhibitors (PPIs) and potassium competitive acid blockers (PCABs), are used to treat ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer. These drugs can influence serum gastrin and pepsinogen (PG) levels; however, their definite effects remain unclear. This open-label, randomized study investigated the effect of acid secretion inhibitors on the serum gastrin and pepsinogen levels. In total, 76 patients were enrolled in the study. They underwent gastric ESD and received a PPI (n = 21) or PCAB (n = 55). Changes in the serum gastrin and PG levels before and 4 weeks after administration were examined. Patient factors associated with the alteration of serum PG or gastrin levels were identified. The median serum levels of gastrin, PGI, and PGII before the administration of the acid secretion inhibitors were 110.5 pg/mL, 36.4 ng/mL, and 8.9 ng/mL, respectively; after administration, the levels increased to 300 pg/mL, 64.7 ng/mL, and 15.8 ng/mL, respectively (P < 0.01). Univariate analysis revealed that PCABs led to a more significant increase in the serum gastrin and PG levels as compared to PPIs. Furthermore, the PG levels were significantly increased in patients with previous Helicobacter pylori infections than in those with current infections. In conclusion, the serum gastrin and PG levels increased after the use of acid secretion inhibitors. This elevation was affected by the type of drug used, whereas the elevation in PGs was affected by the patient's background as well.


Evidence for co-existence of thyrotropin-releasing hormone, substance P and serotonin in ventral medullary neurons that project to the intermediolateral cell column in the rat.
The present study was conducted to determine if substance P-, thyrotropin-releasing hormone- and/or serotonin-immunoreactivities coexist in ventral medullary neurons that project to the intermediolateral cell column in the rat. Neurons that projected to the intermediolateral cell column were identified by the presence of retrogradely transported rhodamine bead-labeled microspheres in the cell body after an injection of the microspheres into the intermediolateral cell column of the third thoracic spinal cord segment. Co-existence was determined by using a combination of dual color immunohistochemistry and serial 4-microns sections that were immunostained with different antibodies. Antibodies to substance P, serotonin, and pre-pro-thyrotropin releasing hormone160-169 were used to identify substance P, serotonin and thyrotropin-releasing hormone, respectively. Neurons that contained substance P-, thyrotropin-releasing hormone- and/or serotonin-immunoreactivities and that projected to the intermediolateral cell column were present in the nucleus raphe magnus, the nucleus raphe pallidus, the nucleus reticularis magnocellularis pars alpha, the paragigantocellular reticular nucleus and the parapyramidal region. Neurons that projected to the intermediolateral cell column, in each of these regions, were found to contain each of the following combinations of immunoreactive neurochemicals: substance P and thyrotropin-releasing hormone: substance P and serotonin; thyrotropin-releasing hormone and serotonin; or substance P, thyrotropin-releasing hormone and serotonin. In addition, most of the regions also contained neurons that appeared to contain only one of the neurochemicals and that also projected to the intermediolateral cell column. The greatest number of neurons that projected to the intermediolateral cell column and that also contained two or more co-existing neurochemicals was present in the midline regions. This study demonstrates the presence of neurons in the ventral medulla that project to the intermediolateral cell column and contain three co-existing neurochemicals. This study also demonstrates the use of a new method for the localization of three neurochemicals in single projection-specific neurons.


Elucidating a Complicated Enantioselective Metabolic Profile: A Study From Rats to Humans Using Optically Pure Doxazosin.
Doxazosin (DOX) is prescribed as a racemic drug for the clinical treatment of benign prostatic hyperplasia and hypertension. Recent studies found that the two enantiomers of DOX exhibit differences in blood concentration and pharmacological effects. However, the stereoselective metabolic characteristics and mechanisms for DOX are not yet clear. Herein, we identified 34 metabolites of DOX in rats based on our comprehensive and effective strategy. The relationship among the metabolites and the most discriminative metabolites between (-)-DOX and (+)-DOX administration was analyzed according to the kinetic parameters using state-of-the-art multivariate statistical methods. To elucidate the enantioselective metabolic profile in vivo and in vitro, we carefully investigated the metabolic characteristics of metabolites after optically pure isomers administration in rat plasma, rat liver microsomes (RLMs) or human liver microsomes (HLMs), and recombinant human cytochrome P450 (CYP) enzymes. As a result, the differences of these metabolites were found based on their exposure and elimination rate, and the metabolic profile of (±)-DOX was more similar to that of (+)-DOX. Though the metabolites identified in RLMs and HLMs were the same, the metabolic profiles of the metabolites from (-)-DOX and (+)-DOX were greatly different. Furthermore, four human CYP enzymes could catalyze DOX to produce metabolites, but their preferences seemed different. For example, CYP3A4 highly specifically and selectively catalyzed the formation of the specific metabolite (M22) from (-)-DOX. In conclusion, we established a comprehensive metabolic system using pure optical isomers from in vivo to in vitro, and the complicated enantioselectivity of the metabolites of DOX was clearly shown. More importantly, the comprehensive metabolic system is also suitable to investigate other chiral drugs.


Curcumin supplementation ameliorated vascular dysfunction and improved antioxidant status in rats fed a high-sucrose, high-fat diet.
Vascular endothelial dysfunction is a potential risk factor for cardiovascular disease. This study evaluated the effect of curcumin on factors associated with vascular dysfunction using rats fed a high-sucrose, high-fat (HSF) diet. The experiment included 2 animal feeding phases. In the first feeding phase, male Sprague-Dawley rats were randomly divided into 2 groups: the control group (n = 8) was fed a standard diet (AIN-93G) and the HSF group (n = 24) was fed an HSF diet for 8 weeks to induce obesity. In the second feeding phase, lasting 4 weeks, the HSF group was randomly divided into 3 subgroups: the O group (n = 8) continued feeding on the HSF diet, the OA group (n = 8) had the HSF diet replaced with AIN-93G, and the OC group (n = 8) was fed the HSF diet supplemented with curcumin (300 mg/kg body weight daily). After 8 weeks, the HSF diet significantly elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), insulin, homeostatic model assessment insulin resistance (HOMA-IR), low-density lipoprotein cholesterol (LDL-C), homocysteine (Hcy), C-reactive protein (CRP), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) but significantly reduced levels of nitric oxide (NO) and high-density lipoprotein cholesterol (HDL-C). After dietary intervention, the OA and OC groups exhibited significantly lower levels of AST, ALT, HOMA-IR, cholesterol, LDL-C, Hcy, CRP, VCAM-1, and ICAM-1 and higher levels of NO and catalase (CAT) activity compared with the O group. Superoxide dismutase, CAT, and glutathione peroxidase activities were increased in the OA group, while CAT levels were enhanced in the OC group. In conclusion, this study showed that curcumin supplementation and diet modification can inhibit HSF diet-induced vascular dysfunction potentially by enhancing NO production and antioxidant enzyme activities, thereby suppressing inflammation and oxidative damage in the vascular endothelium.


Protective effect of Nocardia rubra cell wall skeleton on experimental infection in normal and immunosuppressed mice.
The protective effect of Nocardia rubra cell wall skeleton (N-CWS) on experimental infections was investigated in normal and immunosuppressed mice. Pretreatment with N-CWS provided protection against acute systemic infections due to Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Listeria monocytogenes in normal mice. N-CWS administered before or after challenge also showed protective activity against Herpes simplex virus infection in normal mice. N-CWS was the most effective against extracellular parasitic Pseudomonas aeruginosa infection when administered 1 day before challenge, but displayed the most potent protective activity against infection with Listeria monocytogenes, a facultative intracellular parasite, when administered 7 to 14 days before challenge. In mice with subcutaneous Pseudomonas aeruginosa infection, N-CWS suppressed abscess formation and decreased the viable cell count in the resultant abscess foci when administered either intraperitoneally or subcutaneously to the infected site. In addition, treatment with N-CWS markedly restored host defense ability against pseudomonal infection in mice immunosuppressed with cyclophosphamide, hydrocortisone and X-ray irradiation.


Interstitial therapy suing non-absorbable (Ir192 nylon ribbon) and absrobable (I125 "Vicryl") suturing techniques.
Permanent and removable interstitial implantation techniques using absorbable and unabsorbable sutures are described. Most of these techniques can be performed in the clinic easily and quickly with basic instruments: needle holder, needle book, and hemoclips. Specifically, Ir192 (74-4 day half life, 300-610 keV, and 6.0 cm. hvl in tissue) nylon ribbon and I125 (60 day half life, 27-35 keV, and 2.0 cm. hvl in tissue) Vicryl sutures are described. A major advantage of the I125 over the Ir192 see (other than the fact that it can be permanently implanted and needs less radiation protection) is that the patient does not remain highly radioactive for as long a period due to hte extremely low I125 energy and may be allowed to leave the hospital. Both nuclides have the advantage of a long shelf life, making their use practical and economically feasible.


Achieving health, safety, and performance improvements through enhanced cost visibility and workplace partnerships.
Reduction in the environment, safety, and occupational health (ESOH) component of operational costs requires not only a better understanding of ESOH costs and requirements, but also the formation of effective partnerships between ESOH professionals, financial analysts, and shop workers to identify viable improvements to current practices. This article presents two case studies of efforts to enhance productivity and ESOH in corrosion control facilities at Randolph Air Force Base (AFB), Texas, and Robins AFB, Ga. At each site, activity-based cost models were created to increase the visibility of ESOH-related costs and target improvement opportunities. Analysis of the strip-and-paint processes for the T-38 aircraft at Randolph and the F-15 radome and C-141 aft cowl at Robins revealed that a large proportion of operating costs were tied to ESOH requirements and practices (22 and 39%, respectively). In each case ESOH professionals teamed with shop personnel to identify potential improvements in personal protective equipment use, waste disposal, tool selection, and work methods. This approach yielded alternatives projected to reduce total shop costs by 5 to 7%. This case study demonstrates how workplaces can identify cost-saving and efficiency-enhancing practices by partnering with ESOH professionals in planning and decision-making activities.


Student generation and peer review of examination questions in the dental curriculum: Enhancing student engagement and learning.
Writing, sharing, answering, discussing and rating examination questions are a way to involve students in creating content and applying their knowledge. The PeerWise online question-setting platform facilitates student communities in this activity. This mixed-methods study asks the question: Does students' writing and answering examination questions enhance their engagement and learning of Neurology as a Life Science topic? Over a 2-year period, self-assembled groups of 3-4 students submitted 1-2 multiple-choice questions (MCQs) every 2 weeks into the PeerWise portal for review by their peers. Summative examination results were compared with previous year's control group. Data were also collected regarding student engagement (number of MCQs answered or submitted comments) are compared to summative assessment results at the end of semester. Post-intervention student satisfaction surveys were analysed qualitatively and quantitatively to assess the effectiveness of the exercise. With 174 and 80 student participants in intervention and control groups, respectively, no statistical difference was found in the average marks between the cohorts. However, within intervention group, positive correlation (Spearman's r = .272-.333) was found between higher level of student engagement with PeerWise and higher examination result. Positive correlation remained persistent after completion of the PeerWise exercise. Student survey revealed greater engagement with subject content, and qualitative thematic analysis was mapped to define various ways students engaged with the PeerWise activity. Tasking students to regularly generate and review MCQs enhances engagement with the topic, and higher engagement with PeerWise correlating to higher examination scores.


Dietary inflammatory index in relation to severe coronary artery disease in Iranian adults.
Limited findings are available on the relationship between dietary inflammation index (DII) and severe coronary artery disease (CAD). Considering the high prevalence of CAD and its complications, we examined the relationship between DII and CAD. This cross-sectional study was conducted on 275 adults who underwent elective angiography. Severe coronary artery disease was measured by the gensini scoring system. DII was measured by a valid semi-quantitative 168-item food frequency questionnaire (FFQ). Blood samples were collected after 12 h of fasting to measure serum lipid profile and quantitative C-reactive protein (q-CRP) levels. Binary logistic regression was used to calculate the odds (OR) and 95% confidence interval (CI). People in the last tertile of the DII had a higher chance of suffering from severe coronary artery disease (OR: 3.71; 95% CI: 1.97-6.98), hypercholesterolemia (OR: 2.73; 95% CI: 5.03-1.48), reduced HDL-cholesterol levels (OR: 3.77; 95% CI: 9.34-1.52), and hypertension (OR: 1.93; 95% CI: 3.49-1.06) compared to people in the first tertile. After adjusting for confounding factors, the relationship remained significant. A direct and significant relationship was observed between the DII and increased q-CRP levels, which disappeared after adjusting for confounding factors in the adjusted model (OR: 2.02; 95% CI: 0.86-4.73). This cross-sectional study showed a direct and linear relationship between following an anti-inflammatory diet and decreasing the chance of severe CAD. Therefore, it seems necessary to implement community-based educational programs to promote healthy nutrition in order to prevent CADs.


Large-Scale Crowd Analysis through the Use of Passive Radio Sensing Networks.
The creation of an automatic crowd estimation system capable of providing reliable, real-time estimates of human crowd sizes would be an invaluable tool for organizers of large-scale events, particularly so in the context of safety management. We describe a set of experiments in which we installed a passive Radio Frequency (RF) sensor network in different environments containing thousands of human individuals and discuss the accuracy with which the resulting measurements can be used to estimate the sizes of these crowds. Depending on the selected training approach, a median crowd estimation error of 184 people could be obtained for a large scale environment which contained 3227 people at its peak. Additionally, we look into the potential benefits of dividing one of our experimental environments into multiple subregions and open up a potentially interesting new topic of research regarding the estimation of crowd flows. Finally, we investigate the combination of our measurements with another sources of crowd-related data: sales data from drink stands within the environment. In doing so, we aim to integrate the concept of an automatic RF-based crowd estimation system into the broader domain of crowd analysis.


Cholesterol sulfate imaging in human prostate cancer tissue by desorption electrospray ionization mass spectrometry.
Development of methods for rapid distinction between cancerous and non-neoplastic tissues is an important goal in disease diagnosis. To this end, desorption electrospray ionization mass spectrometry (DESI-MS) imaging was applied to analyze the lipid profiles of thin tissue sections of 68 samples of human prostate cancer and normal tissue. The disease state of the tissue sections was determined by independent histopathological examination. Cholesterol sulfate was identified as a differentiating compound, found almost exclusively in cancerous tissues including tissue containing precancerous lesions. The presence of cholesterol sulfate in prostate tissues might serve as a tool for prostate cancer diagnosis although confirmation through larger and more diverse cohorts and correlations with clinical outcome data is needed.


Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water.
The prediction of the binding affinity between a protein and ligands is one of the most challenging issues for computational biochemistry and drug discovery. While the enthalpic contribution to binding is routinely available with molecular mechanics methods, the entropic contribution is more difficult to estimate. We describe and apply a relatively simple and intuitive calculation procedure for estimating the free energy of binding for 53 protein-ligand complexes formed by 17 proteins of known three-dimensional structure and characterized by different active site polarity. HINT, a software model based on experimental LogP(o/w) values for small organic molecules, was used to evaluate and score all atom-atom hydropathic interactions between the protein and the ligands. These total scores (H(TOTAL)), which have been previously shown to correlate with DeltaG(interaction) for protein-protein interactions, correlate with DeltaG(binding) for protein-ligand complexes in the present study with a standard error of +/-2.6 kcal mol(-1) from the equation DeltaG(binding) = -0.001 95 H(TOTAL) - 5.543. A more sophisticated model, utilizing categorized (by interaction class) HINT scores, produces a superior standard error of +/-1.8 kcal mol(-1). It is shown that within families of ligands for the same protein binding site, better models can be obtained with standard errors approaching +/-1.0 kcal mol(-1). Standardized methods for preparing crystallographic models for hydropathic analysis are also described. Particular attention is paid to the relationship between the ionization state of the ligands and the pH conditions under which the binding measurements are made. Sources and potential remedies of experimental and modeling errors affecting prediction of DeltaG(binding) are discussed.


High incidence of pertussis among Hajj pilgrims.
Prolonged cough occurs in a large proportion of the 2 million pilgrims who participate in the annual Hajj in Saudi Arabia. In a prospective seroepidemiological study to determine the incidence of pertussis among 358 adult pilgrims, 5 (1.4%) were found to have acquired pertussis (defined as prolonged cough and a >4-fold increase in the level of immunoglobulin G to whole-cell pertussis antigen). Of the 40 pilgrims who had no pre-Hajj immunity to pertussis, 3 (7.5%) acquired pertussis. Administration of acellular pertussis vaccine to pilgrims before the Hajj should be considered to address this problem.


Cathelicidin peptide sheep myeloid antimicrobial peptide-29 prevents endotoxin-induced mortality in rat models of septic shock.
The present study was designed to investigate the antiendotoxin activity and therapeutic efficacy of sheep myeloid antimicrobial peptide (SMAP)-29, a cathelicidin-derived peptide. The in vitro ability of SMAP-29 to bind LPS from Escherichia coli 0111:B4 was determined using a sensitive limulus chromogenic assay. Two rat models of septic shock were performed: (1) rats were injected intraperitoneally with 1 mg E. coli 0111:B4 LPS and (2) intraabdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg/kg SMAP-29, 1 mg/kg polymyxin B or 20 mg/kg imipenem. The main outcome measures were: abdominal exudate and plasma bacterial growth, plasma endotoxin and tumor necrosis factor-alpha concentrations, and lethality. The in vitro study showed that SMAP-29 completely inhibited the LPS procoagulant activity at approximately 10 microM peptide concentration. The in vivo experiments showed that all compounds reduced the lethality when compared with control animals. SMAP-29 achieved a substantial decrease in endotoxin and tumor necrosis factor-alpha plasma concentrations when compared with imipenem and saline treatment and exhibited a slightly lower antimicrobial activity than imipenem. No statistically significant differences were noted between SMAP-29 and polymyxin B. SMAP-29, because of its double antiendotoxin and antimicrobial activities, could be an interesting compound for septic shock treatment.


[History of tuberculosis: a century after the discoveries of Koch and Forlanini].
A century after the discovery of the etiological agent of tubercolosis, the author remembers the steps of study of the disease. Fracastoro supposed the existence of small bodies, epidemiological studies pointed attention to the transmissibility until 1882, when Koch communicated to the Physiological Society of Berlin that bacteria had been evidenced in biological material of the lungs from tuberculosis patients. The method of coloration of Koch rapidly spread, but no therapy was found. In the same year Forlanini proposed the artificial pneumothorax as cure.


Quantification of taurodontism: interests in the early diagnosis of hypohidrotic ectodermal dysplasia.
The aim of this study was to provide a quantification of taurodontism in Hypohidrotic Ectodermal Dysplasia (HED) and to report its occurrence in a cohort of HED patients to assess phenotypic-genotypic correlations. Of 68 HED patients retrospectively reviewed, 16 patients aged 7-51 years were selected and compared with a control sample (n = 351). The pulp surface index of the first lower permanent molar was calculated from the panoramic radiograph of each individual, and statistical comparisons between the HED patients and the control sample were performed. Whatever the genetic disorder, 81.25% of the HED patients exhibited a relative enlargement (>or=1 s.d.) of the pulp. Major deviations (>5 s.d.) were respectively related to men affected by large deletion of the EDA gene or missense mutation. The autosomal recessive form was linked to a relative moderate pulp enlargement (3.44 s.d.). In NEMO forms, the increase of pulp size in men appeared to be less marked than in EDA mutations. This study provides for the first time an objective assessment of pulp enlargement in HED patients, and the various degrees of taurodontism depicted could be interesting dental phenotypic markers of HED forms.


Scope of SARS-CoV-2 variants, mutations, and vaccine technologies.
The COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is disseminated by respiratory aerosols. The virus uses the spike protein to target epithelial cells by binding to the ACE2 receptor on the host cells. As a result, effective vaccines must target the viral spike glycoprotein. However, the appearance of an Omicron variant with 32 mutations in its spike protein raises questions about the vaccine's efficacy. Vaccines are critical in boosting immunity, lowering COVID-19-related illnesses, reducing the infectious burden on the healthcare system, and reducing economic loss, according to current data. An efficient vaccination campaign is projected to increase innate and adaptive immune responses, offering better protection against SARS-CoV-2 variants. The presence of altered SARS-CoV-2 variants circulating around the world puts the effectiveness of vaccines already on the market at risk. The problem is made even worse by the Omicron variant, which has 32 mutations in its spike protein. Experts are currently examining the potential consequences of commercial vaccines on variants. However, there are worries about the vaccines' safety, the protection they provide, and whether future structural changes are required for these vaccines to be more effective. As a result of these concerns, new vaccines based on modern technology should be developed to guard against the growing SARS-CoV-2 variations. The choice of a particular vaccine is influenced by several factors including mode of action, storage conditions, group of the vaccinee, immune response mounted, cost, dosage protocol, age, and side effects. Currently, seven SARS-CoV-2 vaccine platforms have been developed. This comprises of inactivated viruses, messenger RNA (mRNA), DNA vaccines, protein subunits, nonreplicating and replicating vector viral-like particles (VLP), and live attenuated vaccines. This review focuses on the SARS-CoV-2 mutations, variants of concern (VOCs), and advances in vaccine technologies.


Effectiveness of the actions of antimicrobial control in the intensive care unit.
There are various strategies to improve the effectiveness of antibiotics in hospitals. In general, for the implementation of guidelines for appropriate antibiotic therapy, the participation of infectious disease (ID) physicians deserves considerable attention. This study was a prospective ecological time-series study that evaluates the effectiveness of the ID physician's opinion to rationalize and control the use of antibiotics in medical-surgical intensive care units (ICU), and the impact of their intervention on treatment expenditures. There was significant change in the pattern of use of antimicrobials, this pattern approximating that of a medical-surgical ICU that participates in the ICARE (Intensive Care Antimicrobial Resistance Epidemiology) Project. For example, there was a significant increase in the consumption of antimicrobials of the ampicillin group (Relative Risk [RR]=3.39; 95% CI: 2.34-4.91) and antipseudomonal penicillins (RR=2.89; 95% CI: 1.70-4.92). On the other hand, there was a significant reduction in the consumption of 3(rd)/4(th )generation cephalosporins (RR=0.66; 95% CI: 0.57-0.77) and carbapenems (RR=0.43; 95% CI: 0.33-0.56). On average, for every patient-day antibiotic expense was reduced 37.1% during calendar year 2001, when compared with 2000. The ID specialists' opinion and the adoption of guidelines for empirical antibiotic therapy of hospital-acquired pneumonia contributed to a reduction in the use of antimicrobials in medical-surgical ICU. However, further studies that have more control over confounding variables are needed to help determine the relevance of these discoveries.


Comprehensive analysis of etiology on the prognosis of urethral strictures.
Urethral strictures remain a reconstructive dilemma, due to high incidence of recurrence and less than satisfactory outcomes. Even experienced surgeons following strict surgical principles have not achieved optimal results, leading us to think whether the etiology of strictures dictate the outcome . We evaluated this "cause-effect" relationship highlighting the significance of the etiology on the overall prognosis of urethral strictures. A total of 302 males with urethral strictures were assessed (both retrospectively and prospectively) over a period of ten years. The preoperative evaluation was performed by retrograde urethrogram, urethrosonogram, and uroflowmetry and categorized, based on etiology: a) as post traumatic, b) post infective, c) iatrogenic or d) unknown. Traumatic strictures were subjected to pelvic X-ray and sub-categorized into grades A, B and C, following the TILE classification. Patients were operated; with tunica albuginea urethroplasty for anterior strictures and U shape prostato-bulbar anastomosis for posterior strictures. Traumatic strictures accounted for 54% of cases. 127 of the 302 patients were treated using Tunica Albuginea Urethroplasty, while U shaped Prostatobulbar Anastomosis was performed on others. Post traumatic strictures had best outcome whereas post infective strictures had the worse outcome. Among strictures following pelvic fractures, TILE grades A and B had a better post operative course as compared to TILE C. Overall complication rate was 13.24%. Our study demonstrated that etiology of urethral strictures may play a vital role for the overall prognosis of urethral strictures.


Surface-enhanced Raman scattering of a gold core-silver shell-sponge substrate for detection of thiram and diquat.
Aiming at the difficulty of traditional pesticide sampling, a low-cost and convenient flexible surface enhanced Raman scattering (SERS) gold core-silver shell-sponge (Au-Ag-sponge) substrate was synthesized by chemical reduction. The SERS substrate consisted of Au-AgNPs and a melamine sponge. The sponge had a rich open pore structure, which could well "capture" Au-AgNPs, generating a large number of "hot spots". The SERS enhancement activity of the flexible substrate was characterized with rhodamine 6G (R6G) Raman probe molecules. The substrate showed good activity to 10-12 M rhodamine 6G with an enhancement factor (EF) of 7.72 × 106. Applying this substrate to the qualitative and quantitative detection of pesticide residues, the results showed that the Raman intensity was well related to the concentration of pesticide solution with the range of 0.1-10 mg L-1 of thiram and 1-10 mg L-1 of diquat. Furthermore, the substrate was analyzed by finite difference time domain (FDTD) simulation and the results were in good agreement with the experimental results. The reason for the difference in Raman signals of pesticide molecules on the same substrate was the different binding modes of Au-AgNPs on the sponge. Finally, we pointed out the advantages of flexible substrates in the field of pesticide residues, as well as future opportunities and challenges.