An analytical approximation of the Bragg curve for therapeutic proton beams.
The knowledge of proton depth-dose curves, or "Bragg curves," is a fundamental prerequisite for dose calculations in radiotherapy planning, among other applications. In various cases it is desirable to have an analytical representation of the Bragg curve, rather than using measured or numerically calculated data. This work provides an analytical approximation of the Bragg curve in closed form. The underlying model is valid for proton energies between about 10 and 200 MeV. Its main four constituents are: (i) a power-law relationship describing the range-energy dependency; (ii) a linear model for the fluence reduction due to nonelastic nuclear interactions, assuming local deposition of a fraction of the released energy; (iii) a Gaussian approximation of the range straggling distribution; and (iv) a representation of the energy spectrum of poly-energetic beams by a Gaussian with a linear "tail." Based on these assumptions the Bragg curve can be described in closed form using a simple combination of Gaussians and parabolic cylinder functions. The resulting expression can be fitted to measurements within the measurement error. Very good agreement is also found with numerically calculated Bragg curves.


Pattern of blood pressure in African diabetics: report from Sudan.
The objective of this study was to determine the prevalence of hypertension in diabetic patients in an urban Sudanese population compared with a non-diabetic group. It was found that there was a higher prevalence of diastolic hypertension (44%) in the non-insulin-dependent (NIDM) patients. The blood pressures did not correlate with age, duration of diabetes or nephropathy (9% of cases), but obesity which was detected in 34% of the NIDD group may possibly explain the high prevalence of hypertension.


Anticonvulsants in epileptic fowl.
The high seizure susceptibility in epileptic fowl is an autosomal recessive trait characterized in homozygotes by seizures that occur spontaneously and in response to photic stimulation or hyperthermia. Both of the latter stimuli can be used to evoke seizures in drug studies. Epileptic fowl have abnormal inter-ictal EEG activity. When exposed to photic stimulation spiking is apparent on the EEG at seizure onset. Phenobarbital, primidone, phenytoin, and valproic acid reduce seizure susceptibility at plasma concentrations approximating those used to control generalized and focal cortical tonic-clonic seizures in humans. Carbamazepine and the benzodiazepines also reduce seizure susceptibility. These data indicate that epileptic fowl provide a useful model for generalized and focal cortical tonic-clonic epilepsies. Ethosuximide was inactive in epileptic fowl. However, trimethadione had anticonvulsant activity indicating that this model is only relatively specific for the above seizure types. When seizures were evoked by hyperthermia phenobarbital but not phenytoin or valproate reduced seizure susceptibility. GABA (gamma-aminobutyric acid), AOAA (amino-oxyacetic acid) and THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ole, a glial specific inhibitor of GABA uptake) all have anticonvulsant activity against seizures evoked by photic stimulation in young chicks. These data indicate that this model may be particularly useful for studies of the anticonvulsant activity of compounds designed to enhance GABAergic transmission.


[Role of the vitamin factor in preventing phenol poisoning].
Experiments on rats were made to examine the effect of vitamin B1, pantothenic and ascorbic acids on the acetylation system and some characteristics of protein metabolism under chronic exposure to phenol. Inhibition of phenol vapours led to inhibition of the acetylation on the 105th day of the experiment, to accumulation of pyruvic acid by the blood and diurnal urine, to elevation of cholesterol content in the blood serum. The total content of protein and protein fractions in the blood serum remained unchanged. Additional vitaminization of the animals with thiamine (150 micrograms), calcium pantothenate (650 micrograms) or with their mixture containing ascorbic acid (2 mg) resulted in normalization of the test characteristics of carbohydrate and fat metabolism. The data obtained and the clinical trials carried out by the authors suggest introduction of the physiological doses of thiamine, calcium pantothenate and ascorbic acid into the diet of the workers in order to prevent phenol poisonings more effectively.


Interaction of Natronobacterium pharaonis phoborhodopsin (sensory rhodopsin II) with its cognate transducer probed by increase in the thermal stability.
Pharaonis phoborhodopsin (ppR, also called Natronobacterium pharaonis sensory rhodopsin II) and its transducer protein, pharaonis halobacterial transducer of ppR (pHtrII), form a signaling complex, and light signals are transmitted from the sensor to the transducer by the protein-protein interaction. A truncated pHtrII(1-159) consisting of intramembrane helices (expressing amino acid residues from the first to the 159th position) and ppR form the complex in a solution containing 0.1% n-dodecyl-beta-D-maltoside. At 75-85 degrees C, the time-dependent color loss of ppR was caused by denaturation. We found that pHtrII(1-159) retarded the denaturation rate of ppR. This increase in the thermal stability was used as a probe for the binding ability in the dark. Tyr199 of ppR and Asn74 of pHtrII(1-114) were proposed as amino acid residues interacting with each other through hydrogen bonding. Then,ppR and pHtrII(1-159) mutants at these positions were prepared to examine the effect on the binding in the dark. The wild-type and Y199F mutant can bind pHtrII(1-159), suggesting that the hydrogen bonding between these specific amino acid residues may not be the only cause of the binding, but the hydrophobic interaction via phenyl ring of ppR may contribute dominantly.


An increased content of protease La, the lon gene product, increases protein degradation and blocks growth in Escherichia coli.
The lon gene product in Escherichia coli is an ATP-dependent protease (La) that plays an important role in the breakdown of abnormal proteins and certain normal polypeptides. Since transcription of the lon gene rises as part of the heat-shock response, we studied the physiological effects of increased levels of protease La. In cells carrying additional copies of the lon gene under the control of the lac or tac promoter, induction of the protease resulted in a rapid cessation of cell growth and in a loss of viability at stationary phase. Similarly, cells carrying a multicopy plasmid encoding the lon gene contained 2-5-fold more protease La and grew much more slowly than did control cells. In such cells, insertion sequences appeared spontaneously in the lon gene on the plasmid and prevented the excess protease production and allowed more rapid growth. The cells with increased content of protease La (due to the lon plasmid or induction of the lon gene) exhibited severalfold higher rates of degradation of abnormal proteins containing amino acid analogs and of incomplete polypeptides containing puromycin. Also, a beta-galactosidase fusion protein with enzymatic activity was relatively stable in control cells but unstable in the cells with high protease La content. In these cells, the overall degradation of normal proteins increased 2-fold, and certain cellular polypeptides appeared particularly sensitive to proteolysis. Thus, rates of protein degradation in vivo are limited in part by the cellular content of the ATP-dependent protease, and increases in transcription of the lon gene enhance proteolysis and can be deleterious to the cell.


A survey of needle handling practices and needlestick injuries in veterinary technicians.
A survey of veterinary technicians identified that needlestick injuries are very common, with 210/226 (93%) technicians reporting at least one needlestick injury over the course of their career. One hundred sixty-seven (74%) had experienced a needlestick injury during the preceding year. Exposure to animal blood and various drugs was common. It was particularly concerning that needlestick injuries involving chemotherapeutic agents and prostaglandin were reported. Eight (3.5%) technicians had required medical care for a needlestick injury and 2 (0.8%) had lost time at work. The approach to sharps handling and needlestick injury avoidance was poor and most needlestick injuries had not been reported to employers. Measures need to be undertaken to improve sharps handling practices to reduce the number of needlestick injuries among veterinary technicians.


Steady-state somatosensory evoked potentials: suitable brain signals for brain-computer interfaces?
One of the main issues in designing a brain-computer interface (BCI) is to find brain patterns, which could easily be detected. One of these pattern is the steady-state evoked potential (SSEP). SSEPs induced through the visual sense have already been used for brain-computer communication. In this work, a BCI system is introduced based on steady-state somatosensory evoked potentials (SSSEPs). Transducers have been used for the stimulation of both index fingers using tactile stimulation in the "resonance"-like frequency range of the somatosensory system. Four subjects participated in the experiments and were trained to modulate induced SSSEPs. Two of them learned to modify the patterns in order to set up a BCI with an accuracy of between 70% and 80%. Results presented in this work give evidence that it is possible to set up a BCI which is based on SSSEPs.


A cytometric bead assay for sensitive DNA detection based on enzyme-free signal amplification of hybridization chain reaction.
A versatile flow cytometric bead assay (CBA) is developed for sensitive DNA detection by integrating the advantages of hybridization chain reaction (HCR) for enzyme-free signal amplification, flow cytometry for robust and rapid signal readout as well as magnetic beads (MBs) for facile separation. In this HCR-CBA, a biotinylated hairpin DNA (Bio-H1) is firstly immobilized on streptavidin-functionalized MBs. Upon the addition of target DNA, each target would hybridize with one Bio-H1 to open its hairpin structure and subsequently initiate a cascade of hybridization events between two species of fluorescent DNA hairpin probes (H1*/H2*) to form a nicked double helical DNA structure, resulting in amplified accumulation of numerous fluorophores on the MBs. Finally, the fluorescent MBs are directly analyzed by flow cytometry. This technique enables quantitative analysis of the HCR products anchored on the MBs as a function of target DNA concentration, and analysis of each sample can be completed within few minutes. Therefore, the HCR-CBA approach provides a practical DNA assay with greatly improved sensitivity. The detection limit of a model DNA target is 0.5 pM (3σ), which is about 3 orders of magnitude lower compared with traditional hybridization methods without HCR. Furthermore, the signal of complementary target can be clearly distinguished from that of single-base mismatched sequences, indicating the high specificity of the HCR-CBA. Moreover, this strategy is also successfully applied to the DNA analysis in complex biological samples, showing great potential in gene analysis and disease diagnosis in clinical samples.


Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography.
Angiographic studies of the regression of coronary artery disease are invasive and costly, and they permit only limited assessment of changes in the extent of atherosclerotic disease. Electron-beam computed tomography (CT) is noninvasive and inexpensive. The entire coronary-artery tree can be studied during a single imaging session, and the volume of coronary calcification as quantified with this technique correlates closely with the total burden of atherosclerotic plaque. We conducted a retrospective study of 149 patients (61 percent men and 39 percent women; age range, 32 to 75 years) with no history of coronary artery disease who were referred by their primary care physicians for screening electron-beam CT. All patients underwent base-line scanning and follow-up assessment after a minimum of 12 months (range, 12 to 15), and a volumetric calcium score was calculated as an estimate of the total burden of plaque. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors was begun at the discretion of the referring physician. Serial measurements of low-density lipoprotein (LDL) cholesterol were obtained, and the change in the calcium-volume score was correlated with average LDL cholesterol levels. One hundred five patients (70 percent) received treatment with HMG-CoA reductase inhibitors, and 44 patients (30 percent) did not. At follow-up, a net reduction in the calcium-volume score was observed only in the 65 treated patients whose final LDL cholesterol levels were less than 120 mg per deciliter (3.10 mmol per liter) (mean [+/-SD] change in the score, -7+/-23 percent; P=0.01). Untreated patients had an average LDL cholesterol level of at least 120 mg per deciliter and at the time of follow-up had a significant net increase in mean calcium-volume score (mean change, +52+/-36 percent; P<0.001). The 40 treated patients who had average LDL cholesterol levels of at least 120 mg per deciliter had a measurable increase in mean calcium-volume score (25+/-22 percent, P<0.001), although it was smaller than the increase in the untreated patients. The extent to which the volume of atherosclerotic plaque decreased, stabilized, or increased was directly related to treatment with HMG-CoA reductase inhibitors and the resulting serum LDL cholesterol levels. These changes can be determined noninvasively by electron-beam CT and quantified with use of a calcium-volume score.


Can we identify the poorest quality of life? Assessing the importance of quality of life using the WHOQOL-100.
In this study, WHOQOL survey data obtained from 4802 sick and well participants in 15 countries were used to investigate the relationship between judgements about different dimensions of quality of life (QOL) (core scores) and the importance attributed to them. As a theoretical framework, we applied the WHOQOL Group's (1995) definition of QOL which indicates that those who report the very poorest QOL will be least likely to have met their own '...goals, expectations, standards and concerns'. Those with the poorest QOL would therefore be expected to show the biggest difference between core and importance scores, and therefore be distinguishable from respondents whose QOL was poor, better or best. The main effects from overall analyses confirmed that those reporting the largest negative differences tended to report the poorest QOL and also attached a high degree of importance to these dimensions. Evidence for a decreasing differential across the four groups (poorest to best) was confirmed for the majority (18) of facets. However facet level analyses comparing groups with different levels of QOL showed that only five facets distinguished those with the poorest QOL from those whose QOL was poor, so the theory is not well supported. Furthermore the contribution of core-importance facet differences reduced the overall prediction of QOL, when compared with a regression of core scores alone. Importance information about specific facets may have limited potential to be used alongside the main instrument to identify areas of the poorest QOL for clinical or social action.


Role of the hypothalamo-pituitary-liver axis in sex differences in susceptibility of the liver to toxic agents.
At birth testicular androgens irreversibly program brain centers involved in hypothalamopituitary control of hepatic sex-dependent steroid and drug metabolism. This imprinting process results in activation of a hypothalamic "feminostatin"-a secreting center that is turned on just before puberty. Feminostatin inhibits pituitary secretion of "feminizing factor," a pituitary hormone that feminizes the basal type of metabolism characterizing the liver of hypophysectomized and gonadectomized rats. Consequently, female rats that are devoid of feminostatin will secrete feminizing factor from the pituitary, leading to a feminine type of hepatic metabolism. Male rats have an active feminostatin-secreting center, and inhibition of pituitary feminizing factor release results in an autonomous type of liver metabolism. Female rats show a relative androgen unresponsiveness and seem incapable of releasing feminostatin after treatment with natural androgens, possibly because of more efficient metabolism (breakdown) of androgen in the female than in the male rat brain. Frontal deafferentation at the retrochiasmatic and suprachiasmatic level resulted in a complete "feminization" of hepatic steroid metabolism in male rats. Such an effect was also seen when lesions involving mainly the anterior periventricular hypothalamic area and the suprachiasmatic nucleus were performed in male rats. No effects were seen in analogous lesions in female rats in any of the cases studied. These findings suggest that a region including the anterior hypothalamic periventricular area, the suprachiasmatic nucleus and adjacent areas is involved in the control of hepatic steroid metabolism. It is postulated that the neuronal cell bodies that produce feminostatin have their origins in this area of the hypothalamus or may send axons through this area to the basal hypothalamus and thus directly or indirectly influence the anterior pituitary gland. Regulation by the central nervous system of a "lactogenic" (prolactin, Prl) receptor, present in the female rat liver, was also studied. This receptor is present in very low concentration or absent in the male rat. Anterior hypothalamic deafferentation at the retrochiasmatic level in male rats increased the hepatic Prl receptor concentration to the female level 3-4 days following the operation. A transection rostral to the suprachiasmatic nucleus had no effect on the concentration of Prl receptors in male animals. Our results demonstrate that the number of Prl receptors is regulated by the hypothalamo-pituitary system. The receptor-inducing pituitary factor might be related to the feminizing factor. Experiments were carried out to elucidate the nature of the Prl receptor-inducing pituitary factor. Human growth hormone (hGH) continuously administered was shown to induce Prl receptors in livers from male and female hypophysectomized-gonadectomized rats. The prolactin receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and thyroidectomized male rats. The induced Prl receptors in male rats had similar characteristics as hepatic Prl receptors in female rats. Also the endogenous rat hormones, rPrl and rGH, were administered in minipumps. In the concentration used (10 mug/mul), rPrl had no effect whereas rGH increased Prl receptor levels to approximately 37% of the female control level. These results indicate that GH or a peptide related to GH may be involved in the regulation of hepatic Prl receptors. The hypothalamo-pituitary-liver axis represents a new concept in endocrine regulation of drug toxicity. The male rat liver has been shown to be more susceptible than the female rat liver to the hepatocarcinogenic action of certain drugs, and it is conceivable that sex differences in the metabolic activation of the drugs in the liver may explain the greater sensitivity of male rats to chemically induced hepatocellular carcinoma. Similar sex differences in liver cancer incidence have been reported in the human.


Evaluation of the effect of co-financing on collaboration between health care, social services and social insurance in Sweden.
In this paper, we present an ongoing research project aimed to determine the impact of co-financing on collaboration around patients with musculoskeletal disorders. A trial legislation that allows the social insurance, social services and health care services to unite in co-financing under joint political steering has been tested in different areas in Sweden. In a series of studies, we compare collaboration processes and health outcome for patients with musculoskeletal disorders between health centres with co-financing projects and control health centres without co-financing projects. In this paper the studies are described and some preliminary results are discussed.


Nicotine relieves anxiogenic-like behavior in mice that overexpress the read-through variant of acetylcholinesterase but not in wild-type mice.
Stress increases vulnerability and causes relapse to drugs of abuse. The usually rare read-through variant of acetylcholinesterase (AChE-R) is causally involved in stress-related behaviors, and transgenic mice constitutively overexpressing AChE-R (TgR) show behaviors characteristic of chronic stress. We measured anxiety-like behavior on TgR and control mice under normal conditions and under long-term nicotine treatment. In addition, we measured epibatidine binding in the brain and transcription status in the striatum, using microarrays, in wild-type and TgR mice. TgR mice behaved as more anxious than controls, an effect normalized by long-term nicotine intake. In control mice, long-term nicotine augmented epibatidine binding in several areas of the brain, including the hippocampus and striatum. In TgR transgenics, long-term nicotine increased epibatidine binding in some areas but not in the hippocampus or the striatum. Because the striatum is involved in the mechanisms of drug addiction, we studied how the transgene affected striatal gene expression. Whole-genome DNA microarray showed that 23 transcripts were differentially expressed in TgR mouse striata, including 15 known genes, 7 of which are anxiety-related. Subsequent reverse-transcriptase polymerase chain reaction validated changes in 7 of those 15 genes, confirmed the increase trend in 5 more transcripts, and further revealed changes in 5 genes involved in cholinergic signaling. In summary, we found that nicotine acts as an anxiolytic in TgR mice but not in control mice and that continuously overexpressed AChE-R regulates striatal gene expression, modulating cholinergic signaling and stress-related pathways.


Identification of the 'Streptococcus anginosus group' by matrix-assisted laser desorption ionization--time-of-flight mass spectrometry.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) provides rapid, accurate and cost-effective identification of a range of bacteria and is rapidly changing the face of routine diagnostic microbiology. However, certain groups of bacteria, for example streptococci (in particular viridans or non-haemolytic streptococci), are less reliably identified by this method. We studied the performance of MALDI-TOF MS for identification of the 'Streptococcus anginosus group' (SAG) to species level. In total, 116 stored bacteraemia isolates identified by conventional methods as belonging to the SAG were analysed by MALDI-TOF MS. Partial 16S rRNA gene sequencing, supplemented with sialidase activity testing, was performed on all isolates to provide 'gold standard' identification against which to compare MALDI-TOF MS performance. Overall, 100 % of isolates were correctly identified to the genus level and 93.1 % to the species level by MALDI-TOF MS. However, only 77.6 % were correctly identified to the genus level and 59.5 % to the species level by a MALDI-TOF MS direct transfer method alone. Use of a rapid in situ extraction method significantly improved identification rates when compared with the direct transfer method (P<0.001). We recommend routine use of this method to reduce the number of time-consuming full extractions required for identification of this group of bacteria by MALDI-TOF MS in the routine diagnostic laboratory. Only 22 % (1/9) of Streptococcus intermedius isolates were reliably identified by MALDI-TOF MS to the species level, even after full extraction. MALDI-TOF MS reliably identifies S. anginosus and Streptococcus constellatus to the species level but does not reliably identify S. intermedius.


[Clinical history: the cornerstone for defining the cause of syncope].
Syncope is a transient loss of consciousness (LOC) due to transient global cerebral hypoperfusion characterized by rapid onset, short duration, and spontaneous complete recovery. However, there are no signs or symptoms specific for LOC due to global cerebral hypoperfusion, and other diseases, commonly defined as non-syncopal LOC, can induce transient LOC with other mechanisms. Moreover, since there are many causes of transient LOC, an adequate method in taking clinical history, which is the cornerstone of diagnosing patients with transient LOC, must be utilized. The first question to be answered is whether the patient had a real LOC, characterized by loss of postural control and unresponsiveness. Therefore, events with similar clinical features, such as falls, drop attack, etc., should be ruled out. Once a LOC is diagnosed, the questions that need an answer are: was LOC with rapid onset and short duration? Did the patient recover spontaneously? If the answers to these questions are positive (therefore, after exclusion of affections such as coma, cardiac arrest, etc.), we are dealing with a transient LOC, which can be an expression of syncope or non-syncopal LOC. From a methodological point of view, we should try to exclude a non-syncopal LOC. Once syncope is diagnosed, we should define the cause. There are some findings in the clinical history that can be considered diagnostic of the cause of syncope. In many other situations, the findings do not permit a definite diagnosis to be made but suggest some causes and, therefore, specific examinations.


Dissociation of activated protein C functions by elimination of protein S cofactor enhancement.
Activated protein C (APC) plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va and factor VIIIa and thus down-regulating thrombin generation. In addition, APC bound to the endothelial cell protein C receptor can initiate protease-activated receptor-1 (PAR-1)-mediated cytoprotective signaling. Protein S constitutes a critical cofactor for the anticoagulant function of APC but is not known to be involved in regulating APC-mediated protective PAR-1 signaling. In this study we utilized a site-directed mutagenesis strategy to characterize a putative protein S binding region within the APC Gla domain. Three single amino acid substitutions within the APC Gla domain (D35T, D36A, and A39V) were found to mildly impair protein S-dependent anticoagulant activity (<2-fold) but retained entirely normal cytoprotective activity. However, a single amino acid substitution (L38D) ablated the ability of protein S to function as a cofactor for this APC variant. Consequently, in assays of protein S-dependent factor Va proteolysis using purified proteins or in the plasma milieu, APC-L38D variant exhibited minimal residual anticoagulant activity compared with wild type APC. Despite the location of Leu-38 in the Gla domain, APC-L38D interacted normally with endothelial cell protein C receptor and retained its ability to trigger PAR-1 mediated cytoprotective signaling in a manner indistinguishable from that of wild type APC. Consequently, elimination of protein S cofactor enhancement of APC anticoagulant function represents a novel and effective strategy by which to separate the anticoagulant and cytoprotective functions of APC for potential therapeutic gain.


Scanning electron, light, and transmission electron microscopy of intestine of gnotobiotic calf.
Adjacent areas of upper, middle, and lower parts of the small intestine and spiral colon from a 48-hour-old gnotobiotic calf were compared by scanning electron microscopy (SEM), light microscopy (LM), and transmission electron microscopy (TEM). As visualized by all 3 methods, small intestinal histologic features, except for apical location of villous epithelial cell nuclei in sections of upper and middle parts of small intestine, were similar to those described for other species. The colonic surface visualized by SEM was composed of flattened ridges separated by furrows into which opened the crypts of Lieberkühn. The epithelial surfaces of the ridges and the furrows had an extensive microvillous covering and scattered goblet cell openings.


Plasma 25(OH)D Concentrations and Gestational Diabetes Mellitus among Pregnant Women in Taiwan.
Vitamin D's function in the development of gestational diabetes mellitus (GDM) is not consistent in the literature. We examined the association between maternal plasma 25(OH)D concentration and GDM risk. A national cross-sectional study (1497 pregnant women) was conducted between 2017 and 2019 across Taiwan. Blood samples were drawn at recruitment to assess 25(OH)D concentrations, including vitamin D deficiency (VDD) (<20 ng/mL), insufficiency (<32 ng/mL), and sufficiency (≥32 ng/mL). GDM was detected from 24 to 28 weeks of gestation with the results extracted from the antenatal visit records. The prevalence of GDM was 2.9%. Logistic model analysis showed that 25(OH)D concentrations were not significantly associated with the risk of GDM (adjusted odds ratio (AOR) = 0.97, p = 0.144). However, subjects with VDD had a significantly greater risk of GDM (AOR = 2.26, p = 0.041), but not in those with vitamin D insufficiency (AOR = 1.20, p = 0.655). Furthermore, cubic piecewise spline regression was used to explore the relationship between five-unit intervals of 25(OH)D and the predicted probability of GDM. As the proportion of GDM increased for low 25(OH)D concentrations, it decreased at moderate concentrations and increased again at higher concentrations. These findings revealed a nonlinear relationship between 25(OH)D and GDM risk. VDD would be risky for GDM occurrence.


Current management of fecal incontinence: choosing amongst treatment options to optimize outcomes.
The severity of fecal incontinence widely varies and can have dramatic devastating impacts on a person's life. Fecal incontinence is common, though it is often under-reported by patients. In addition to standard treatment options, new treatments have been developed during the past decade to attempt to effectively treat fecal incontinence with minimal morbidity. Non-operative treatments include dietary modifications, medications, and biofeedback therapy. Currently used surgical treatments include repair (sphincteroplasty), stimulation (sacral nerve stimulation or posterior tibial nerve stimulation), replacement (artificial bowel sphincter or muscle transposition) and diversion (stoma formation). Newer augmentation treatments such as radiofrequency energy delivery and injectable materials, are minimally invasive tools that may be good options before proceeding to surgery in some patients with mild fecal incontinence. In general, more invasive surgical treatments are now reserved for moderate to severe fecal incontinence. Functional and quality of life related outcomes, as well as potential complications of the treatment must be considered and the treatment of fecal incontinence must be individualized to the patient. General indications, techniques, and outcomes profiles for the various treatments of fecal incontinence are discussed in detail. Choosing the most effective treatment for the individual patient is essential to achieve optimal outcomes in the treatment of fecal incontinence.


Intrapartum management of the fetus with idiopathic hydrocephalus.
Intrapartum management of fetal idiopathic hydrocephalus (IH) diagnosed late in pregnancy is controversial. Normal intellectual development is possible in many of these infants when neurosurgical intervention is undertaken in the neonatal period. Aggressive intrapartum management is indicated in most of these cases regardless of cortical mantle thickness. However, routine abdominal delivery is associated with increased maternal morbidity without proven fetal benefit. Transvaginal cephalocentesis for fetuses with IH in the cephalic presentation, followed by spontaneous vaginal delivery, lessens maternal morbidity and is compatible with good neonatal outcome.


Electronic claims can be a remedy for cash flow troubles.
Electronic claims processing systems and their related applications have the potential to speed payments from insurers and other payers to healthcare providers. Various services are available, including direct data entry terminals, software created by hospital information system vendors, and electronic claims processing clearinghouses. A clearinghouse allows providers to interface with insurer databases.


Incorporation of polymer microspheres within fibrin scaffolds for the controlled delivery of FGF-1.
The purpose of this work was to examine the feasibility of a hybrid scaffold in which fibroblast growth factor-1 (FGF-1)-encapsulated microspheres are embedded within a fibrin gel. Such a tissue-engineered scaffold could be incorporated into surgical procedures to promote healing while simultaneously delivering therapeutic agents that promote angiogenesis. Fibrin has been extensively studied as an adhesive in plastic and reconstructive surgery and the enhancement of wound healing with embedded growth factors is desirable. We report the release of a fluorescently-labeled model protein, bovine serum albumin (BSA-FITC), from poly(D,L-lactic-co-glycolic acid) microspheres embedded in the fibrin scaffold. The protein release was found to be significantly delayed as compared to microspheres alone during the initial 24 h of release. Additionally, FGF-1 was examined for efficient incorporation into these scaffolds as a potential mitogen for fibroblasts. The optimal concentration of FGF-1 in the media that enhanced NIH-3T3 fibroblast proliferation over 48 h was determined to be 0.1 microg/ml. The release of FGF-1 from microspheres embedded in fibrin gels was compared to FGF-1-encapsulated microspheres alone. The release of FGF-1 from the microsphere/scaffolds was delayed as compared to the release of FGF-1 from microspheres alone. This novel hybrid fibrin/microsphere scaffold is a feasible delivery system for growth factors.


Preliminary report of HLA (DNA) typing of Nigerians using sequence-specific primer technique.
This communication is an attempt to present the experience and a preliminary report of results over a one-year period. From December 2011 to December 2012, a prospective determination of the HLA types of 20 individuals referred to the Tissue Typing Laboratory of the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife was done. These consisted of prospective transplant recipients, their donors, and a migrant pair for kinship determination. DNA was extracted from the client's peripheral blood sample, using the QIAmp Blood DNA Mini kit, (Qiagen). PCR was done using OlerupR low-resolution PCR-SSP typing kit. The PCR product was resolved in 2% agarose gel, and the bands visualised under UV light. The HLA types were determined using provided tables and/or Helmberg software. Data were presented using descriptive statistics whileHLA antigen frequency (AF) was expressed in percentage and gene frequency (GF) was determined using square root method (1-(1-AF)1/2). A total of 20 individuals (13males and 7females) consisting of seven renal transplant recipients and seven prospective donors; a stem cell recipient and three donors and a migrant pair for kinship determination were typed. Age ranged from 4-65 years. 44 HLA alleles were detected, while HLA-A, B, C, DRB1 and DQB1 were 7, 10, 11, 8, 8 alleles respectively. The alleles were heterogeneous in distribution while 6 antigens (HLA-A*02, B*30, C*15, DRB1*03, DRB1*08 and DQB1*06) were having frequencies e"25%. This report confirms that DNA-based HLA typing is feasible locally, andit was observed that renal transplantation procedure is the most frequent indication. The HLA antigens observed to have very high frequencies (e"25% frequency) in this population were HLA-A*02, B*30, C*15, DRB1*03, DRB1*08 and DQB1*06. There is a strong need to develop a broad-based HLA data bank for Nigeria to further strengthening her transplantation programmes.


Right diagnosis, wrong care: patient management reasoning errors in emergency care computer-based case simulations.
The pervasiveness of reasoning errors in emergency care (EC) is commonly acknowledged in clinical research. Much of this work has focused on diagnostic errors; yet, in EC, providing a specific diagnosis is generally secondary to managing the patient. To gain insights into non-diagnostic, treatment-related errors, we presented EC residents with computer-based case simulations and recorded their actions and verbalized thoughts. Nearly all participants diagnosed both study cases correctly yet made a variety of patient management errors, some with serious consequences. More substantial errors could be classified as stemming from incorrect patient status and treatment inferences. These EC reasoning errors are discussed within the framework of underlying cognitive processes.


Recombination between homologous chromosomes induced by unrepaired UV-generated DNA damage requires Mus81p and is suppressed by Mms2p.
DNA lesions caused by UV radiation are highly recombinogenic. In wild-type cells, the recombinogenic effect of UV partially reflects the processing of UV-induced pyrimidine dimers into DNA gaps or breaks by the enzymes of the nucleotide excision repair (NER) pathway. In this study, we show that unprocessed pyrimidine dimers also potently induce recombination between homologs. In NER-deficient rad14 diploid strains, we demonstrate that unexcised pyrimidine dimers stimulate crossovers, noncrossovers, and break-induced replication events. The same dose of UV is about six-fold more recombinogenic in a repair-deficient strain than in a repair-proficient strain. We also examined the roles of several genes involved in the processing of UV-induced damage in NER-deficient cells. We found that the resolvase Mus81p is required for most of the UV-induced inter-homolog recombination events. This requirement likely reflects the Mus81p-associated cleavage of dimer-blocked replication forks. The error-free post-replication repair pathway mediated by Mms2p suppresses dimer-induced recombination between homologs, possibly by channeling replication-blocking lesions into recombination between sister chromatids.


c-Myc in breast cancer.
Ever since Bishop and his co-workers discovered the c-myc gene in the late 1970s (Bishop 1982), voluminous literature has documented its central role in proliferation and malignant transformation of human and animal cells (Amati et al. 1998, Bouchard et al. 1998, Dang et al. 1999). Most, if not all, types of human malignancy have been reported to have amplification and/or overexpression of this gene, although the frequency of these alterations varies greatly among different reports (Nesbit et al. 1999). In 1992, researchers started to realize that aberrant expression of c-myc could cause apoptosis (Evan et al. 1992, Shi et al. 1992), although the phenomenon had actually been observed much earlier (Wurm et al. 1986). Studies in recent years have further shown that the c-myc gene regulates growth, both in the sense of cell size and in the context of tissue differentiation (Gandarillas & Watt 1997, Iritani & Eisenman 1999, Johnston et al. 1999, Schmidt 1999, Schuhmacher et al. 1999). Thus, it is now known that the c-myc gene participates in most aspects of cellular function, including replication, growth, metabolism, differentiation, and apoptosis (Packham & Cleveland 1995, Hoffman & Liebermann 1998, Dang 1999, Dang et al. 1999, Elend & Eilers 1999, Prendergast 1999). How the c-Myc protein may be specifically directed to perform one, but not the others, of these functions is still obscure, despite the fact that the relevant literature has been accumulating at a fast pace in the past two decades. This review focuses on the profound roles of c-Myc in breast cancer and in the actions of the hormones that are eitologically related to breast cancer.


THE ROLE OF TEMPERATE BACTERIOPHAGE IN THE PRODUCTION OF ERYTHROGENIC TOXIN BY GROUP A STREPTOCOCCI.
Non-lysogenic, non-toxinogenic Group A streptococci when infected by temperate bacteriophages isolated from known scarlatinal toxin-producing strains acquire the capacity to form erythrogenic toxin. This toxin causes a characteristic erythematous reaction in the skin of rabbits and is readily neutralizable by standard scarlatinal antitoxins. The production of toxin appears to be related to the synthesis of mature phage particles since ultraviolet enhancement of phage production results in a concomitant increase in toxin titer. In contrast, there is no increase in the production of another extracellular product, deoxyribonuclease, by these lysogenized streptococci. Furthermore, cellular disruption studies indicate that the toxin probably does not exist in a preformed state within the cell. Double diffusion reactions in agar indicate that a newly formed protein appears in the lysogenic culture filtrate and is absent in the non-lysogenic filtrates.


Divergence in age patterns of mortality change drives international divergence in lifespan inequality.
In the past six decades, lifespan inequality has varied greatly within and among countries even while life expectancy has continued to increase. How and why does mortality change generate this diversity? We derive a precise link between changes in age-specific mortality and lifespan inequality, measured as the variance of age at death. Key to this relationship is a young-old threshold age, below and above which mortality decline respectively decreases and increases lifespan inequality. First, we show for Sweden that shifts in the threshold's location have modified the correlation between changes in life expectancy and lifespan inequality over the last two centuries. Second, we analyze the post-World War II (WWII) trajectories of lifespan inequality in a set of developed countries-Japan, Canada, and the United States-where thresholds centered on retirement age. Our method reveals how divergence in the age pattern of mortality change drives international divergence in lifespan inequality. Most strikingly, early in the 1980s, mortality increases in young U.S. males led to a continuation of high lifespan inequality in the United States; in Canada, however, the decline of inequality continued. In general, our wider international comparisons show that mortality change varied most at young working ages after WWII, particularly for males. We conclude that if mortality continues to stagnate at young ages yet declines steadily at old ages, increases in lifespan inequality will become a common feature of future demographic change.


The value of microscopic features in the examination of human head hairs: statistical analysis of questionnaire returns.
There is an apparent diversity of opinion with respect to the probative value of hair in the United Kingdom and in North America. A questionnaire was devised and widely circulated in an attempt to discover the reasons behind this diversity and to seek the views of a broad range of hair examiners. This paper reports on the statistical analyses of the answers to the closed form questions. The majority of replies to most questions favored the number of categories given in the questionnaire. The general impression is that U.K. scientists tend to want fewer categories for classification of microscopic features than the North Americans. The largest divisions of opinion concerned pigment distribution and density and the medulla, where North American scientists want more categories for classification and the U.K. scientists fewer. The implications of these results in the choice and description of features to be examined in human hairs is considered in the second paper concerned with this questionnaire.


Determination of regional blood volume and intra-extracapillary water exchange in human myocardium using Feruglose: First clinical results in patients with coronary artery disease.
The aim of this pilot study in humans was to investigate the effect of an intravascular contrast agent (CA) on relaxation rate in myocardium (R(1,myo)) in the steady state. The dependence of R(1,myo) on R(1,blood) was characterized and compared with a theoretical model which allowed determination of the intra- extracapillary water proton exchange frequency (f = 0.48 s(-1)) and the intracapillary blood volume (RBV = 12.9 %). A linear response range of DeltaR(1,myo) on DeltaR(1,blood) was estimated which in future studies will allow the determination of RBV with intravascular CA.


DNA Methylation Controls Metastasis-Suppressive 14q32-Encoded miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer. In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2'-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs. SIGNIFICANCE: This study investigates epigenetic regulation of metastasis-suppressive miRNAs and the effect on metastasis.


Parasitological efficacy of antimalarials in the treatment and prevention of falciparum malaria in pregnancy 1998 to 2009: a systematic review.
Pregnant women are at increased risk from malaria. Resistance to all classes of antimalarials has affected the treatment and prevention of malaria in pregnancy. To review the therapeutic efficacy of antimalarials used for treatment and intermittent preventive treatment (IPT) in pregnancy. We searched MEDLINE and the Cochrane Library between January 1998 and December 2009 for publications using the medical subject headings: efficacy, antimalarials, malaria, pregnancy, pharmacokinetics, treatment, IPT and placenta positive. In May 2010 we searched the register of clinical trials (http://clinicaltrials.gov/) and of WHO (http://apps.who.int/trialsearch/) using 'malaria', and 'pregnancy' and 'treatment'. We identified 233 abstracts, reviewed 83 full text articles and included 60 studies. Two authors entered extracted data to an excel spreadsheet. Parasitological failure rates, placenta positivity rates (assessed by microscopy) or both were reported in 44% (21/48), 46% (22/48) and 10% (5/48) of articles, respectively. Most pharmacokinetic studies (9/12) suggested dose optimisation. In 23 treatment studies 17 different antimalarial drugs were delivered in 53 study arms; 43.4% (23/53) reported a failure rate of < 5%; 83.3% of sulphadoxine-pyrimethamine (SP) arms and 9% of artemisinin combination therapy (ACT) arms had failure rates ≥ 10%. Placenta-positive rates (mostly reported in the context of IPT in pregnancy) were > 10% in 68% (23/34) of SP trial arms and > 15% in all seven chloroquine arms. The ACT provided lower parasitological failure and gametocyte carriage rates. Drugs used in pregnancy should aim for 95% efficacy but many currently deployed regimens are associated with much lower cure rates.


Evolution of the temporal persistence of immune protection.
The evolution of resistance to parasites has been the focus of numerous theoretical studies and several mechanisms, ranging from innate to acquired immune responses, have been considered. Life-history theory predicts that long-lived species should invest more resources into maintenance and immunity than short-lived species. Here, we provide further theoretical and empirical support for this hypothesis. First, an analysis of the evolution of the persistence of immune protection in a theoretical framework accounting for maternal transfer of immunity reveals that longer-lived hosts are expected to invest in more persistent intragenerational and transgenerational immune responses. Controlling for phylogenetic structure and for the confounding effect of catabolic activity, we further showed that immunoglobulin half-life and longevity are positively correlated in mammal species. Our study confirms that persistence of immunity has evolved as part of elaborate anti-parasitic defence strategies.


How attention influences perceptual decision making: Single-trial EEG correlates of drift-diffusion model parameters.
Perceptual decision making can be accounted for by drift-diffusion models, a class of decision-making models that assume a stochastic accumulation of evidence on each trial. Fitting response time and accuracy to a drift-diffusion model produces evidence accumulation rate and non-decision time parameter estimates that reflect cognitive processes. Our goal is to elucidate the effect of attention on visual decision making. In this study, we show that measures of attention obtained from simultaneous EEG recordings can explain per-trial evidence accumulation rates and perceptual preprocessing times during a visual decision making task. Models assuming linear relationships between diffusion model parameters and EEG measures as external inputs were fit in a single step in a hierarchical Bayesian framework. The EEG measures were features of the evoked potential (EP) to the onset of a masking noise and the onset of a task-relevant signal stimulus. Single-trial evoked EEG responses, P200s to the onsets of visual noise and N200s to the onsets of visual signal, explain single-trial evidence accumulation and preprocessing times. Within-trial evidence accumulation variance was not found to be influenced by attention to the signal or noise. Single-trial measures of attention lead to better out-of-sample predictions of accuracy and correct reaction time distributions for individual subjects.


The effects of cognitive behavioral therapy on health-related quality of life, anxiety, depression, illness perception, and in atrial fibrillation patients: a six-month longitudinal study.
Atrial fibrillation (AF) often leads to an impaired Health-Related Quality of Life (HRQoL) in many patients. Moreover, psychological factors such as depression, anxiety, and illness perception have been found to significantly correlate with HRQoL. This study aims to evaluate the long-term effectiveness of Cognitive Behavioral Therapy (CBT) in enhancing HRQoL and mitigating psychological distress among AF patients. Employing a prospective, open design with pseudo-randomization, this study encompassed pre-tests, post-treatment evaluations, and a 6-month follow-up. A total of 102 consecutive patients diagnosed with paroxysmal AF were initially enrolled. Out of these, 90 were assigned to two groups; one to receive a 10-week CBT treatment specifically focusing on anxiety, and the other to receive standard care. Outcome measures were evaluated using tools such as the Item Short Form Health Survey (SF-12), General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), University of Toronto Atrial Fibrillation Severity Scale (AFSS), and Brief Illness Perception Questionnaire (BIPQ). These assessments were conducted at pre-treatment, post-treatment, and at the 6-month follow-up mark. We explored the effectiveness of CBT using Generalized Estimating Equations (GEE). Our analysis revealed a notable improvement in the CBT group relative to the control group. All metrics displayed consistent improvement across a 6-month duration. At the 6-month checkpoint, the CBT group exhibited a more favorable SF-12 Mental Component Score (MCS) (50.261 ± 0.758 vs. 45.208 ± 0.887, p < 0.001), reduced GAD-7 (4.150 ± 0.347 vs. 8.022 ± 0.423, p < 0.001), BIPQ (34.700 ± 0.432 vs. 38.026 ± 0.318, p < 0.001), and AFSS (9.890 ± 0.217 vs. 10.928 ± 0.218, p = 0.001) scores when compared to the TAU group. Conversely, the SF-12 PCS (44.212 ± 0.816 vs. 47.489 ± 0.960, p = 0.139) and PHQ-9 scores (8.419 ± 0.713 vs. 10.409 ± 0.741, p = 0.794) manifested no significant difference between the two groups. The findings suggest that CBT is effective in improving HRQoL and reducing psychological distress among patients with AF at 6 month follow-up. This highlights the potential benefits of integrating CBT into the therapeutic regimen for AF patients. Retrospectively registered with ClinicalTrials.gov (NCT05716828). The date of registration : 5 June 2023.


Brief Cost Analysis of Surgical Personal Protective Equipment During the COVID-19 Pandemic.
This study aimed to compare the costs incurred and saved from universal use of N95 respirators with surgical masks for operating room providers in the United States during the COVID-19 pandemic. We built a decision analytic model to compare direct medical costs of healthcare workers (HCWs) infected with COVID-19 during operating room procedures from expected transmission when using an N95 respirator relative to a surgical mask. We also examined quarantine costs. Results varied depending upon prevalence and false-negative rates of tests, but if N95 respirators reduce transmission by 2.8%, prevalence is at 1%, and testing yields 20% false negatives, providers should be willing to pay an additional $0.64 per HCW for the additional protection. Under this scenario, approximately 11 COVID-19 cases would be averted among HCWs per day. Potential savings depend on disease prevalence, rate of asymptomatic patients with COVID-19, accuracy of testing, the marginal cost of respirators, and the quarantine period. We provide a range of calculations to show under which conditions N95 respirators are cost saving.


The Antibacterial Resistance Leadership Group: Scientific Advancements and Future Directions.
In this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.


[Effect of propranolol in silent myocardial ischemia induced by anthracyclines].
Effect of propranolol on pain-free myocardial ischemia induced by exposure to anthracyclinic antibiotics were assessed by findings from Holter ECG monitoring in 36 patients with acute lymphoblast leukemia against the background of a complete clinical-and-hematological remission. In those patients having received small cumulative doses of anthracyclines (less than 550 mg/m2) in whom depression of ST-segment had an apparent tachydependent character the severity of pain-free ischemia was shown to be alleviated by a 3-week intake of propranolol. Remarkably, those patients with "silent" myocardial ischemia having received high cumulative doses of cytostatics (more than 550 mg/m2) did not derive much benefit from beta-adrenoblocker, which fact might be associated with the presence in this case of ischemic episodes unrelated to tachycardia.


Evidence for a novel gene expression program in peripheral blood mononuclear cells from Mycobacterium avium subsp. paratuberculosis-infected cattle.
A bovine-specific cDNA microarray system was used to compare gene expression profiles of peripheral blood mononuclear cells (PBMCs) from control uninfected (n = 4) and Johne's disease-positive (n = 6) Holstein cows. Microarray experiments were designed so that for each animal, a direct comparison was made between PBMCs stimulated in vitro with Mycobacterium avium subsp. paratuberculosis and PBMCs stimulated with phosphate-buffered saline (nil-stimulated PBMCs). As expected, M. avium subsp. paratuberculosis stimulation of infected cow PBMCs enhanced expression of gamma interferon transcripts. In addition, expression of 15 other genes was significantly affected (>1.25-fold change; P < 0.05) by in vitro stimulation with M. avium subsp. paratuberculosis. Similar treatment of control cow PBMCs with M. avium subsp. paratuberculosis resulted in significant changes in expression of 13 genes, only 2 of which were also affected in PBMCs from the infected cow PBMCs. To compare gene expression patterns in the two cow infection groups (infected cows and uninfected cows), a mixed-model analysis was performed with the microarray data. This analysis indicated that there were major differences in the gene expression patterns between cells isolated from the two groups of cows, regardless of in vitro stimulation. A total of 86 genes were significantly differentially expressed (P < 0.01) in M. avium subsp. paratuberculosis-stimulated PBMCs from infected cows compared to expression in similarly treated PBMCs from control cows. Surprisingly, a larger number of genes (110 genes) were also found to be significantly differentially expressed (P < 0.01) in nil-stimulated cells from the two infection groups. The expression patterns of selected genes were substantiated by quantitative real-time reverse transcriptase PCR. Flow cytometric analysis indicated that there were no gross differences in the relative populations of major immune cell types in PBMCs from infected and control cows. Thus, data presented in this report indicate that the gene expression program of PBMCs from M. avium subsp. paratuberculosis-infected cows is inherently different from that of cells from control uninfected cows.


Prevalence of Periodontal Disease in Type 2 Diabetes Mellitus Patients: A Cross-sectional Study.
The aim of this study was to determine the prevalence of periodontal disease in type 2 diabetes mellitus (T2DM) patients of North India. A total of 500 patients fulfilling the selection criteria were initially given a health questionnaire to gather information regarding their demographic characteristics, attitude for oral hygiene, and disease status. Based on eligibility 427 patients were finally recruited for statistical analysis. A partial-mouth periodontal examination (PMPE) protocol which assessed one maxillary quadrant and one mandibular quadrant was used to examine three fixed sites per tooth (mesiobuccal, midbuccal, and distobuccal). Gingival Index, Oral Hygiene Index-Simplified, Debris Index-Simplified, Calculus Index-Simplified (CI-S), probing pocket depth, and clinical attachment level were examined. More than 90% (95.1%) of the total diabetic participants had some degree of periodontal destruction. Of the total population, 27.1% of participants had good oral hygiene, 68.8% had fair oral hygiene, and 3.9% had poor oral hygiene status. The prevalence of severe periodontitis in participants with good, fair, and poor oral hygiene status was reported as 0.8%, 17%, and 29.4%, respectively. The prevalence of severe periodontitis in participants with good, fair, and poor oral hygiene status with poor glycemic control (glycated hemoglobin ≥8%) was 2.5%, 28.1%, and 30.7%, respectively. This single-centered cross-sectional study represents that more than 95% of type 2 diabetic patients have some periodontal destruction. These results may act as baseline data to promote the collaborative integrated management of diabetes for reducing its burden on society.


Enhancing a de novo enzyme activity by computationally-focused ultra-low-throughput screening.
Directed evolution has revolutionized protein engineering. Still, enzyme optimization by random library screening remains sluggish, in large part due to futile probing of mutations that are catalytically neutral and/or impair stability and folding. FuncLib is a novel approach which uses phylogenetic analysis and Rosetta design to rank enzyme variants with multiple mutations, on the basis of predicted stability. Here, we use it to target the active site region of a minimalist-designed, de novo Kemp eliminase. The similarity between the Michaelis complex and transition state for the enzymatic reaction makes this system particularly challenging to optimize. Yet, experimental screening of a small number of active-site variants at the top of the predicted stability ranking leads to catalytic efficiencies and turnover numbers (∼2 × 104 M-1 s-1 and ∼102 s-1) for this anthropogenic reaction that compare favorably to those of modern natural enzymes. This result illustrates the promise of FuncLib as a powerful tool with which to speed up directed evolution, even on scaffolds that were not originally evolved for those functions, by guiding screening to regions of the sequence space that encode stable and catalytically diverse enzymes. Empirical valence bond calculations reproduce the experimental activation energies for the optimized eliminases to within ∼2 kcal mol-1 and indicate that the enhanced activity is linked to better geometric preorganization of the active site. This raises the possibility of further enhancing the stability-guidance of FuncLib by computational predictions of catalytic activity, as a generalized approach for computational enzyme design.


Employment and work schedule are related to telomere length in women.
To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. This cross-sectional analysis of 608 women aged 35-74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of -329 bp (95% CI -110 to -548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of -472 bp, 95% CI -786 to -158 for 20+ vs 1-5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL.


Mmp25β facilitates elongation of sensory neurons during zebrafish development.
Matrix metalloproteinases (MMPs) are a large and complex family of zinc-dependent endoproteinases widely recognized for their roles in remodeling the extracellular matrix (ECM) during embryonic development, wound healing, and tissue homeostasis. Their misregulation is central to many pathologies, and they have therefore been the focus of biomedical research for decades. These proteases have also recently emerged as mediators of neural development and synaptic plasticity in vertebrates, however, understanding of the mechanistic basis of these roles and the molecular identities of the MMPs involved remains far from complete. We have identified a zebrafish orthologue of mmp25 (a.k.a. leukolysin; MT6-MMP), a membrane-type, furin-activated MMP associated with leukocytes and invasive carcinomas, but which we find is expressed by a subset of the sensory neurons during normal embryonic development. We detect high levels of Mmp25β expression in the trigeminal, craniofacial, and posterior lateral line ganglia in the hindbrain, and in Rohon-Beard cells in the dorsal neural tube during the first 48 h of embryonic development. Knockdown of Mmp25β expression with morpholino oligonucleotides results in larvae that are uncoordinated and insensitive to touch, and which exhibit defects in the development of sensory neural structures. Using in vivo zymography, we observe that Mmp25β morphant embryos show reduced Type IV collagen degradation in regions of the head traversed by elongating axons emanating from the trigeminal ganglion, suggesting that Mmp25β may play a pivotal role in mediating ECM remodeling in the vicinity of these elongating axons.


Coalescent-based hypothesis testing supports multiple Pleistocene refugia in the Pacific Northwest for the Pacific giant salamander (Dicamptodon tenebrosus).
Phylogeographic patterns of many taxa are explained by Pleistocene glaciation. The temperate rainforests within the Pacific Northwest of North America provide an excellent example of this phenomenon, and competing phylogenetic hypotheses exist regarding the number of Pleistocene refugia influencing genetic variation of endemic organisms. One such endemic is the Pacific giant salamander, Dicamptodon tenebrosus. In this study, we estimate this species' phylogeny and use a coalescent modeling approach to test five hypotheses concerning the number, location and divergence times of purported Pleistocene refugia. Single refugium hypotheses include: a northern refugium in the Columbia River Valley and a southern refugium in the Klamath-Siskiyou Mountains. Dual refugia hypotheses include these same refugia but separated at varying times: last glacial maximum (20,000 years ago), mid-Pleistocene (800,000 years ago) and early Pleistocene (1.7 million years ago). Phylogenetic analyses and inferences from nested clade analysis reveal distinct northern and southern lineages expanding from the Columbia River Valley and the Klamath-Siskiyou Mountains, respectively. Results of coalescent simulations reject both single refugium hypotheses and the hypothesis of dual refugia with a separation date in the late Pleistocene but not hypotheses predicting dual refugia with separation in early or mid-Pleistocene. Estimates of time since divergence between northern and southern lineages also indicate separation since early to mid-Pleistocene. Tests for expanding populations using mismatch distributions and 'g' distributions reveal demographic growth in the northern and southern lineages. The combination of these results provides strong evidence that this species was restricted into, and subsequently expanded from, at least two Pleistocene refugia in the Pacific Northwest.


Retinal Artery Contraction After Phenylephrine as a Cardiovascular Risk Biomarker.
We investigated the in vivo changes of artery diameter (AD) and vein diameter (VD) after topical phenylephrine 2.5% instillation, and its relationship with the Systematic Coronary Risk Evaluation (SCORE). This is a cross-sectional study. Healthy control patients were included. All of the participants underwent enhanced depth imaging by spectral-domain optical coherence tomography before and 30 minutes after phenylephrine instillation, using eye-tracking and follow-up software. Changes in AD and VD were assessed. The study included 45 eyes of 45 patients (14 males and 31 females). The mean age was 58.6 ± 15.1 years (26-88 years). Mean SCORE risk estimation value was 2.0 (0-14). No significant correlation was found between pre-phenylephrine AD or VD with age (p=0.237 and p=0.821, respectively), SCORE (p=0.545 and p=0.723, respectively). AD significant thinned after phenylephrine (p<0.001), whereas no significant changes could be depicted in VD (p=0.474). Changes in AD after phenylephrine were significantly related with SCORE risk estimation (p=0.035). Discordantly, changes in VD after phenylephrine were not significantly related with SCORE (p=0.505). As a significant thinning of AD occurred following phenylephrine instillation, and as the magnitude of this thinning is related with SCORE, it is useful to test the retinal artery contraction to infer the cardiovascular health status.


Economic evaluation in the context of rare diseases: is it possible?
This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.


Rational harmonic mode-locking pulse quality of the dark-optical-comb injected semiconductor optical amplifier fiber ring laser.
We study the rational harmonic mode-locking (RHML) order dependent pulse shortening force and dynamic chirp characteristics of a gain-saturated semiconductor optical amplifier fiber laser (SOAFL) under dark-optical-comb injection, and discuss the competition between mode-locking mechanisms in the SOAFL at high-gain and strong optical injection condition at higher RHML orders. The evolutions of spectra, mode-locking and continuous lasing powers by measuring the ratio of DC/pulse amplitude and the pulse shortening force (I(pulse)/P(avg)(2) ) are performed to determine the RHML capability of SOAFL. As the rational harmonic order increases up to 20, the spectral linewidth shrinks from 12 to 3 nm, the ratio of DC/pulse amplitude enlarges from 0.025 to 2.4, and the pulse-shortening force reduces from 0.9 to 0.05. At fundamental and highest RHML condition, we characterize the frequency detuning range to realize the mode-locking quality, and measure the dynamic frequency chirp of the RHML-SOAFL to distinguish the linear and nonlinear chirp after dispersion compensation. With increasing RHML order, the pulsewidth is broadened from 4.2 to 26.4 ps with corresponding chirp reducing from 0.7 to 0.2 GHz and linear/nonlinear chirp ratio changes from 4.3 to 1.3, which interprets the high-order chirp becomes dominates at higher RHML orders.


Evaluation of a long-term community based rehabilitation program for adult stroke survivors.
To evaluate the functional status, leisure activity and satisfaction in adult stroke survivors participating in a community rehabilitation program, and to compare these outcomes with stroke survivors not attending any program. Subjects included in the study were survivors of a first stroke that received inpatient rehabilitation and were living at home at least one year post onset. Twenty seven were participants in a community rehabilitation program and 56 were non-participants. The outcome measures were the Stroke impact Scale (SIS), Functional Independence Measure (FIM), Instrumental Activities of Daily Living Questionnaire (IADLq), Activity Card Sort (ACS), and the Life-Satisfaction questionnaire (Li-Sat-9). The results revealed severe stroke impact and low functioning in activities of daily living in the participant group, yet the level of participation in leisure activities improved significantly after attending the program (t=-8.1, p=0.000). The comparison with the non participant group revealed that participants were even more disabled in basic activities of daily living (as measured by the FIM) than non-participants (t=-3.1, p=0.004). However, the satisfaction rates of the participants were significantly higher than non participants from "life as a whole" and from their leisure situation (p<0.05). Stroke survivors participating in a community based rehabilitation program did not show an advantage in terms of disability levels over non-participants. However, their activity level increased due to the program and their satisfaction scores were higher than non-participants.


Evaluation of Serious Postmarket Safety Signals Within 2 Years of FDA Approval for New Cancer Drugs.
We examined how often new serious safety signals were identified by the U.S. Food and Drug Administration within the first 2 years after approval for new molecular entities (NMEs) for treatment of cancer that required specific regulatory actions described here. We identified, for all NMEs approved for treatment of cancer or malignant hematology indications between 2010 and 2016, substantial safety-related changes within the first 2 years after approval, which included a new Boxed Warning or Warning and Precaution; requirement for (or modification of existing) Risk Evaluation and Mitigation Strategies (REMS); and withdrawal from the market because of safety concerns. Fifty-five NMEs were approved between 2010 and 2016: 32 (58%) under regular approval (RA) and 23 (42%) under accelerated approval (AA). Of these 55 NMEs, 9 (16%) had substantial safety-related changes after approval. Across all 55 NMEs, one was temporarily withdrawn from the market for safety reasons (1.8%); one (1.8%) required a new REMS; nine required labeling revisions-new Boxed Warnings were required for two NMEs (3.6%), and new Warnings and Precautions subsections were required for eight (14.6%). One drug (ponatinib) was responsible for several of the substantial safety-related changes (withdrawal, REMS, Boxed Warnings). One of 32 NMEs approved under RA required a new Warning and Precaution, whereas 7 of 23 NMEs approved under AA had substantial safety-related changes in the first 2 years after approval. Based on our analysis we conclude that although there was a greater incidence of substantial safety-related changes to AA drugs versus RA drugs, the majority of these were changes to the Warnings and Precautions and did not substantially alter the benefit-risk profile of the drug. The majority of new cancer drugs (84%) approved in the U.S. do not have new substantial safety information being added to the label within the first 2 years of approval. Unprecedented efficacy seen in contemporary cancer drug development has led to early availability of effective cancer therapies based on large effects in smaller populations. More limited premarket safety data require diligent postmarketing safety surveillance as we continue to learn and update drug labeling throughout the product lifecycle.


Monoclonal antibodies define a domain on herpes simplex virus glycoprotein B involved in virus penetration.
In an earlier report (S.D. Marlin, S.L. Highlander, T.C. Holland, M. Levine, and J.C. Glorioso, J. Virol. 59: 142-153), we described the production and use of complement-dependent virus-neutralizing monoclonal antibodies (MAbs) and MAb-resistant (mar) mutants to identify five antigenic sites (I to V) on herpes simplex virus type 1 glycoprotein B (gB). In the present study, the mechanism of virus neutralization was determined for a MAb specific for site III (B4), the only site recognized by MAbs which exhibited complement-independent virus-neutralizing ability. This antibody had no detectable effect on virus attachment but neutralized viruses after adsorption to cell monolayers. These findings implied that the mechanism of B4 neutralization involved blocking of virus penetration. The remaining antibodies, which recognized sites I, II, and IV, required active complement for effective neutralization. These were further studied for their ability to impede virus infectivity in the absence of complement. Antibodies to sites I (B1 and B3) and IV (B6) slowed the rate at which viruses penetrated cell surfaces, supporting the conclusion that antibody binding to gB can inhibit penetration by a virus. The data suggest that MAbs can interfere with penetration by a virus by binding to a domain within gB which is involved in this process. In another assay of virus infection, MAb B6 significantly reduced plaque development, indicating that antibody binding to gB expressed on infected-cell surfaces can also interfere with the ability of a virus to spread from cell to cell. In contrast to these results, antibodies to site II (B2 and B5) had no effect on virus infectivity; this suggests that they recognized structures which do not play a direct role in the infectious process. To localize regions of gB involved in these phenomena, antibody-binding sites were operationally mapped by radioimmunoprecipitation of a panel of truncated gB molecules produced in transient-expression assays. Residues critical to recognition by antibodies which affect penetration by a virus (sites I, III, and IV) mapped to a region of the molecule (amino acid residues 241 to 441) which is centrally located within the external domain. Antibodies which had no effect on penetration (site II) recognized sequences distal to this region (residues 596 to 737) near the transmembrane domain. The data suggest that these gB-specific MAbs recognize two major antigenic sites which reside in physically distinct components of the external domain of gB.(ABSTRACT TRUNCATED AT 400 WORDS)


Aberrant sphingomyelin/ceramide metabolic-induced neuronal endosomal/lysosomal dysfunction: potential pathological consequences in age-related neurodegeneration.
Alterations in the trafficking and function of the endocytic pathway have been extensively documented to be one of the earliest pathological changes in sporadic Alzheimer's disease (AD). Although the pathophysiological consequences of these endosomal/lysosomal changes are currently unknown, several recent studies have suggested that such changes in endocytic function are able to cause a redistribution of several lysosomal hydrolases into early endosomes, leading to the overproduction of neurotoxic amyloid peptide. Recently, we and others have demonstrated that abnormal endocytic pathology within post-mitotic neurons can, in part, be attributed to alterations in sphingomyelin/ceramide metabolism, resulting in the intracellular accumulation of ceramide. Once inside the cell, the ability of ceramide to physically alter membrane structure, formation, and fusion, rather than serving solely as a lipid secondary messenger, may severely compromise normal endocytic trafficking. In this review, we will discuss the potential pathological effects of abnormal sphingomyelin/ceramide metabolism on intracellular vesicular transport in relation to both amyloid accumulation in AD and various neurodegenerative diseases associated with lysosomal abnormalities.


MIS priorities for MSO's (management services organization) & clinics without walls.
Organized and efficient systems that are responsive to the needs of the medical group, hospital and management services organization are at the heart of successful integrated healthcare systems. Unfortunately, selecting the right systems solution can be a time-consuming and difficult process, at best. The problems are many. First, not all management services organizations look alike. Some are limited in scope and function. Others offer an expansive menu of services to the participating groups and physicians. Second, the level of sophistication of clinic or MSO personnel evaluating systems varies. Often, hospital systems personnel with little experience in the practice management arena are assigned the job of evaluating practice systems. Third, the budget for a data processing system may be limited. The process of forming an MSO and organizing a group without walls may be very expensive. Unless adequate budgeting is done in advance, only limited funds may be left for investment in systems. Lastly, identifying viable systems which are available can be an arduous undertaking. Literally, hundreds of possible systems are available. Unfortunately, few sources offer comprehensive information on each system suitable for proper evaluation. This has led many organizations to strategically design and develop their own physician network solutions and options using such applications as 4th generation data base language. According to Mick Bassell of Partners in HealthCare, a systems consulting group in San Rafael, CA., "a request for proposal process is usually the best way to identify systems that meet the group's needs, weaknesses and strengths. This should be done before vendors are asked to supply information about various computer systems. Developing a good RFP is a building process for both the MSO and group which will help them to jointly identify, organize and prioritize system requirements."


Corynebacterium pelargi sp. nov., isolated from the trachea of white stork nestlings.
A Gram-stain-positive, pleomorphic, oxidase-negative, non-motile isolate from the trachea of a white stork from Poland, designated strain 136/3(T), was subjected to a comprehensive taxonomic investigation. A comparative analysis of the 16S rRNA gene sequence showed highest similarities to Corynebacterium mustelae , Corynebacterium pseudotuberculosis , Corynebacterium vitaeruminis and Corynebacterium ulcerans (96.0-96.3%). The quinone system consisted of major amounts of MK-8(H2), minor amounts of MK-9(H2) and traces of MK-8 and MK-9. The polar lipid profile of strain 136/3(T) contained phosphatidylinositol and phosphatidylinositol-mannoside as major lipids and phosphatidylglycerol and an acidic glycolipid in moderate amounts. In addition small amounts of diphosphatidylglycerol, a phospholipid, an aminolipid and two lipids of unknown group affiliation were found. The polyamine pattern was composed of the major components spermidine and spermine. Putrescine, 1,3-diaminopropane, cadaverine, sym-homospermidine and tyramine were found in minor or trace amounts. The diamino acid of the peptidoglycan was meso-diaminopimelic acid. In the fatty acid profile straight-chain, saturated and mono-unsaturated fatty acids predominated (C(18 : 1)ω9c, C(16 : 1)ω7c, C16 : 0, C(18 : 0)). Corynemycolic acids were detected. Physiological traits as well as unique traits of the polar lipid profile and the fatty acid pattern distinguished strain 136/3(T) from the most closely related species. All these results indicate that strain 136/3(T) represents a novel species of the genus Corynebacterium for which we propose the name Corynebacterium pelargi sp. nov. The type strain is 136/3(T) ( =CIP 110778(T) =CCM 8517(T) =LMG 28174(T)).


Estimating the population attributable risk for multiple risk factors using case-control data.
A straightforward and unified approach is presented for the calculation of the population attributable risk per cent (etiologic fraction) in the general multivariate setting, with emphasis on using data from case-control studies. The summary attributable risk for multiple factors can be estimated, with or without adjustment for other (confounding) risk factors. The relation of this approach to procedures in the literature is discussed. Given values of the relative risks for various combinations of factors, all that is required is the distribution of these factors among the cases only. The required information can often be estimated solely from case-control data, and in some situations relative risk estimates from one population can be applied to calculation of attributable risk for another population. The authors emphasize the benefits to be obtained from logistic regression models, so that risks need not be estimated separately in a large number of strata, some of which may contain inadequate numbers of individuals. This approach allows incorporation of important interactions between factors, but does not require that all possible interactions be included. The approach is illustrated with data on four risk factors from a pair-matched case-control study of participants in a multicenter breast cancer screening project.


Penetration Route of the Selective Glucocorticoid Receptor Agonist SA22465 and Betamethasone into Rabbit Meibomian Gland Based on Pharmacokinetics and Autoradiography.
Meibomian glands are modified sebaceous glands embedded within specific types of dense connective tissues. This study investigated drug penetration into meibomian glands following a single topical administration in rabbits. We measured time course concentrations of the selective glucocorticoid receptor agonist (SEGRA) SA22465 and betamethasone in lid margins, palpebral conjunctival epithelium, and meibomian glands following a single instillation using a newly established collection method. We also visualized the distribution of 14C-SA22465 in eyelid tissue sections using microautoradiography. Concentrations of SA22465 and its major metabolite SA22313 were highest in lid margins, followed by palpebral conjunctival epithelium and meibomian glands in a 100-fold descending order. Betamethasone exhibited similar distribution profiles with smaller concentration differences. The distribution of silver grains as a quantitative index of radioactivity in eyes and eyelids was determined in a subjective manner using microautoradiographs, which revealed that the highest distribution of silver grains was associated with the cornea, followed by posterior segment tissues, such as the sclera, choroid, and retina. Low levels were associated with more internal ocular tissues and a greater number of compartments. Moderate levels of radioactivity were associated with meibomian glands and connective tissues, including the nictitating membrane. In contrast, meibomian ducts contained only background levels of radioactivity. Our findings indicate that the transconjunctiva is the most likely route of drug entry into meibomian glands following ocular administration rather than the central meibomian duct; however, this distribution is limited. A physiologic barrier may restrict drug penetration across the tarsal plate.


Liquid crystals for holographic optical data storage.
A tutorial review is presented to inform and inspire the reader to develop and integrate strong scientific links between liquid crystals and holographic data storage, from a materials scientist's viewpoint. The principle of holographic data storage as a means of providing a solution to the information storage demands of the 21st century is detailed. Holography is a small subset of the much larger field of optical data storage and similarly, the diversity of materials used for optical data storage is enormous. The theory of polarisation holography which produces holograms of constant intensity, is discussed. Polymeric liquid crystals play an important role in the development of materials for holographic storage and photoresponsive materials based on azobenzene are targeted for discussion due to their ease of photo-reversion between trans- and cis-states. Although the final polymer may not be liquid crystalline, irradiation can induce ordered domains. The mesogens act in a co-operative manner, enhancing refractive indices and birefringences. Surface relief gratings are discussed as a consequence of holographic storage. Cholesteric polymers comprising azobenzene are briefly highlighted. Irradiation causing cis-trans-isomerisation can be used to control helix pitch. A brief mention of liquid crystals is also made since these materials may be of future interest since they are optically transparent and amenable to photo-induced anisotropy.


Early gastric cancer of signet ring cell carcinoma is more amenable to endoscopic treatment than is early gastric cancer of poorly differentiated tubular adenocarcinoma in select tumor conditions.
Recently, endoscopic submucosal dissection has been carefully applied in early gastric cancer (EGC) with undifferentiated type. However, there are no individual guidelines for endoscopic treatment of EGCs with poorly differentiated tubular adenocarcinoma or signet ring cell carcinoma. The aim of this study was to investigate and compare the clinicopathologic features of these two types of EGC to guide the application of endoscopic treatment. Patients to undergo radical gastrectomy for the treatment of EGC were selected for inclusion in this study. Histology was classified according to the Japanese Gastric Cancer Association. Between January 2005 and December 2008, 288 patients with poorly differentiated EGC and 419 patients with signet ring cell EGC were enrolled. Their medical records were reviewed retrospectively. Compared with signet ring cell EGC, poorly differentiated EGC had higher rates of male gender, old age (≥45 years), large tumor length (>20 mm), ulcer, submucosal invasion, lymphovascular invasion, and lymph node metastasis. In the multivariate analyses, poorly differentiated EGC was significantly associated with ulcer (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.5-3.8), submucosal invasion (OR: 3.6, 95% CI: 2.6-5.1) and lymphovascular invasion (OR: 2.0, 95% CI: 1.1-3.6) with a reference of signet ring cell EGC. The independent risk factors for lymph node metastasis were large tumor length, submucosal invasion, and lymphovascular invasion in both types of EGC. Young age was an independent risk factor of lymph node metastasis only in poorly differentiated EGC. Poorly differentiated EGC has clinicopathologic features that are less favorable to endoscopic treatment than are those of signet ring cell EGC. Therefore, these two types of EGC should be approached separately, not as a united type of undifferentiated histology, during the planning of endoscopic treatment.


Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis.
Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular processes to clinical outcome, we aimed to identify transcriptional nodes regulating cancer cell metastasis. Using rodent xenograft models that we previously developed, we identified the transcription factor Fos-related antigen-1 (Fra-1) as a key coordinator of metastasis. Because Fra-1 often is overexpressed in human metastatic breast cancers and has been shown to control their invasive potential in vitro, we aimed to assess the implication and prognostic significance of the Fra-1-dependent genetic program in breast cancer metastasis and to identify potential Fra-1-dependent therapeutic targets. In several in vivo assays in mice, we demonstrate that stable RNAi depletion of Fra-1 from human breast cancer cells strongly suppresses their ability to metastasize. These results support a clinically important role for Fra-1 and the genetic program it controls. We show that a Fra-1-dependent gene-expression signature accurately predicts recurrence of breast cancer. Furthermore, a synthetic lethal drug screen revealed that antagonists of the adenosine receptor A2B (ADORA2B) are preferentially toxic to breast tumor cells expressing Fra-1. Both RNAi silencing and pharmacologic blockade of ADORA2B inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs. These data show that Fra-1 activity is causally involved in and is a prognostic indicator of breast cancer metastasis. They suggest that Fra-1 activity predicts responsiveness to inhibition of pharmacologically tractable targets, such as ADORA2B, which may be used for clinical interference of metastatic breast cancer.


[Bath Plug Closure Method for Cerebrospinal Fluid Leakage by Endoscopic Endonasal Approach:Cooperative Treatment by Neurosurgeons and Otolaryngologists].
Endoscopic endonasal surgery, an innovative surgical technique, is used to approach sinus lesions, lesions of the skull base, and intradural tumors. The cooperation of experienced otolaryngologists and neurosurgeons is important to achieve safe and reliable surgical results. The bath plug closure method is a treatment option for patients with cerebrospinal fluid(CSF)leakage. Although it includes dural and/or intradural procedures, surgery tends to be performed by otolaryngologists because its indications, detailed maneuvers, and pitfalls are not well recognized by neurosurgeons. We reviewed the cases of patients with CSF leakage treated by using the bath plug closure method with an endoscopic endonasal approach at our institution. Three patients were treated using the bath plug closure method. CSF leakage was caused by a meningocele in two cases and trauma in one case. No postoperative intracranial complications or recurrence of CSF leakage were observed. The bath plug closure method is an effective treatment strategy and allows neurosurgeons to gain in-depth knowledge of the treatment options for CSF leakage by using an endoscopic endonasal approach.


Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides.
Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC(90) concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.


New Butyroside D from Argan Press Cake Possess Anti-Melanogenesis Effect via MITF Downregulation in B16F10 and HEM Cells.
Hyperpigmentation is a skin condition where patches of skin become darker in color due to excess melanin production upon UV exposure leading to melasma, which are lentigines or post inflammatory hyperpigmentation that psychologically affecting a great number of people. The present study investigates the anti-melanogenic effect of Butyroside D and the underling mechanism. After the confirmation of the non-cytotoxic effect of Butyroside D on B16F10 cells, we proceeded with analyzing the impact of the treatment at low and high concentration (i.e., 0.2 μM and 2 μM) using gene profiling analysis and examined the differentiation in gene expression. Our results identify cyclic adenosine monophosphate (cAMP), Wnt/β-catenin and Mitogen-Activated Protein Kinase (MAPK) signaling pathways to be downregulated upon treatment with Butyroside D. These pathways were targeted to further validate the effect of Butyroside D on membrane receptors melanocortin 1 receptor (MC1R) and receptor tyrosine kinase (c-Kit), related microphthalmia-associated transcription factor (MITF) and consequently tyrosinase (TYR), and tyrosine-related protein-1 (TYRP-1) that were all shown to be downregulated and, therefore, leading to the repression of melanin biosynthesis. Finally, the anti-melanogenic effect of Butyroside D was confirmed on human epidermal melanocytes (HEM) cells by inhibiting the activation of cAMP pathway generally mediated through α-melanocyte-stimulating hormone (α-MSH) and MC1R. Overall, this study suggests the potential applicability of this purified compound for the prevention of hyperpigmentation conditions.