Blood selenium concentrations and glutathione peroxidase activities in patients with breast cancer and with advanced gastrointestinal cancer.
Recent prospective epidemiological studies have shown an association between a low prediagnostic serum selenium (Se) concentration and the risk of cancer. Se concentrations in whole blood and plasma, and the activity of red cell and plasma glutathione peroxidase (GSH-Px) were measured in patients with breast cancer, gastric cancer and colorectal cancer. The observed whole blood and plasma Se concentrations of healthy persons were 99.5 and 78.5 micrograms/L, respectively. Red cell and plasma GSH-Px activities of this group were: 21.0 U/g Hb and 256 U/L plasma. In all investigated cancer patients significantly lower whole blood and plasma Se concentrations, and significantly lower red cell and plasma GSH-Px activities were found, as compared with the values of healthy controls. Low Se concentrations of blood components may be indicative of increased cancer risk.


Microswimmers with Heat Delivery Capacity for 3D Cell Spheroid Penetration.
Micro- and nanoswimmers are a fast emerging concept that changes how colloidal and biological systems interact. They can support drug delivery vehicles, assist in crossing biological barriers, or improve diagnostics. We report microswimmers that employ collagen, a major extracellular matrix (ECM) constituent, as fuel and that have the ability to deliver heat via incorporated magnetic nanoparticles when exposed to an alternating magnetic field (AMF). Their assembly and heating properties are outlined followed by the assessment of their calcium-triggered mobility in aqueous solution and collagen gels. It is illustrated that the swimmers in collagen gel in the presence of a steep calcium gradient exhibit fast and directed mobility. The experimental data are supported with theoretical considerations. Finally, the successful penetration of the swimmers into 3D cell spheroids is shown, and upon exposure to an AMF, the cell viability is impaired due to the locally delivered heat. This report illustrates an opportunity to employ swimmers to enhance tissue penetration for cargo delivery via controlled interaction with the ECM.


Treatment of colorectal injuries in the civil war and the factors affecting mortality.
Colorectal injuries are one of the most common causes of mortality in war. Mainstay treatment of these injuries include primary repair or stoma creation. Clinical data of the patients were evaluated retrospectively. Time from injury to hospital admission, method of treatment, the colorectal area affected, injury severity score ISS, hemodynamic instability, and mortality rate were determined. Of the 61 patients included in the study. Mean time from injury to hospital admission was 160±19 minutes. The injury was in the right colon in 24 patients 39.3%, in the left colon in 18 29.5%, and in the rectum in 19 31.2% patients. Median ISS value of 61 patients was 16, IQR 5. Mortality and complication rates were higher in patients with hemodynamic instability and stoma requirement was also higher in this group p<0.05. Total mortality occurred in 15 24.5% patients. Of these, 10 66.6% patients had hemodynamic instability. Hemodynamic instability is the most important factor affecting the mortality and the treatment method in wartime colorectal injuries. We believe that in victims of war with colorectal injuries, surgical intervention before the development of hemodynamic instability may reduce the rate of mortality and stoma requirement. Colorectal injury, Firearm injury, Hemodynamic instability, Stoma.


Combined dispersive solid-phase extraction-dispersive liquid-liquid microextraction-derivatization for gas chromatography-mass spectrometric determination of aliphatic amines on atmospheric fine particles.
Short-chain aliphatic amines are ubiquitous in the atmospheric environment. They play an important role in the formation and growth of atmospheric particles. As such, there is a pressing need to monitor these particle-bound compounds present at trace quantities. The present work describes an efficient, one-step microextraction technique for the preconcentration and detection of trace levels of 10 aliphatic amines on fine particles (particulate matter of 2.5μm or less (PM2.5)) in the atmosphere. After extraction of amines from particles in acidified water samples, carbon-based sorbents (in dispersive solid-phase extraction mode), and vortex agitation were utilized for simultaneous derivatization-extraction and dispersive liquid-liquid microextraction. The approach significantly increased the recoveries and enrichment of the amine derivatives. This one-step, combined technique is proposed for the first time. Several influential factors including type and concentration of derivatization reagent (for gas chromatographic separation), type of buffer, sample pH, types and volumes of extraction and disperser solvents, type and amount of sorbent, vortex time and temperature, desorption solvent type and volume, and salt content were investigated and optimized. Under the optimum conditions, high enrichment factors (in the range of between 307 and 382) and good reproducibility (relative standard deviations, below 7.0%, n=5) were achieved. The linearity ranged from 0.1μg/L-100μg/L, and from 0.5μg/L-100μg/L, depending on the analytes. The limits of detection were between 0.02μg/L (corresponding to ∼0.01ng/m3 in air) and 0.09μg/L (corresponding to ∼0.04ng/m3 in air). The developed method was successfully applied to the analysis of PM2.5 samples collected by air sampling through polytetrafluoroethylene filters. The concentration levels of amines ranged from 1.04 to 4.16ng/m3 in the air sampled.


Impact of home-delivered meal programs on diet and nutrition among older adults: a review.
Poor diet quality and insufficient nutrient intake is of particular concern among older adults. The Older Americans Act of 1965 authorizes home-delivered meal services to homebound individuals aged 60 years and older. The purpose of this study was to review scientific evidence on the impact of home-delivered meal services on diet and nutrition among recipients. Keyword and reference searches were conducted in Cochrane Library, Google Scholar, PubMed and Web of Science. Inclusion criteria included: study design (randomized controlled trials, cohort studies, pre-post studies, or cross-sectional studies); main outcome (food and nutrient intakes); population (home-delivered meal program participants); country (US); language (articles written in English); and article type (peer-reviewed publications or theses). Eight studies met the inclusion criteria, including two randomized controlled trial studies (from the same intervention), one cohort study, two pre-post studies, and three cross-sectional studies. All but two studies found home-delivered meal programs to significantly improve diet quality, increase nutrient intakes, and reduce food insecurity and nutritional risk among participants. Other beneficial outcomes include increased socialization opportunities, improvement in dietary adherence, and higher quality of life. Home-delivered meal programs improve diet quality and increase nutrient intakes among participants. These programs are also aligned with the federal cost-containment policy to rebalance long-term care away from nursing homes to home- and community-based services by helping older adults maintain independence and remain in their homes and communities as their health and functioning decline.


Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients.
Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A4*1/*1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A5*1 allele (CYP3A5 expresser) and among those with CYP3A5*3/*3 genotype (nonexpresser) were also studied. A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype. The dose-adjusted AUC₀₋₁₂ and C₀ of tacrolimus were significantly lower in patients with the CYP3A4*1G allele and CYP3A5 expressers than those with the CYP3A4*1/*1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC₀₋₁₂ and C₀ values were associated with CYP3A4*1/*1 (p = 0.018 and 0.040, respectively) and CYP3A5*3/*3 (p < 0.001 each). The standardized regression coefficient for the AUC₀₋₁₂ of tacrolimus was approximately twofold less for CYP3A4*1/*1 than CYP3A5*3/*3. The lowest dose-adjusted AUC₀₋₁₂ was found in CYP3A5 expressers with the CYP3A4*1G allele. The CYP3A4*1/*1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A5*1/*3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A4*1/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.


Growth performance, metabolic and endocrine traits, and absorptive capacity in neonatal calves fed either colostrum or milk replacer at two levels.
Colostrum (CO) contains high amounts, whereas whole milk and milk replacer (MR) contain small amounts, of bioactive and growth-promoting substances, such as IGF-I. An experiment was designed to study the effects of feeding CO or MR on the first 3 d to neonatal calves, followed by whole milk up to d 7, at low and high density. Intestinal absorptive capacity, plasma metabolite and hormone concentrations, and growth performance were measured during the 1st wk of life. Body weight increased (P < .05) similarly in calves fed low or high amounts of CO but did not rise in MR-fed calves. Loose feces were more frequent (P < .05) and absorption of xylose on d 5 was lower (P < .01) in MR- than in CO-fed calves, but there were no effects of feeding density within CO-fed or within MR-fed groups. However, high feeding density within CO-fed groups enhanced (P < .05) total protein, globulin, triglyceride, cholesterol, and insulin concentrations, whereas in the initially high and low MR-fed groups only plasma glucose and insulin after the first meal and plasma NEFA on d 2 were modified (P < .05) by different feeding density. Thus, feeding different amounts of CO partly influenced protein and fat metabolism in calves during the 1st wk of life, but it did not measurably affect intestinal function. However, feeding different amounts of MR, in the absence of CO, barely affected metabolic and endocrine traits and absorptive capacity. Thus, high density CO feeding, and therefore a high supply of nutrients, together with greater amounts of bioactive and growth-promoting substances influenced neonatal metabolism and growth more than a high density of MR feeding containing only small amounts of bioactive and growth-promoting substances. Factors in addition to nutrient density seem to be important for the development of neonatal calves.


[A case of M. fortuitum lung disease with small-cell lung cancer].
A 58-year-old man was admitted to our hospital because of an abnormal shadow found on chest radiography. Chest radiographs and chest CT on admission showed a bulla with a niveau and infiltration in the right upper lobe. Smear of sputum and bronchial lavage were negative for acid-fast bacilli. Despite treatment with meropenem and clindamycin, the infiltrating shadow worsened. Since bronchial lavage and sputum culture were positive for M. fortuitum, these drugs were replaced with minocycline and imipenem. Thereafter, the shadow on the chest radiograph improved. After discharge, outpatient treatment with clarithromycin and levofloxacin was continued. After 4 months, the residual tumor shadow in the right upper lobe gradually grew. When a CT-guided transcutaneous needle lung biopsy was undertaken, malignant cells were found. Right upper lobectomy was performed. Pathological examination of the lesion demonstrated small-cell lung cancer. If a lesion does not change after nontuberculous mycobacteria treatment, the physician should consider other lesions such as lung cancer.


Dynamic expression patterns of RhoV/Chp and RhoU/Wrch during chicken embryonic development.
Rho GTPases play central roles in the control of cell adhesion and migration, cell cycle progression, growth, and differentiation. However, although most of our knowledge of Rho GTPase function comes from the study of the three classic Rho GTPases RhoA, Rac1, and Cdc42, recent studies have begun to explore the expression, regulation, and function of some of the lesser-known members of the Rho GTPase family. In the present study, we cloned the avian orthologues of RhoV (or Chp for Cdc42 homologous protein) and RhoU (or Wrch-1 for Wnt-regulated Cdc42 homolog-1) and examined their expression patterns by in situ hybridization analysis both during early chick embryogenesis and later on, during gastrointestinal tract development. Our data show that both GTPases are detected in the primitive streak, the somites, the neural crest cells, and the gastrointestinal tract with distinct territories and/or temporal expression windows. Although both proteins are 90% identical, our results indicate that cRhoV and cRhoU are distinctly expressed during chicken embryonic development.


Interfering with free recall of words: Detrimental effects of phonological competition.
We examined the effect of different distracting tasks, performed concurrently during memory retrieval, on recall of a list of words. By manipulating the type of material and processing (semantic, orthographic, and phonological) required in the distracting task, and comparing the magnitude of memory interference produced, we aimed to infer the kind of representation upon which retrieval of words depends. In Experiment 1, identifying odd digits concurrently during free recall disrupted memory, relative to a full attention condition, when the numbers were presented orthographically (e.g. nineteen), but not numerically (e.g. 19). In Experiment 2, a distracting task that required phonological-based decisions to either word or picture material produced large, but equivalent effects on recall of words. In Experiment 3, phonological-based decisions to pictures in a distracting task disrupted recall more than when the same pictures required semantically-based size estimations. In Experiment 4, a distracting task that required syllable decisions to line drawings interfered significantly with recall, while an equally difficult semantically-based color-decision task about the same line drawings, did not. Together, these experiments demonstrate that the degree of memory interference experienced during recall of words depends primarily on whether the distracting task competes for phonological representations or processes, and less on competition for semantic or orthographic or material-specific representations or processes.


Economy, efficacy, and feasibility of a risk-based control program against paratuberculosis.
Long-term effects of paratuberculosis on within-herd prevalence and on-farm economy of implementing risk-based control strategies were compared with alternative strategies by using a herd-simulation model. Closing transmission routes is essential for effective control of paratuberculosis. However, many farmers lack the resources to carry out these procedures for all cows in the herd. When using risk-based control strategies 1) all cows are tested quarterly with a milk ELISA, 2) specific cows with a high risk of being infectious are identified, and 3) the farmer can focus only on these infectious animals to close infection routes. In this way the workload can be reduced, making these control strategies more feasible. This study evaluates potential long-term effects of the risk-based approach compared with non-risk-based strategies by simulations conducted with the herd-simulation model PTB-Simherd. Seven control strategies were simulated in herds with initial true herd prevalences of 5, 25, and 50%, respectively. The results predicted the risk-based control strategies to be very efficient and comparable to the best whole-herd strategies in reducing the within-herd prevalence of paratuberculosis with considerably less labor. If infection routes are closed efficiently, prevalence can be reduced to 10% of initial prevalence within 5 to 7 yr. Test-and-cull strategies without closing infection routes were found, by simulation, to be ineffective in reducing prevalence and were not cost-effective methods. The profitability of the various control strategies depends on hourly wages and time spent per cow/calving. Furthermore, simulations show that immediate culling of highly infectious cows is only necessary and cost-effective if infection routes from these cows are not efficiently closed. The risk-based control strategies are recommended in the Danish voluntary control program "Operation Paratuberculosis," which was initiated in February 2006 and now includes 1,220 dairy farmers in Denmark.


An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.
Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.


Osmotically induced natriuresis and blood pressure response involves angiotensin AT1 receptors in the subfornical organ.
In the present study we tested the hypothesis of whether the centrally induced natriuresis and blood pressure increase after intracerebroventricular injection of hypertonic saline involves the subfornical organ, as suggested by the occurrence of osmosensitive cells as well as a high concentration of angiotensin II receptors in this brain area. All experiments were performed in conscious Wistar rats. A chronic cannula was inserted into the lateral brain ventricle for intracerebroventricular injection and a chronic indwelling intracranial guide cannula for microinjection was placed in the subfornical organ. In addition, the rats were provided with ureter catheters for urine collection. Intracerebroventricular injections of hypertonic saline (0.3 mol/l; n = 7) increased renal sodium excretion from 180.0 +/- 30.0 to 279.0 +/- 34.0 mol/l/60 min (P < 0.001) accompanied by an increase in mean arterial pressure of 8.3 +/- 1.2 mmHg (P < 0.01). No change in urinary volume was observed. After injection of the specific AT1 receptor antagonist, losartan, into the subfornical organ (5 micrograms/200 nl; n = 8) the natriuresis and blood pressure response to intracerebroventricular hypertonic saline was completely abolished. Control injections of losartan into areas adjacent to the subfornical organ had no effect on the responses to hypertonic saline. Our results suggest that the centrally induced natriuresis and blood pressure responses to hypertonic saline are mediated by an angiotensinergic mechanism involving the subfornical organ.


Autophagy in advanced low- and high-grade tubular adenocarcinomas of the stomach: An ultrastructural investigation.
Autophagy represents a catabolic process in which cellular protein and organelles are engulfed into autophagosomes, digested in lysosomes and reutilized for the cellular metabolism. In neoplastic conditions, autophagy may act either as a tumour suppressor avoiding the accumulation of damaged proteins and organelles or as a mechanism of cell survival promoting the tumour growth. Although enhanced autophagy has been reported in hypoxic areas of solid tumors, there are only few ultrastructural reports concerning the relationships between autophagy and tumor grade. In the present study, we have performed an ultrastructural investigation aimed to document autophagy in a cohort of advanced gastric carcinomas of tubular type, correlating the observed findings with low and high tumor grade. Among 71 surgically resected cases of advanced gastric carcinomas, we have selected twelve low-grade and thirteen high-grade tubular adenocarcinomas. Autophagic vacuoles (AV) were only occasionally found in low-grade tubular carcinomas, while they constituted a frequent finding in high-grade ones (p < 0.01). Moreover, in high-grade tubular adenocarcinomas, our data revealed a morphologic association between autophagy and nuclear changes, such as multinucleation, micronucleation and nuclear buds, largely considered as ultrastructural aspects of mitotic instability. However, an increased autophagy was associated with organelle-poor cytoplasm or a senescent phenotype, characterized by lipofuscin granules and cytoplasmic vacuoles. In the light of our observations, it may be suggested that autophagy should be considered a phenomenon mainly related to the cellular differentiation and tumor progression.


[Association between ultrasound screening frequency and mortality in patients with hepatocellular carcinoma].
Objective: To discuss the association between ultrasound screening frequency and total mortality in patients with HCC before diagnosing HCC, and explore the optimal ultrasound screening frequency for HCC high-risk groups. Methods: Retrospectively collected clinical data of 615 cases of liver cirrhosis who developed to HCC from January 1, 2010 to December 31, 2015. Before diagnosing HCC, all patients were divided into five groups according to ultrasound screening frequency: 0-6, 7-12, 13-24, 25-36 months and not screened within 3 years (never screened). The chance to receive curative therapy, 5-year cumulative mortalities and independent factors of mortality in patients with HCC were analyzed. Results: Chances to receive curative therapy among the 0-6, 7-12, 13-24, 25-36 months and never screened groups were 38.2%, 27.2%, 25.4%, 23.8% and 19.7%, respectively (P<0.05). The 5-year overall mortality rates were 76.4%, 77.7%, 79.3%, 82.5% and 84.6%, respectively. Compared with 0-6 months, the adjusted OR of mortality for the other groups were 1.112, 1.235, 1.305 and 1.451, respectively (all P<0.05). Multivariate analysis showed that ultrasound screening frequency, curative treatment and Child-Pugh (class A/B) were the factors to affect long-term survival in patients with HCC (all P<0.05). Conclusion: For HCC high-risk groups, optimal ultrasound screening frequency is within 6 months, and high-frequency ultrasound screening can increase the chance of receiving curative treatment, reduce total mortality, and improve overall survival.


Stenotic Bicuspid and Tricuspid Aortic Valves - Micro-Computed Tomography and Biological Indices of Calcification.
Valve calcification is well estimated by ex-vivo micro-computed tomography (micro-CT). The objective of this study was to investigate the associations between micro-CT findings and biological indices of calcification in aortic stenosis (AS), as well as differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV).Methods and Results:Aortic valves and plasma were obtained from patients undergoing valve surgery. Valves were dissected and underwent micro-CT, genetic analyses, and calcium content assessment. Plasma levels of calcification markers were measured. Forty-two patients with isolated severe AS, including 22 with BAV, were studied. BAV patients had a lower median CT value (140.0 [130.0-152.0] vs. 157.0 [147.0-176.0], P=0.002) and high-density calcification (HDC) fraction (9.3 [5.7-23.3] % vs. 21.3 [14.3-31.2] %, P=0.01), as compared with TAV. Calcification fraction (CF) correlated with AS severity (measured as maximal transvalvular pressure gradient [r=0.34, P=0.03], maximal flow velocity [r=0.38, P=0.02], and indexed aortic valve area [r=-0.37, P=0.02]). For TAV patients only, mRNA expression of integrin-binding sialoprotein correlated with CF (r=0.45, P=0.048), and the receptor activator of the nuclear factor κ-B ligand transcript correlated with HDC corrugation (r=0.54, P=0.01). TAV patients with AS present more mineralized calcifications in micro-CT than BAV subjects. The relative volume of calcifications increases with the AS severity. In TAV patients, upregulated expression of genes involved in osteoblastogenesis in AS correlates with leaflet mineralization in micro-CT.


Calretinin immunoreactivity in taste buds and afferent fibers of the grey mullet Chelon labrosus.
The presence of the calcium-binding protein calretinin in taste buds of a teleost, the thick-lipped grey mullet, was investigated using immunohistochemical techniques. Taste bud sensory cells had calretinin immunoreactivity. The nerve fiber plexus innervating taste buds, the ganglia and the viscerosensory roots projecting to the vagal lobe, also showed calretinin immunoreactivity. These results demonstrate for the first time the occurrence of calretinin in the taste buds and the taste afferent system of a teleost.


Middle turbinate primary mucocele in a child masquerading as a nasal tumour.
Middle turbinate primary mucocele in a child masquerading as a nasal tumour. Nasal obstruction in children is a very common complaint in daily ENT consultations. The common cold, rhinosinusitis, allergic rhinitis, hypertrophy and inflammation of the adenoid pad are very common causes of nasal obstruction, but there are numerous other causes for which the clinician must be aware. The authors report a very unusual case of a primary mucocele of the middle turbinate of a 7-year-old girl masquerading as a nasal tumour. The mucocele was successfully marsupialized surgically using an endonasal endoscopic approach. The authors report the case, imaging, and review the pertinent literature. Clinicians must be aware of less common aetiologies of nasal obstruction in order to orientate the diagnostic work-up and to propose adequate management.


Simplifying and improving soft-tissue management for fixed-prosthodontic impressions.
It is apparent that conventional impressions, usually made in vinyl polysiloxane or polyether material, could be better. One of the significant reasons for impressions' inadequacy is incomplete inclusion of the tooth preparation margins in the impression. There are numerous reasons for this challenge, some of which could be overcome by implementing the technique changes I have described in this column.


Ovicidal and larvicidal effectiveness of insecticides applied by dipping apples on the small fruit tortrix Grapholita lobarzewskii.
The larvicidal and ovicidal effectiveness of twelve insecticides on Grapholita lobarzewskii Nowicki was tested by dipping apples in different concentrations of the insecticides. Emamectin was the most effective larvicidal product, with an LC(50) of 0.01 mg kg(-1), closely followed by spinosad, methoxyfenozide and chlorpyrifos-methyl, with LC(50) values between 0.2 and 0.7 mg kg(-1). Products like imidacloprid, indoxacarb, phosmet and thiacloprid gave LC(50) values between 1 and 2 mg kg(-1). Lastly, chlorpyrifos-ethyl and phosalone had LC(50) values of around 4 mg kg(-1), whereas tebufenozide and diflubenzuron had almost no larvicidal effect. Most of the products tested had low ovicidal effectiveness, and only fenoxycarb and emamectin gave LC(50) values worthy of note, close to 2 mg kg(-1).


Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells.
The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored.


[119 emergency medical transport of the elderly].
A retrospective analysis of emergency ambulance transports in the EMS-Tainan was made to evaluate the utilization of emergency medical system by the elderly and to determine the factors that may influence these transports. The study group consisted of 4,090 emergency ambulance transports from 1/1/1195 to 30/4/1995. 1,017 patients (24%) were aged over 65. The main characteristics of these elderly patients were as follows: more non-trauma cases, higher severity of triage, and longer total transport time (23.0 +/- 0.5 vs. 18.9 +/- 0.2 minutes) were noted. In addition, 136 (13.4%) of the elderly patients were not received by the EMS network hospital. The most important factors that affect the total transport time in the elderly group were triage classification and trauma, which determined that speed of transport. In the elderly group, female patients tend to be older, of more severe triage classification, more nontrauma-related, have longer total transport time, and have less access to the EMS than male patient. Based on these results, we recommended make efficient transport in order to provide better emergency care for the elderly. A network linking the elder users with EMS dispatch center should improve the efficiency in fulfilling the EMS calls, and further investigation about the value of such a network is warranted. It is also important to establish a competent and countrywide database for EMS users and to pursue ongoing planning in order to evaluate and investigate the needs of EMS for elderly patients in the future.


Special patient populations: onychomycosis in the diabetic patient.
There are approximately 14 million persons with diabetes in the United States. These patients must cope with the serious complications of this disease, including neuropathy and impaired circulation (leading to the "diabetic foot" and possible amputation), renal disease, cardiovascular disease, and retinopathy (possibly leading to blindness). Although onychomycosis is no more common in diabetics than in the general population, it poses a greater risk because of the possible sequelae. Most notably, impaired sensation can make many diabetics less aware of minor abrasions and ulcerations on their feet that may be caused by trauma from poor nail grooming or by the nail changes characteristic of onychomycosis. These lesions, in turn, may develop into serious bacterial infections and contribute to the severity of the diabetic foot. Thus there is an important clinical rationale for treating diabetic patients with fungal nail infections. A secondary benefit is the improved self-esteem and enhanced quality of life.


A comparison between the effects of medial septal lesions and entorhinal cortex lesions on performance of nonspatial working memory tasks and reversal learning.
Rats with either electrolytic medial septal lesions or cytotoxic entorhinal lesions were compared to unoperated controls on a series of delayed matching-to-sample (DMS) tasks. A DMS trial consisted of two runs. In the first (information) run, the subject was familiarized with a sample discriminandum. In the second (choice) run, the subject was required to discriminate the sample discriminandum from a novel one. When a set of 20 discrete complex objects were used as discriminanda and each discriminandum was used once per day, neither lesions impaired choice accuracy. However, when a single pair of simple discriminanda was employed and re-used between trials within a day, rats with medial septal lesions were severely impaired whereas rats with entorhinal lesions performed at a level comparable to unoperated controls. Next, proactive interference was demonstrated by the introduction of an extra run prior to the information run. When this extra (pre-information) run required the subjects to visit the (eventual) negative discriminandum such that correct choice had to be guided by relative familiarity judgement, choice performance was reduced. Neither lesion group was selectively affected by this manipulation. But when the relative reinforcement history of the pre-information run and the information run was manipulated, such that a correct response required the subject to approach a discriminandum that had recently been non-rewarded, rats with entorhinal lesions were selectively impaired. The effect of delay was demonstrated when a 20-s interval was imposed between information run and choice run. This reduced overall choice accuracy, and this effect appeared to be more pronounced in both lesion groups, although not significantly so. Finally, neither lesion affected the acquisition of a simple discrimination task, but reversal learning was selectively enhanced in the entorhinal lesion group.


Seizure outcome after AED failure in pediatric focal epilepsy: impact of underlying etiology.
This study aimed to identify long-term seizure outcome in pediatric nonsyndromic focal epilepsy after failure of serial antiepileptic drugs (AEDs) due to lack of efficacy. Children (1 month-17 years) with new-onset focal epilepsy not meeting the criteria for a defined electroclinical syndrome diagnosed between 1980 and 2009 while residing in Olmsted County, MN, were retrospectively identified. Medical records of those followed for ≥2 years were reviewed to assess etiology, the number of AEDs that failed due to lack of efficacy, and seizure outcome at final follow-up. Etiology was classified into structural/metabolic, genetic, or unknown. Favorable outcome was defined as seizure freedom ≥1 year, on or off AEDs, without prior epilepsy surgery. Poor outcome was defined as ongoing seizures in the preceding year or having undergone prior epilepsy surgery. Nonsyndromic focal epilepsy accounted for 275/468 (59%) of all patients with newly diagnosed epilepsy--of these, 256 (93%) were followed for a minimum of two years and were included in the study. Median duration of follow-up was 10.0 years. At least one AED had failed due to lack of efficacy in 100 (39.1%) children. Favorable outcomes occurred in 149/156 (95.5%) children with no AED failure, 16/30 (53.3%) with one AED failure, 8/25 (32%) with two AED failures, and only 2/45 (4.4%) with three AED failures. After two AED failures, the seizures of nearly one-quarter of children who had epilepsy with an unknown cause responded favorably to the third AED compared with only 7.8% of the cohort that had epilepsy with a structural/metabolic cause. Children with a remote brain insult had a significantly higher likelihood of favorable outcome with serial AEDs than those with other structural abnormalities. Etiology is an important determinant of pharmacoresistance in nonsyndromic focal epilepsy. Surgical evaluation should be considered after failure of 1-2 AEDs in those who have epilepsy with structural causes, excluding remote brain insults. Conversely, as surgical success is lower with normal MRI or more diffuse brain insults, it appears reasonable to hold off surgical evaluation until 2-3 AEDs have failed in such children.


Pulmonary sequestrations of the upper lobe in children: three presentations.
Pulmonary sequestrations are congenital abnormalities where nonfunctioning lung tissue receives its vascular supply from the systemic circulation (thoracic or abdominal aorta). It is necessary to establish the diagnosis in childhood when the lesions are uncomplicated. The authors present three cases of sequestration of the apex (2 extralobar and 1 atypical) with the main clinical and radiological features. Sequestrations in the upper lobe are rare, and the usual site is the left lower lobe. Plain x-rays show a dense opacity, sometimes air-filled and sometimes with an air-fluid level: angiography is currently the best mean for definitive diagnosis; however, computed tomography will probably be very useful in the future. Differential diagnosis includes tumours of the superior mediastinum (neurogenic tumours, digestive duplication, bronchogenic cysts, pheochromocytoma and hydatid cysts).


The export of glutathione from human diploid cells in culture.
The export of glutathione from cultured human diploid fibroblasts into the surrounding medium was found by isotopic labeling experiments using [35S]cystine and by enzymatic measurements. The major part of the glutathione exported from the cells was found in normal culture medium as mixed disulfide of glutathione and cysteine. Radioactivity of 35S, mostly derived from cellular glutathione, was mainly located in glutathione moiety, not in cysteine moiety, of the mixed disulfide. Export of free glutathione was found when cystine-free medium was used. It was, therefore, concluded that mixed disulfide of glutathione and cysteine was formed in the medium by exported glutathione and medium cystine via sulfhydryl-disulfide exchange reaction. Amount of total glutathione exported from the cells was measured by enzymatic method and it was found that more than 10% of normal cellular glutathione was exported within 2 h. Apparent concentration of glutathione in the medium after a day of culture reached 3 to 4 micrometer, which was comparable to that observed in normal plasma by the same enzymatic method.


Antibacterial and bioactive alpha- and beta-chitin hydrogel/nanobioactive glass ceramic/nano silver composite scaffolds for periodontal regeneration.
Alveolar bone loss and bone defects are the commonly encountered periodontal problems. Large defects do not heal spontaneously and thus require surgical interventions with bone substitutes. Bone grafts have the disadvantages of eliciting an immunologic response with subsequent graft rejection. The success rate of Guided Tissue Regeneration (GTR) is variable because of high susceptibility to infection. Thus emerged the important role of synthetic biomaterials and hence for this purpose we developed a nanocomposite scaffold, using alpha- and beta-chitin hydrogel with bioactive glass ceramic nanoparticles (nBGC) and silver nanoparticles (nAg) by lyophilization technique (aalpha and beta-chitin hydrogel/nBGC/nAg nanocomposite scaffold). The prepared nanoparticles and nanocomposite scaffolds were characterized. In addition, the porosity, swelling, mechanical properties, antibacterial activity, in vitro degradation and biomineralization, cell viability, cell attachment and cell proliferation ability of the prepared composite scaffolds were also evaluated. The results showed that alpha- and beta-chitin/nBGC/nAg composite scaffolds were porous and have the capacity to absorb fluids and swell. The composite scaffolds also showed enhanced antibacterial activity, bioactivity and controlled degradation in comparison to the control scaffolds. Cell viability studies proved the non-toxic nature of the nanocomposite scaffolds. Cell attachment and cell proliferation studies revealed the attachment and spreading nature of cells. All these studies revealed that, these antibacterial nanocomposite scaffolds could be a promising approach for the management of periodontal defects.


Oxidative DNA damage correlates with carotid artery atherosclerosis in hemodialysis patients.
Oxidative stress is accepted as a nonclassical cardiovascular risk factor in chronic renal failure patients. The aim of this study was to evaluate the relation between oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine [8-OHdG/dG] ratio), oxidative stress biomarkers, antioxidant enzymes, and carotid artery intima-media thickness (CIMT) in hemodialysis (HD) patients. Forty chronic HD patients without known atherosclerotic disease and 48 age- and sex-matched healthy individuals were included in the study. Plasma malondialdehyde (MDA) levels and 8-OHdG/dG ratio were determined as oxidative stress markers. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. CIMT was assessed by carotid artery ultrasonography. 8-OHdG/dG ratios and MDA levels were higher; SOD and GPx activities were lower in HD patients compared to controls. HD patients had significantly higher CIMT compared to controls (0.61 ± 0.08 vs. 0.42 ± 0.05, p < 0.001). There was a significant positive correlation between CIMT and 8-OHdG/dG ratio (r = 0.57, p < 0.01) and MDA levels (r = 0.41, p < 0.01), while there was a significant negative correlation between CIMT and SOD (r = -0.47, p < 0.01) and GPx levels (r = -0.62, p < 0.01). It is firstly demonstrated that CIMT is positively correlated with oxidative DNA damage in HD patients without known atherosclerotic disease.


Analysis of brain and cerebrospinal fluid volumes with MR imaging: impact on PET data correction for atrophy. Part II. Aging and Alzheimer dementia.
A new, computerized segmentation technique, in which magnetic resonance (MR) imaging produces accurate volumetric measurements of brain and cerebrospinal fluid (CSF) without the limitations of computed tomography, was used in a retrospective analysis of digitized T2-weighted MR images of 16 healthy elderly control subjects and 16 patients with Alzheimer dementia. Ventricular and extraventricular CSF was quantified, and the effects of aging were studied; in both groups, the atrophy measurement was used to correct metabolic values obtained with positron emission tomography. Patients with Alzheimer dementia had higher total CSF; extraventricular, total ventricular, and third ventricular CSF volumes (49%, 37%, 99%, and 74%, respectively); and 7% lower brain volumes than the control group. The patients also showed a more marked decline in brain volumes and a greater increase in CSF volumes with advancing age than the control group. They had a 25.0% increase in corrected whole-brain metabolic rates; the control group had only a 15.8% increase. The use of this technique may provide a basis for further studies of aging and dementia, including regional volume analysis.


Ethanolgel sclerotherapy of venous malformations improves health-related quality-of-life in adults and children - results of a prospective study.
To assess the treatment-induced changes of health-related quality-of-life (HRQoL) in patients with venous malformations (VM) who underwent ethanol gel sclerotherapy. The prospective study in children and adults was approved by the local ethics committee. 31 patients (mean age 23.42 years, range 6.6 - 46.5; 26 female, 5 male) with VM were included. Patients' self-assessed HRQoL was measured before and after treatment using psychometrically validated questionnaires for adults and children. Differences were analysed with a paired t test. 58 sclerotherapy sessions were performed. The Physical Component Summary (PCS) at baseline was 43.69 and increased significantly (p = 0.01122) to 48.95 after treatment. The bodily pain (BP) scale increased significantly from 37.94 to 48.56 (p = 0.00002), the general health (GH) scale increased significantly from 46.69 to 52.17 (p = 0.00609). Baseline Physical Summary Score (PHS) in children increased significantly after treatment (p < 0.00001) from 25.25 to 45.89. The baseline Psychosocial Summary Score (PSS) in children was 51.08 and increased significantly (p = 0.00031) after treatment to 58.84. Paediatric and adult patients with VM suffer from bodily pain with overall reduced physical functioning. After sclerotherapy, these restrictions are successfully returning to normal levels with a positive effect on mental and psychosocial domains. • Sclerotherapy in venous malformation patients has an unknown effect on health-related quality-of-life • Prospective study showed improvements in bodily pain and general health in adults • Children and adults improved from treatment with ethanol gel • Sclerotherapy is an appropriate therapy.


Computer-guided microsurgery: surgical evaluation of a telerobotic arm.
A new telerobotic arm was evaluated in different microsurgical procedures. The system consisted of a robotic arm bearing a microsurgical forceps controlled by a joystick-like master unit operated by the surgeon's hand. The robotic arm functioned as an operating as well as assisting instrument. Advantages of the system were its precise functioning, which was especially important when tissue or instruments had to be held for a longer period of time, as well as its ability to replace an assisting person to some extent. Deficiencies of the system were its 10-min startup, the spatial conflict with in the operative field, and the poor rotation of the robotic tip. In some procedures, the telerobotic arm could replace the standard microsurgical instrument guided by the surgeon's second hand; in other maneuvers it could function as the surgeon's third hand with precision and void of tremor.


[Interventional radiology and abdominal emergencies].
Interventional radiology used in acute abdominal diseases has demonstrated its efficacy in most emergency cases especially in patients at high risk for surgery. Percutaneous drainage is a reference standard for abscesses located within the abdomen and pelvis with high success rates of up to 80%. The diagnosis and treatment of gastrointestinal hemorrhage have changed over the past two decades, with decreased diagnostic examinations and advances in pharmacologic therapy and improved endoscopic techniques. On the other hand, embolization techniques and new procedures such as trans jugular intra hepatic porto systemic shunt have been developed. Arterial embolisation in many situations such as blunt or direct trauma, obstetric or post operative hemorrhage, can be used as an effective easy and relatively safe technique with high success rates to stop bleeding and save the organ. Percutaneous drainage and angiographic techniques adapted to biliary and urinary tree have also been developed as well as endoscopic procedures, allowing treatment of stenoses by balloon dilatation, or plastic or metal prostheses. Indications, technical aspects, complications and limits of these various procedures are presented.


Ganglioside GM2 catabolism is inhibited by storage compounds of mucopolysaccharidoses and by cationic amphiphilic drugs.
The catabolism of ganglioside GM2 is dependent on the lysosomal enzyme β-hexosaminidase A and a supporting lipid transfer protein, the GM2 activator protein. A genetically based disturbance of GM2 catabolism, leads to several subtypes of the GM2 gangliosidosis: Tay-Sachs disease, Sandhoff disease, the AB-variant and the B1-variant, all of them having GM2 as major lysosomal storage compound. Further on it is known that the gangliosides GM2 and GM3 accumulate as secondary storage compounds in mucopolysaccharidoses, especially in Hunter disease, Hurler disease, Sanfilippo disease and Sly syndrome, with chondroitin sulfate as primary storage compound. The exact mechanism of ganglioside accumulation in mucopolysaccaridoses is still a matter of debate. Here, we show that chondroitin sulfate strongly inhibits the catabolism of membrane-bound GM2 by β-hexosaminidase A in presence of GM2 activator protein in vitro already at low micromolar concentrations. In contrast, hyaluronan, the major storage compound in mucopolysaccharidosis IX, a milder disease without secondary ganglioside accumulation, is a less effective inhibitor. On the other hand, hydrolysis of micellar-bound GM2 by β-hexosaminidase A without the assistance of GM2AP was not impeded by chondroitin sulfate implicating that the inhibition of GM2 hydrolysis by chondroitin sulfate is most likely based on an interaction with GM2AP, the GM2AP-GM2 complex or the GM2-carrying membranes. We also studied the influence of some cationic amphiphilic drugs (desipramine, chlorpromazine, imipramine and chloroquine), provoking drug induced phospholipidosis and found that all of them inhibited the hydrolysis of GM2 massively.


[Pulmonary hemorrhage and anti-phospholipid syndrome].
The presence of anti-phospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) associated to venous and/or arterial thrombotic phenomena and fetal losses define the anti-phospholipid syndrome. On rare occasions severe hypoprothrombinemia associated with this disease as a cause of hemorrhagic manifestations has been described. In addition very few cases of alveolar hemorrhage in anti-phospolipid syndrome (APS) have been described, being this complication usually related to microthrombosis and/or capillaritis of pulmonary vessels. We describe two patients without previous clinical manifestations of anti-phospholipid syndrome that showed pulmonary hemorrhage with anticardiolipin antibodies positivity. The first of them, a 33-year-old male, began his disease with low prothrombin time and the presence of antiprothrombin antibodies. In the biopsy by thoracoscopy the presence of pulmonary hemorrhage without capillaritis nor thrombotic phenomena was demonstrated, becoming evident certain clinical improvement and normalization of the prothrombin time after receiving immunosuppressive treatment but with persistence of the pulmonary hemorrhage 5 years later. The second case, a 89-year-old male, began his condition with bilateral lung infiltrates and hemoptysis, anticardiolipin antibodies positivity, and thrombopenia, with recurrence of the condition 1 year later. After other etiological possibilities were ruled out, and despite hemorrhagic trait in both patients, we consider that they should be in the clinical context of the anti-phospholipid syndrome, although at this time they did not meet the criteria recognized in order to diagnose this disease. Within the ampliable clinical spectrum of the anti-phospholipid syndrome we should take into account the pulmonary hemorrhage.


Microsurgical Management of Vascular Malformations of the Pineal Region.
Vascular pineal malformations are rare and technically demanding lesions. Because the locations of these lesions, endovascular techniques and radiosurgery have been increasingly used in the recent decades to accomplish safe occlusion. Nevertheless, microsurgical treatment may be required sometimes. We present a retrospective review of the vascular pineal malformations operated by the senior author. Moreover, we report illustrative cases for the various types of vascular lesions with a careful analysis of the different microsurgical stages. Eighteen patients with pineal vascular lesions were operated on between 1980 and 2015: 6 patients had vein of Galen malformations, 5 plexiform arteriovenous malformations, 6 cavernous malformations, and 1 patient had a ruptured medial posterior choroidal artery aneurysm. A complete resection and occlusion was possible in all vascular malformations. The pineal region is an infrequent but challenging location for vascular lesions. A careful and stepwise operative strategy for the different types of vascular lesion is paramount to accomplish an effective and safe microsurgical treatment when other alternatives fail or are not available.


Haplotype-specific sequence encoding the protein kinase, interferon-inducible double-stranded RNA-dependent activator in the human leukocyte antigen class II region.
The protein kinase, interferon-inducible double-stranded (ds)RNA-dependent activator (PRKRA) is a dsRNA-binding protein which activates a protein kinase participating in the antiviral activity of interferon. Our previous studies indicated that the nucleotide sequence encoding PRKRA, which appeared to be an intronless gene, was present in PAC HS265J14 containing the human leukocyte antigen (HLA) DR subregion. In this study, we further investigated and characterized the PRKRA gene on the human genome by means of Southern blotting and polymerase chain reaction with homozygous typing cell lines for HLA genes. Results indicated that the presence of PRKRA in the DR subregion was dependent on the DR53 group. Consistently, fluorescence in situ hybridization profiles with PRKRA as a probe showed that the hybridization signal on Chromosome (Chr) 6p21.3 was seen only in the samples carrying the DR haplotypes that belonged to the DR53 group. Interestingly, another hybridization signal, which was mapped on Chr 2q31.2-q32.1, was always detected in the samples examined, i.e., even in the samples negative for the DR53 group. The outcome of a sequence-database homology search further indicated that the PRKRA gene with introns appeared to be present in a recently opened draft-sequence, RP11-65L3 (GenBank accession number AC009948), which is located between D2S335 and D2S2257. Together, the data presented here indicate that the PRKRA gene in the DR subregion is a processed pseudogene (PRKRApsi), which could have been generated only on the DR53 common ancestor's genome, and that the master copy of PRKRApsi is most probably present on Chr 2q31.2-q32.1.


Analgesia at the department of intensive care.
Analgesia at the Department of intensive care can be distributed into three groups, with respect to the patient's respiratory status: 1) analgesia in a patient on controlled ventilation; 2) analgesia in a patient who is being weaned from a respirator; 3) analgesia in a patient breathing spontaneously. In patients of group 1, analgesia, respiratory depression and sedation are achieved with morphine applied parenterally or epidurally. While patients on assisted ventilation (group 2) require good analgesia and sedation, they should remain cooperative; this is achieved with tramadol or ketamine. Spontaneously breathing patients are maintained on tramadol in combination with NSAID. In all patients the dosage needs to be adjusted with respect to the type of pain, age, nutrition status, and previous use of analgesics.


[Corneal graft rejection and corticoid iontophoresis: 3 case reports].
This is the first report of three cases of severe acute corneal graft rejection, treated by transscleral methylprednisolone (Solumédrol) iontophoresis. The efficacy of the treatment was evaluated by corneal transparency, visual acuity and corneal inflammation parameters. The patient was treated with Solumédrol iontophoresis once a day for 3 days with a topical corticotherapy reduced to three drops of dexamethasone per day. Iontophoresis was performed, under topical anesthesia, and lasted 3 minutes with a 1.5-mA current. The subjective and objective tolerance of iontophoresis was good. No side-effect was observed. Corneal transparency and visual acuity improved rapidly after the second iontophoresis procedure. These observations show that Solumédrol iontophoresis might be an alternative to pulse therapy in the treatment of corneal graft rejection. Further comparative studies are necessary to confirm these preliminary observations.


[Activity of short-lived suppressor lymphocytes in rheumatoid arthritis].
Activity of short-lived suppressor lymphocytes was studied in 26 patients with rheumatoid arthritis. Of these, 14 patients had diverse systemic manifestations: rheumatoid nodules, polyneuropathy. Sjögren's syndrome, and Felty's syndrome. It was established that attenuation of the suppressor activity in rheumatoid arthritis is characteristic of patients with systemic manifestations, who show a high level of circulating immune complexes of rheumatoid factors. The most informative data were obtained as a result of the use of the suboptimal dose of Con A having suppressor activity.


Education Creates Welcoming Environment for Transgender Patients.
The ED often is the access point of choice for transgender patients who may be reluctant to interact with providers. Experts say there is a need for training and education of how to present a gender-affirming healthcare environment. Recommended steps include a review of policies, along with corresponding changes to electronic and paper intake forms to ensure that the language used is inclusive of all genders. While blanket discrimination may be declining, experts note that some providers are uncertain about how to interact with a transgender patient. It's always best to ask patients for their preferred name and pronoun and to repeat this exercise every three to six months for return patients, as gender identify can be fluid. To ease anxiety for transgender patients, consider developing a navigator program that will pair any transgender patient who requests the service with a trained advocate who can support and guide the patient through the system.


The suppression of human prostate tumor growth in mice by the intratumoral injection of a slow-release polymeric paste formulation of paclitaxel.
Most patients that present in the clinic with prostate cancer have either localized or recurrent postradiotherapy therapy tumors that may be amenable to injectable treatments using slow-release cytotoxic drugs. The objective of this preclinical study was to design an injectable polymeric paste formulation of paclitaxel for intratumoral injection into nonmetastatic human prostate tumors grown s.c. in mice. Paclitaxel was dissolved (10% w/w) in a blend of a biodegradable triblock copolymer of a random copolymer of D,L-lactide and epsilon-caprolactone (PLC) with poly(ethyleneglycol) [PEG; PLC-PEG-PLC] blended with methoxypoly(ethylene glycol) in a 40:60 ratio. Human prostate LNCaP tumors grown s.c. in castrated athymic male mice were injected with 100 microl of this paste at room temperature. Changes in tumor progression were assessed using both serum prostate-specific antigen (PSA) levels and tumor size. Paclitaxel inhibited LNCaP cell growth in vitro in a concentration-dependent fashion with an IC50 of 1 nM. Apoptosis was documented using DNA fragmentation analysis. The paste formulation solidified over a period of 1 h both in vivo and in aqueous media at 37 degrees C as the methoxypoly(ethylene glycol) component partitioned out of the insoluble PLC-PEG-PLC/paclitaxel matrix. The semisolid implant released drug at a rate of about 100 microg/day in vitro. In control mice treated with paste without paclitaxel, serum PSA levels increased from 2-8 ng/ml (mean, 4.3+/-2 ng/ml) to 60-292 ng/ml (mean, 181+/-88 ng/ml), and tumor volume increased from 30 to 1000 mm3. In mice treated with a single 100-microl injection 3 weeks after castration (early-phase treatment group), tumors decreased in volume from a mean of 43+/-19 mm3 to nonpalpable, and PSA levels decreased from a mean of 22+/-8 to 2+/-1 ng/ml by 8 weeks after castration. In mice treated 5 weeks after castration (androgen-independent tumors; late-phase treatment group), tumors decreased in volume from a mean of 233+/-136 mm3 to nonpalpable, and serum PSA decreased from 24+/-8 to 9+/-4 ng/ml. Observed side effects of the treatment were limited to minor ulceration at the needle injection site in paclitaxel-treated mice only. The controlled-release formulation can be injected via 22-gauge needles and is effective in inhibiting LNCaP tumor growth and PSA levels in mice bearing multiple nonmetastatic tumors. Paclitaxel may be an effective therapy for patients with localized tumors recurring after radiotherapy and for some patients with localized tumors who are not candidates for radical treatment.


Adjuvant chemotherapy with and without radiotherapy in stage II breast cancer.
The influence of several variables on the effectiveness of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy given to 87 patients with stage II breast cancer was retrospectively analyzed. CMF was given in optimal doses (greater than or equal to 85% of the planned dose) to 17% of the patients; in intermediate doses (66-84% of the planned dose) to 50% of the patients; and in low doses (less than or equal to 65% of the planned dose) to 33% of the patients. Radiotherapy before CMF was given to 68% of the patients; simultaneous radio- and chemotherapy to 17% of the patients; and the remaining 15% received CMF only. At a median follow-up of 8 yr, 61% of the patients were still alive; 54% of them were disease-free. Patients receiving radio- and chemotherapy concomitantly had a higher relapse-free survival (RFS) than those given both treatments sequentially (77% versus 46%; P = 0.05). Dose levels of CMF did not influence RFS. Delay in initiation of CMF, mainly due to the administration of prior radiotherapy was deleterious: patients started on CMF within 3 months of diagnosis had a 77% 8 yr RFS, as compared with 44% for those with a delay of over 3 months (P = 0.01). No differences in local relapse rates were observed between irradiated and non-irradiated patients, although 87% of all distant failures occurred in patients who received radio- and chemotherapy sequentially. The data of this study indicate that delay in onset of CMF is deleterious, and can be avoided by the simultaneous administration of both treatment modalities, since this approach was well tolerated, without significant myelotoxicity.


A novel cell-permeable cromoglycate derivative inhibits type I Fc epsilon receptor mediated Ca2+ influx and mediator secretion in rat mucosal mast cells.
Type I Fc epsilon receptor (Fc epsilon RI) mediated Ca2+ uptake and secretion of rat serosal mast cells have been shown to be inhibited by disodium 1,3-bis [(2'-carboxylatochromon-5'-yl) oxy]-2-hydroxypropane (disodium cromoglycate, DSCG), which is widely employed in the treatment of allergic asthma [Foreman et al. (1977) Br. J. Pharmacol. 59, 473P-474P; Cox (1967) Nature (London) 216, 1328-1329]. This drug was also found to modify the protein phosphorylation pattern of these mast cells. [Theoharides et al. (1980) Science 207, 80-82]. We have isolated by affinity chromatography on a water-insoluble cromoglycate-carrying matrix a cytosolic enzyme recently identified as a nucleoside 5'-diphosphate kinase. In order to examine a possible intracellular activity of the drug, a cell-permeant cromoglycate derivative, 1,3-bis [[2'-[[(acetoxymethyl)oxy]carbonyl]chromon-5'- yl]oxy]-2-hydroxypropane [bis(acetoxymethyl) cromoglycate, CG/AM], has been synthesized, and its uptake and effect on the Fc epsilon RI-mediated exocytosis of mast cells was investigated. A tritium-labeled CG/AM derivative, used as radioactive tracer, was found to permeate mucosal mast cells of the rat line RBL-2H3 and accumulate intracellularly up to 40-fold its extracellular concentration following hydrolysis by cytoplasmic hydrolases. A CG/AM dose dependent inhibition of the Fc epsilon RI-induced mediator secretion was observed in RBL-2H3 cells loaded with this compound (I50 approximately 40 microM extracellular CG/AM). A similar dose-dependent inhibition was observed for both the Fc epsilon RI-mediated transient rise in the concentration of cytosolic free Ca2+ ions [( Ca2+]i) and the net Ca2+ influx, as monitored by the fluorescent indicator Quin2 and the radioactive tracer 45Ca2+, respectively. These results clearly show that cell-permeant cromoglycate inhibits the Fc epsilon RI-mediated Ca2+ influx into the cell and further underscore the dominant role of this process in the coupling of stimulus to secretion in RBL cells. Furthermore, with the identification of nucleoside 5'-diphosphate kinase as a potential intracellular target for CG activity, distinct mechanisms of action may be inferred for cell-permeant and nonpermeant forms of CG.


External validation of Acute Physiology and Chronic Health Evaluation IV in Dutch intensive care units and comparison with Acute Physiology and Chronic Health Evaluation II and Simplified Acute Physiology Score II.
The aim of this study was to validate and compare the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) IV in the Dutch intensive care unit (ICU) population to the APACHE II and Simplified Acute Physiology Score (SAPS) II. This is a prospective study based on data from a national quality registry between 2006 and 2009 from 59 Dutch ICUs. The validation set consisted of 62,737 patients; the 3 models were compared using 44,112 patients. Measures of discrimination, accuracy, and calibration (area under the receiver operating characteristic curve (AUC), Brier score, R(2), and Ĉ-statistic) were calculated using bootstrapping. In addition, the standardized mortality ratios were calculated. The original APACHE IV showed good discrimination and accuracy (AUC = 0.87, Brier score = 0.10, R(2) = 0.29) but poor calibration (Ĉ-statistic = 822.67). Customization significantly improved the performance of the APACHE IV. The overall discrimination and accuracy of the customized APACHE IV were statistically better, and the overall Ĉ-statistic was inferior to those of the customized APACHE II and SAPS II, but these differences were small in perspective of clinical use. The 3 models have comparable capabilities for benchmarking purposes after customization. Main advantage of APACHE IV is the large number of diagnoses that enable subgroup analysis. The APACHE IV coronary artery bypass grafting (CABG) model has a good performance in the Dutch ICU population and can be used to complement the 3 models.


Embolization of type II endoleaks fed by the inferior mesenteric artery: using the superior mesenteric artery approach.
To evaluate the use of a superior mesenteric artery (SMA) approach to embolize type II endoleaks arising from the inferior mesenteric artery (IMA). When reperfusion of the aneurysmal sac via the SMA occurs through the IMA, as shown by computed tomography (CT) and angiography, the IMA origin can be accessed via the marginal artery or the anastomosis of Riolan. The SMA is catheterized with a 5-F catheter, and a coaxial catheter is advanced to the leak to deliver 2- to 8-mm-diameter minicoils to embolize the IMA origin and entire aneurysmal sac. Embolization usually requires from 1 to 2 hours to complete. In our experience with this technique in 11 cases, complications have not occurred, and there has been only one very small residual leak that sealed the next day. Over a 24.5-month follow-up (range 12-39), the endoleaks have remained sealed according to serial color duplex scans. Successful percutaneous treatment of type II endoleak due to IMA inflow can be accomplished using an SMA access via the Riolan anastomosis or marginal artery. The procedure appears to be safe and has no adverse effects.


Composition of the Essential Oil of Agastache foeniculum.
AGASTACHE FOENICULUM contains 0.1-0.3% essential oil and the main components are limonene, beta-caryophyllene, methylchavicol, and germacrene B (92% altogether). In addition 35 components, each accounting for less than 1% of the total essential oil, were identified.


Randomized prospective comparison of visian toric implantable collamer lens and conventional photorefractive keratectomy for moderate to high myopic astigmatism.
To compare the Visian Toric Implantable Collamer Lens (TICL), a toric phakic intraocular lens (IOL), and photorefractive keratectomy (PRK) in the correction of moderate to high myopic astigmatism. This prospective, randomized study consisted of 43 eyes implanted with the TICL (20 bilateral cases) and 45 eyes receiving PRK with mitomycin C (22 bilateral cases) with moderate to high myopia (-6.00 to -20.00 diopters [D] sphere) measured at the spectacle plane and 1.00 to 4.00 D of astigmatism. All patient treatment and follow-up occurred at the Naval Medical Center San Diego. Study follow-up was 1 day, 1 week, 1, 3, 6, and 12 months postoperative. Mean best spectacle-corrected visual acuity (BSCVA), change in BSCVA, proportion of cases with improvement of 1 or more lines of BSCVA, proportion of cases with BSCVA and uncorrected visual acuity (UCVA) 20/12.5 or better, proportion of cases with BSCVA and UCVA 20/16 or better (6 months, 88% vs 54%, P=.002), and predictability +/-1.00 D (6 months, 100% vs 67%, P<.001) were all significantly better in the TICL group than the PRK group at all time periods studied postoperatively. Similarly, contrast sensitivity, tested at both the 5% photopic level and the 25% mesopic level, was significantly better at all postoperative time points in the TICL group. Mean spherical equivalent refraction was closer to emmetropia (0.28+/-0.41 vs 0.76+/-0.86, P=.005), and predictability +/-0.50 D and stability of manifest refraction (+/-0.50 D and +/-1.00 D) were significantly better in the TICL group at all postoperative visits through 6 months. Mean astigmatism correction at 6 months was not significantly different between the two groups (0.52+/-0.33 vs 0.46+/-0.35, P=.450). The TICL performed better than PRK in all measures of safety (BSCVA), efficacy (UCVA), predictability, and stability in this comparison, supporting the TICL as a viable alternative to existing refractive surgical treatments.


A logistic model for the remediation of filamentous bulking in a biological nutrient removal wastewater treatment plant.
Biological nutrient removal (BNR) systems across the globe frequently experience bulking and foaming episodes, which present operational challenges such as poor sludge settling due to excessive filamentous bacteria. A full-scale BNR plant treating primarily domestic wastewater was monitored over a period of 1 year to investigate filamentous bacterial growth response under various plant operating parameters. Identification of filamentous bacteria by conventional microscopy and fluorescent in situ hybridisation indicated the dominance of Eikelboom Type021N, Thiothrix spp., Eikelboom Type 1851 and Eikelboom Type 0092. A cumulative logit model (CLM) was applied to elucidate significant relationships between the filamentous bacteria and plant operational parameters. The model could predict the potential abundance of dominant filamentous bacteria in relation to wastewater treatment plant operational parameters. Data obtained from the model corroborated with previous findings on the dominance of most filaments identified, except for Type 0092, which exhibited some unique traits. With further validation, the model could be successfully applied for identifying specific parameters which could contribute towards filamentous bulking, thus, providing a useful tool for regulating specific filamentous growth in full-scale wastewater treatment plants.


Angina 1 year after percutaneous coronary intervention: a report from the NHLBI Dynamic Registry.
As percutaneous coronary intervention (PCI) is most commonly performed for relief of angina, it is important to identify factors associated with recurrence of anginal symptoms. We examined symptoms at 1-year follow-up in 1755 consecutive NHLBI Dynamic Registry patients who underwent PCI in the setting of symptoms or acute infarction. At 1-year follow-up, 26% of patients reported angina in the previous 6 weeks. Younger patients and females reported more symptoms. History of coronary artery bypass graft (CABG) or PCI, prior myocardial infarction (MI), diabetes, graft disease, and extensive coronary artery disease (CAD) (>4 significant lesions) were also associated with follow-up angina. Patients receiving stents reported less angina (24% vs 29%, P <.05). Completely revascularized patients and those with residual single-vessel disease had comparable 1-year angina rates (23% both subgroups), while 32% of patients with residual multivessel CAD reported symptoms. Patients undergoing repeat PCI during follow-up reported more 1-year angina than others (34% vs 24%, P <.001), whereas those undergoing CABG after post-PCI hospitalization had less symptoms (15% vs 26%, P <.05). After adjustment for baseline symptom status and outcome of index PCI, residual CAD, and reintervention during follow-up, patient characteristics significantly predictive of angina included female sex, age <62 years, and prior MI. While approximately three quarters of patients receiving PCI are angina-free at 1 year, females continue to have more symptoms, as do other subgroups including patients with history of MI or previous intervention. As these symptoms are associated with self-reported activity and quality of life limitation, evaluations of PCI should include angina as a key follow-up outcome.


Innate immunity against Legionella pneumophila during pulmonary infections in mice.
Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns that are absent in host cells. During pulmonary legionella infections, various inflammatory cells such as macrophages, neutrophils, natural killer (NK) cells, large mononuclear cells, B cells, and CD4+ and CD8+ T cells are recruited into infected lungs, and predominantly occupy interstitial areas to control legionella. During pulmonary legionella infections, the interplay between distinct cytokines and chemokines also modulates innate host responses to clear legionella from the lungs. Recognition by NK cell receptors triggers effector functions including secretion of cytokines and chemokines, and leads to lysis of target cells. Crosstalk between NK cells and dendritic cells, monocytes, and macrophages provides a major first-line defense against legionella infection, whereas activation of T and B cells resolves the infection and mounts legionella-specific memory in the host.


Standardizing Key Issues from Hospital Through an Electronic Multi-Professional Discharge Checklist to Ensure Continuity of Care.
This article describes development of the multi-professional discharge checklist and its implementation into the nursing documentation system (NDS) as part of the patient's overall care plan. The aim was to harmonize patient's admission and care period documentation and to improve the quality of electronic nursing discharge summaries. The ultimate goal was to ensure continuity of care. The multidisciplinary discharge checklist was developed in two phases to support the discharge of elderly patients (over 65 years). First, the information content of the checklist was defined, and second, it was integrated into the NDS. Focus groups of social and healthcare professionals (n = 82) in specialist health care, primary health care and social services defined the information content and participated in the feedback and checking rounds. The development work should continue. Particular attention should be given to the technical performance of discharge checklists in the NDS.


Effect of lysophosphatidic acid on motility, polarisation and metabolic burst of human neutrophils.
The effect of lysophosphatidic acid (LPA) on human neutrophil activation was examined by a combination of automated tracking assays, cell shape measurements and assays of the metabolic burst by means of 7-dimethylamino-naphthalene-1,2-dicarbonic acid hydrazide (DNDH)-dependent chemiluminescence. LPA powerfully stimulated polarisation and motility. Polarisation became detectable at 2 microM LPA and virtually 100% of cells were polarised at 20 microM LPA. Cell motility increased with the degree of polarisation, and was diminished at high LPA concentration, but this decrease was reversed by albumin. LPA also inhibited the metabolic burst response to both n-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorobol 12-myristate 13-acetate (PMA). Inhibition of the PMA-induced metabolic burst by LPA was not affected by pertussis toxin, showing that the effect was not mediated by the pertussis toxin-sensitive heterotrimeric G protein, and that inhibition of the PMA-stimulated metabolic burst by LPA could result from a direct action of LPA on the small cytosolic GTP-binding proteins. These results indicate that lysophosphatidic acid production by thrombin-activated platelets could play a significant role in the regulation of the inflammatory response.


1,2,3-Triazole pharmacophore-based benzofused nitrogen/sulfur heterocycles with potential anti-Moraxella catarrhalis activity.
Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9-17 and 25-28), 7-substituted coumarin (18-23 and 29-30) or penciclovir-like subunit (31a,b-38a) were designed and synthesized to evaluate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. Hybridization approach using environmentally friendly Cu(I)-catalyzed click reaction under microwave irradiation was adopted in the synthesis of regioselective 1,4-disubstituted 1,2,3-triazole tethered heterocycles (9-23 and 25-30), while post-N-alkylation of NH-1,2,3-triazoles afforded both 2,4- (31a-38a) and 1,4-disubstituted (31b-33b, 35b-37b) 1,2,3-triazole regioisomers. The compounds 18-23 and 25-30 revealed fluorescence in the violet region of the visible spectrum with a strong influence of phenyl spacer in 25-30 on both wavelength and emission intensity. Fusion of selected subunits led to new hybrid architecture, benzothiazole-1,2,3-triazole-coumarin 29 that demonstrated extremely narrow spectrum activity towards fastidious Gram-negative bacteria Moraxella catarrhalis. Selected hybrid showed the potency against Moraxella catarrhalis (MIC⩽0.25μg/mL) comparable to that of reference antibiotic azithromycin, which suggested that further investigations are necessary to optimize this potential hit compound as a new anti-Moraxella catarrhalis agent.


Strong similarities in antigen fine specificity among DRB1* 1302-restricted tetanus toxin tt830-843-specific TCRs in spite of highly heterogeneous CDR3.
We investigated the Ag fine specificity of four TCRs that shared the same V beta segment but used V alpha s of three different subfamilies and displayed highly heterogeneous alpha and beta CDR3. The TCRs recognized the tetanus toxin tt830-843 (QYIKANSKFIGITE) epitope presented by DRB1*1302. By using a large panel of monosubstituted peptide analogues, we first defined the requirements for tt830-843 binding to DRB1*1302. We found that three residues, I832, N835, and G840, were critical for the interaction with DRB1*1302. Residues potentially contacted by the four TCRs were functionally defined by measuring the IL-2 response to the analogues. Except for the first and the last three residues, as well as I832 and G340, all of the others appeared to provide contacts with the four TCRs, indicating a considerable overlapping in the way these TCRs interact with the peptide. More importantly, and contrary to expectations, the two TCRs expressing the same V alpha/V beta germ-line segments showed a strikingly similar reactivity toward nearly all substitutions; moreover, more pronounced differences were observed when comparing TCRs using different V alpha segments. These results indicate that TCRs with entirely distinct CDR3s in the context of conserved V segments may not differ substantially in the way they recognize the ligand, and may provide new insights into understanding the formation of TCR/peptide/MHC ternary complexes. During these studies, we noticed that analogues with nonconservative substitutions at I832, which bound very unstably to DRB1*1302, could effectively stimulate T cells, suggesting a role of the TCR in contributing toward stabilization of peptide binding.


Morbid obesity in the UK: A modelling projection study to 2035.
Morbid obesity (body mass index ⩾40 kg/m2) carries a higher risk of non-communicable disease and is associated with more complex health issues and challenges than obesity body mass index ≥30kg/m2 and <40kg/m2, resulting in much higher financial implications for health systems. Although obesity trends have previously been projected to 2035, these projections do not separate morbid obesity from obesity. This study therefore complements these projections and looks at the prevalence and development of morbid obesity in the UK. Individual level body mass index data for people aged >15 years in England, Wales (2004-2014) and Scotland (2008-2014) were collated from national surveys and stratified by sex and five-year age groups (e.g. 15-19 years), then aggregated to calculate the annual distribution of healthy weight, overweight, obesity and morbid obesity for each age and sex group. A categorical multi-variate non-linear regression model was fitted to these distributions to project trends to 2035. The prevalence of morbid obesity was predicted to increase to 5, 8 and 11% in Scotland, England and Wales, respectively, by 2035. Welsh women aged 55-64 years had the highest projected prevalence of 20%. In total, almost five million people are forecast to be classified as morbidly obese across the three countries in 2035. The prevalence of morbid obesity is predicted to increase by 2035 across the three UK countries, with Wales projected to have the highest rates. This is likely to have serious health and financial implications for society and the UK health system.


[Recto-vesical fistula (author's transl)].
23 cases of recto-vesical fistula are described; their diagnostic and therapeutic approach are discussed. The entero-vesical fistula result mainly from diverticular disease but may be secondary to tumor or Crohn's disease of the large bowel too. The treatment needs allways surgery: bowel resection and bladder extraperitonisation. Results and literature are compared.


Diabetes Attitudes, Wishes and Needs second study (DAWN2™): cross-national benchmarking indicators for family members living with people with diabetes.
The second Diabetes Attitudes, Wishes and Needs (DAWN2) study examined the experiences of family members of people with diabetes for benchmarking and identifying unmet needs or areas for improvement to assist family members and those with diabetes to effectively self-manage. In total, 2057 family members of people with diabetes participated in an online, telephone or in-person survey designed to assess the impact of diabetes on family life, family support for people with diabetes and educational and community support. Supporting a relative with diabetes was perceived as a burden by 35.3% (range across countries 10.6-61.7%) of respondents. Over half of respondents [51.4% (22.5-76.0%)] rated their quality of life as 'good' or 'very good'. However, distress about the person with diabetes was high, with 61.3% (31.5-86.4%) worried about hypoglycaemia. The impact of diabetes on aspects of life was felt by 51.8% (46.9-58.6%). The greatest negative effect was on emotional well-being [44.6% (31.8-63.0%)], although depression was less common [11.6% (4.2-20.0%)]. Many respondents did not know how to help the person with diabetes [37.1% (17.5-53.0%)] and wanted to be more involved in their care [39.4% (15.5-61.7%)]. Participation in diabetes educational programmes was low [23.1% (9.4-43.3%)], although most of those who participated found them helpful [72.1% (42.1-90.3%)]. Diabetes has a negative impact on family members of people with diabetes. DAWN2 provides benchmarking indicators of family members' psychosocial needs that will help identify the support required for, and from, them to improve the lives of people with diabetes and their families.


High-dose continuous infusion plus pulse interleukin-2 and famotidine in metastatic kidney cancer.
High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.


Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance.
Proliferative changes in the neuroendocrine cells that precede neoplasia are of interest for the understanding of tumorigenesis and the early recognition of neuroendocrine tumors. This review focuses on precursor lesions of duodenal and pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) and also discusses 2 new disease entities of pancreatic microadenomatosis. The gastrinomas observed in MEN1 are almost exclusively localized in the duodenum and are multicentric. It has been shown that, in contrast to sporadic duodenal gastrinomas, they are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing microtumors less than 500 microm in diameter. In the pancreas, microadenomatosis (multiple tumors up to 5 mm in diameter) is a feature of MEN1. These microadenomas predominantly express glucagon and pancreatic polypeptide, but do not cause a hormonal syndrome. Approximately 50% of MEN1 minigastrinomas in the duodenum and almost all microadenomas in the pancreas show allelic deletion of the MEN1 gene and therefore may represent 'initial' neoplasms. In contrast, endocrine cell precursor lesions retain heterozygosity. Pancreatic microadenomatosis was also found unassociated with hereditary syndromes and 2 monohormonal types were identified: (1) glucagon-producing microadenomatosis and (2) insulin-producing microadenomatosis, both associated with macrotumors. Whether these types of microadenomatosis represent novel disease entities and how to diagnose and treat these patients remains to be clarified by further studies.


Downregulation of a unique photoreceptor protein correlates with improper outer segment assembly.
A unique photoreceptor protein has been characterized. This protein, termed XAP-1 antigen, is expressed by photoreceptors exclusively under conditions in which the outer segment membranes are properly assembled. When the retinal pigment epithelium is adherent to the underlying neural retina, the XAP-1 antigen is localized to the plasma membrane that surrounds the inner and outer segments in the areas juxtaposed to the subretinal space. A similar labeling pattern is detected in retinal pigment epithelium-deprived retinas in which assembly of nascent outer segments is supported by lactose. In retinas that undergo degeneration subsequent to the removal of the retinal pigment epithelium, the expression of this protein is completely downregulated. Immunohistochemical analyses and subcellular fractionation along with Western blot analysis, indicate that the XAP-1 antigen is a membrane-associated soluble protein. Mass spectrometric analysis indicates that the XAP-1 antigen shares homology via 12 tryptic peptide masses with the gamma-crystallin (lens structural protein) subclasses, although it does not immunolocalize to the same ocular structures as reported for the gamma-crystallins. We propose that XAP-1 antigen is a unique protein that is expressed extensively by healthy photoreceptor cells; the expression of the XAP-1 antigen exclusively by photoreceptors with organized outer segments suggests that this protein may play a critical role in outer segment assembly.


[Establishment of a hepatic fibrosis model induced by diethylnitrosamine in zebrafish].
To establish a zebrafish model of liver fibrosis via diethylnitrosamine (DEN)-induced liver injury. A total of 120 wild-type 3-month-old zebrafish were randomly divided into DEN-treated group and control group. The survival rate and behavioral changes of each group were observed. After treatment with DEN for 2, 4, and 6 weeks, liver index was measured, and liver fibrosis was evaluated with HE staining, Gomori staining and Sirius red staining. No obvious behavioral change was observed in DEN-treated group during the experiment. Compared with that in control group, the liver index of zebrafish in DEN-treated group showed no significantly changes at the time points of observation. Proliferation of reticulate fibers was found in 30% of zebrafish treated with DEN for 4 weeks, and the rate increased to 80% at 6 weeks when reticulate fibers and collagen fibers actively proliferated to result in fiber collapse and formation of fibrotic nodules. A stable zebrafish liver fibrosis model was successfully established by inducing liver damage to facilitate studies of the pathogenesis of liver fibrosis and screening therapeutic drugs.


[Cystic dilatation of the choledochus: the diagnostic problems].
Choledochal cyst is a rare pathology in western countries and the typical signs and symptoms are not always present at the onset. The diagnosis is often difficult and it needs a long time to be clear. In this paper we review our recent experience with this pathology (8 patients) and particularly we point out the problems of the delate in the diagnosis and the best choice to study these patients.


Comparison of location of mesh placed transvaginally vs mesh placed abdominally at the time of sacrocolpopexy.
The location of mesh placed at the time of abdominal sacrocolpopexy (ASC) is hypothesized to be in the same location histologically as mesh placed via full-thickness vaginal dissection in a cadaver model. Ten fresh frozen cadavers underwent mesh placement via traditional ASC. In the same specimen, a transvaginal mesh (TVM) procedure was performed, attempting a full-thickness dissection. A block section was excised from each area including full thickness of the vagina and bladder with the intervening mesh. This was analyzed by a blinded pathologist. All cadavers underwent successful placement of both transabdominal mesh and TVM. Of the abdominally placed meshes, 6 were located between the vagina and bladder, whereas 3 were situated within the vaginal wall, with an average depth of 0.30 mm. Five of the vaginal mesh pieces were placed between the bladder and vagina, and 4 within the vaginal wall at a depth of 0.25 mm. One specimen placed vaginally was 0.05 mm within the serosa of the bladder. One specimen could not be interpreted, despite multiple cuts. ASC and full-thickness vaginal dissection result in histologically similar locations. Dissection for ASC may only result in the correct plane between the bladder and vagina in approximately 60 % of cases. We achieved full-thickness dissection for the transvaginal approach in 50 % of the cases, with one small penetration into the bladder serosa. Using a full-thickness dissection technique for TVM may be one way of reducing mesh exposure rates in those seen with ASC.


[The pathomorphology of hypophyseal adenomas].
The paper presents the results of morphological study of 668 cases of adenomas of the hypophysis on the basis of light optical and electron microscopy techniques, immunohistochemical analysis and a number of other methods. Correlation between cellular, tissue and hormonal characterization of adenomas and their capacity for invasive, infiltrative growth and relapses have been studied.


Comparative studies of atropine methonitrate and its combination with reproterol in chronic airway obstruction.
The therapeutic value of 80 micrograms atropine methonitrate delivered per metered aerosol and its combination with 450 micrograms reproterol was investigated in a controlled double-blind cross-over trial in 17 patients with chronic bronchitis and airway obstruction. All patients were atropine responders. According to the parameters of FEV1 and SGaw atropine methonitrate induced a statistically definite and clinically relevant bronchodilation for more than 3 h compared with placebo. The combination of 80 micrograms atropine methonitrate and 450 micrograms reproterol, however, proved to be clearly superior compared with the mono-compound atropine methonitrate.


Social engineers and bystanders: the limits of 'responsibility' in Indigenous affairs.
A significant shift is occurring in Australian Indigenous affairs. Contentiously, key Aboriginal and Torres Strait Islander leaders have challenged governments and organizations, both mainstream and Indigenous, to confront 'passive welfare dependence'. This paper explores some of the social justice implications and considers the roles of non-Indigenous professionals. A publication by Pat Dodson and Noel Pearson is used to frame the discussion. Ambiguity surrounding a number of key concepts and the shifting territory of Indigenous rights has contributed to bureaucratic inertia in Indigenous affairs. A range of 'new' concepts is being introduced into the current debate, such as expectancy, reciprocity and mutual obligation, challenging ideas of responsibility, agency and the roles played by non-Indigenous bureaucrats and practitioners. Regardless of good intentions or social justice motivations, non-Indigenous interventions must be informed by an awareness of the potential to undermine Indigenous agency and, consequently, cause harm.


Divalproex utility in bipolar disorder with co-occurring cocaine dependence: a pilot study.
The aim of this open-label pilot study was to evaluate the utility of divalproex in decreasing cocaine use and stabilizing mood symptoms among patients with bipolar disorder with comorbid cocaine dependence. Fifteen patients enrolled in the study and seven met final inclusion criteria of DSM-IV/SCID diagnoses of bipolar I disorder and comorbid cocaine dependence with active cocaine use. Patients were started on open-label divalproex. After stabilization on divalproex sodium, weekly assessments were undertaken for 8weeks. Subjects also attended dual recovery counseling. The results revealed significant improvement on % cocaine abstinent days, dollars spent on cocaine, ASI's drug use severity index, % alcohol abstinent days, drinks per drinking day, marijuana use and cigarettes smoking. They also had significant improvement on manic, depressive, and sleep symptoms and on functioning. There were no reported adverse events or increases in liver function tests. The results of this open-label study point to the potential utility of divalproex in patients with bipolar disorder and primary cocaine dependence. Double-blind, placebo-controlled studies to fully evaluate the efficacy of divalproex in this high risk clinical population are warranted.


Two cases of premenstrual sleep terrors and injurious sleep-walking.
There are currently three recognized menstrual-related sleep disorders: premenstrual insomnia, menopausal insomnia and premenstrual hypersomnia. Another category, premenstrual parasomnia (sleep behavior disorder), is now suggested. Case 1, a 17-year-old female, presented with a 6-year history of exclusively premenstrual sleep terrors and injurious sleep-walking that began 1 year after menarche. During the four nights preceding each menses, she would scream and run from her bed. There was no history of premenstrual syndrome. Neurological evaluations had been unrevealing, apart from mild mental retardation and attention deficit disorder; there was no psychiatric history. Polysomnography 3 days before the onset of menses confirmed the diagnosis of sleep-walking. Pharmacotherapies were not satisfactory, but self-hypnosis at bedtime was rapidly effective with benefit sustained at 2.5-year follow-up. Case 2, a 46-year-old woman without psychiatric disorder, presented with a 5-year history of sleep terrors and injurious sleep-walking that initially was not menstrually related, but beginning 8 months prior to referral, she developed an exclusively premenstrual parasomnia that, after polysomnography, was partially controlled with bedtime self-hypnosis and clonazepam, 0.25 mg.