Poly(ADP-ribose) polymerase 1 inhibition prevents interleukin-1β-induced inflammation in human osteoarthritic chondrocytes.
Osteoarthritis (OA) is an age-related joint disease that is characterized by the degeneration of articular chondrocytes. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with inflammation response. We investigated the role of PARP-1 in interleukin-1β (IL-1β)-stimulated human articular chondrocytes and its underlying mechanism. Cell viability and apoptosis were evaluated by using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry, respectively. Tumor necrosis factor-α (TNF-α) level was measured by enzyme-linked immunosorbent assay. The mRNA and protein expression levels of PARP-1, IL-1 receptor (IL-1R), inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined by real-time reverse transcriptase-polymerase chain reaction and western blot analysis, respectively. The expression and phosphorylation of NF-кB p65 were measured by western blot analysis. Results showed that stimulation of chondrocytes with IL-1β caused a significant up-regulation of PARP-1 and IL-1R, resulting in NF-кB p65 nuclear translocation and phosphorylation associated with an increase of TNF-α secretion and iNOS expression. PARP-1 was inhibited by siRNA transfection. Results showed that PARP-1 inhibition suppressed IL-1β-induced reduction of cell viability and up-regulation of cell apoptosis, with a reduced IL-1R expression. PARP-1 inhibition also effectively reversed IL-1β-induced inflammatory response through inhibiting the IL-1R/NF-кB pathway. These data suggested that PARP-1 inhibition prevents IL-1β-induced inflammation response at least partly by inhibiting the IL-1R/NF-кB signaling pathway in human articular chondrocytes. Moreover, PARP-1 inhibition reduced MMPs expression and increased TIMP-1 expression, suggesting that PARP-1 inhibition could suppress cartilage destruction by modulating the balance between MMPs and TIMP-1. Inhibition of PARP-1 might be useful in the treatment of OA.


Imaging of osteomyelitis in the mature skeleton.
Diagnosis of acute osteomyelitis is often challenging but can be made by plain radiograph, bone scan, or MR imaging. This diagnosis may be more problematic in small bones, in diabetic or immunocompromised patients, those partially treated, post-traumatic, previous surgery, or with pre-existing marrow conditions and associated soft tissue infections. CT is the modality of choice for revealing sequestra and cortical erosions in chronic osteomyelitis. Nonenhanced and enhanced STIR or fat-saturated sequences are essential to reveal the marrow abnormality and its extension for diagnosis of subtle cases with neuropathic or other associated conditions. Combined radionuclide scintigraphy becomes necessary in complicated situations.


[Estimation of the levels of heavy metals in the water courses and drinking water in the south of the Issyk-Kul Region].
The levels of heavy metals were determined in the river and drinking waters of the localities of the Ton and Jety-Oguz Districts of the Issyk-Kul Region. The quality of water was tested for the content of 11 heavy metals (Be, Pb, Cd, Ni, Co, Cr6+, Zn, Ba, Sr, TI, Sn) by emission spectral analysis in 1990-2000. The analysis of the findings indicated that the water levels of the heavy metals, met the sanitary requirements for drinking water, except for those of chromium whose content in the Barskoon and Chon-Kyzyl-Suu rivers in the cold period of 1999 was 2-3 times higher than the allowable levels. There were seasonal variations in the concentrations of heavy metals in the river waters. In most cases, the concentrations of most metals increase in the warm period of a year. The concentrations of heavy metals tended to increase in the river water in 2000 versus 1999.


Treatment of long bone fractures in South American camelids: 5 cases.
An adult llama and four alpacas were referred with long bone fractures. The llama presented with a closed, comminuted fracture of the right metatarsal bones. Two of the alpacas presented with comminuted fractures of the proximal radius. One fracture was closed and one was open. One alpaca had a closed, comminuted fracture of the distal radius, and the final alpaca had a closed, oblique fracture of the metatarsus. A diagnosis was made in each animal on the basis of clinical examination and radiographs. All fractures were managed by open reduction and internal fixation using selective placement of lag screws and dynamic compression plates. Four animals made uneventful recoveries and no long-term complications were encountered. One alpaca was re-admitted for plate failure and non-union of the fracture 5 weeks after surgery. The plate and screws were removed and a transfixation cast was applied. The fracture healed, however the alpaca showed signs of radial nerve paralysis after the cast was removed. With confinement in a small yard, full function gradually returned to the leg over the ensuing 4 months. Using techniques recommended in other species, South American camelids are suitable candidates for long bone fracture repair using open reduction and internal fixation.


[The role of mediator mechanisms in inflammation immunopathogenesis in cardiovascular diseases and osteoporosis].
General pathophysiological mechanisms of inflammation are reviewed on the models of atherosclerosis, calcinating aortic stenosis, cardiac failure and osteoporosis widely encountered at old age.


Topical amphotericin B in ultradeformable liposomes: Formulation, skin penetration study, antifungal and antileishmanial activity in vitro.
Aiming to improve the topical delivery of AmB to treat cutaneous fungal infections and leishmaniasis, ultradeformable liposomes containing amphotericin B (AmB-UDL) were prepared, and structural and functional characterized. The effect of different edge activators, phospholipid and AmB concentration, and phospholipid to edge activator ratio on liposomal deformability, as well as on AmB liposomal content, was tested. Liposomes having Tween 80 as edge activator resulted of maximal deformability and AmB/phospholipid ratio. These consisted of AmB-UDL of 107±8nm diameter, 0.078-polydispersity index and -3±0.2mV Z potential, exhibiting monomeric AmB encapsulated in the bilayer at a 75% encapsulation efficiency. After its cytotoxicity on keratinocytes (HaCaT cells) and macrophages (J774 cells) was determined, the in vitro antifungal activity of AmB-UDL was assayed. It was found that fungal strains (albicans and non-albicans Candida ATCC strains and clinical isolates of C. albicans) were more sensitive to AmB-UDL than mammal cells. Minimum inhibitory concentration values for AmB-UDL were 5-24 and 24-50 times lower than IC50 for J774 and HaCaT cells, respectively. AmB-UDL at 1.25μg/ml also displayed 100 and 75% anti- Leishmania braziliensis promastigote and amastigote activity, respectively. Finally, upon 1h of non-occlusive incubation, the total accumulation of AmB in human skin was 40 times higher when applied as AmB-UDL than as AmBisome. AmB-UDL provided a profound AmB penetration toward deep epithelial layers, achieved without classical permeation enhancers. Because of that, topical treatments of cutaneous fungal infection and leishmaniasis with AmB-UDL may be regarded of potential of clinical significance.


Middle cerebral artery peak systolic velocity in the diagnosis of fetomaternal hemorrhage.
To evaluate whether middle cerebral artery (MCA) peak systolic velocity (PSV) can help to diagnose fetal anemia caused by fetomaternal hemorrhage (FMH). Fifteen women with FMH were included in a longitudinal prospective study. Participants were evaluated via cardiotocography and Doppler assessment of MCA-PSV. Fetomaternal hemorrhage was confirmed via Kleihauer-Betke test, and fetal hemoglobin levels were determined soon after birth. One woman was affected by twin-to-twin transfusion syndrome; FMH was diagnosed with a high MCA-PSV in the recipient fetus, indicating severe anemia. Nine women were referred because of maternal trauma; MCA-PSV values were greater than 1.5 multiples of the median after a mean time of 22.6 hours and cardiotocography showed a sinusoidal pattern in all cases. Mean time of delivery after MCA-PSV assessment was 48.3 hours because of chronic placental abruption. In the other 5 cases, MCA-PSV was normal, cardiotocography showed a sinusoidal pattern, and delivery occurred in a mean time of 3 hours because of acute placental abruption. Kleihauer-Betke testing confirmed FMH, and hemoglobin levels at birth were used to confirm fetal anemia. Assessment of MCA-PSV may help to detect signs of fetal anemia in cases of chronic FMH.


Evidence for the functional association of enzyme I and HPr of the phosphoenolpyruvate-sugar phosphotransferase system with the membrane in sealed vesicles of Escherichia coli.
Several independent assay procedures were used to estimate the activities of the enzyme constituents of the phosphoenolpyruvate-sugar phosphotransferase system (PTS) in osmotically shocked bacterial membrane vesicles. The soluble enzymes of the system were found to be in association with the membrane by several criteria. Phosphoenolpyruvate-dependent sugar phosphorylation was catalyzed by this membrane-bound enzyme system far more efficiently than by a mixture of the individual enzymes at corresponding concentrations. By contrast, the rates of the phosphoryl exchange reactions catalyzed by enzyme I and the enzyme II complexes were essentially the same for the associated and dissociated forms of the system. Functional association of the PTS-enzyme complex was stabilized by Mg++ and phosphoenolypyruvate and could be destroyed by detergent treatment, sonication, or by passage of the vesicle preparation through a French pressure cell. These results lead to the possibility that in the intact bacterial cell the soluble enzymes of the phosphotransferase system exist, in part, as peripheral membrane constituents associated with the integral membrane enzyme II complexes.


Reacting to antibiotic allergies.
About 10-15% of all adults report that they are allergic penicillin or other antibiotics, although the accuracy and significance these reports remain unclear. In the outpatient setting, clinicians face a dilemma in prescribing for patients with a history of an allergic reaction to antibiotics. Which drugs should these patients avoid? Are these patients at increased risk for an allergic reaction to related drugs? This Issue Brief summarizes several large studies that can help guide improve the management of patients with antibiotic allergies.


Bioassay-guided fractionation of a hepatoprotective and antioxidant extract of pea by-product.
The hepatoprotective and antioxidant activities of the hydroalcoholic extract (PE) of pea (Pisum sativum L.) by-product were evaluated, using CCl4-induced oxidative stress and hepatic damage in rats. These activities were assessed via measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin, malondialdehyde (MDA), reduced glutathione (GSH), protein thiols (PSH), nitrite/nitrate levels, glutathione-peroxidase (GSH-Px), glutathione-S-transferase (GST) activities, as well as, histopathological evaluation. PE revealed significant hepatoprotective and antioxidant activities mostly found in n-butanol fraction. Chromatographic fractionation of this active fraction led to the isolation of five flavonoid glycosides namely, quercetin-3-O-sophorotrioside (1), quercetin-3-O-rutinoside (2), quercetin-3-O-(6″″-O-E sinapoyl)-sophorotrioside (3), quercetin-3-O-(6″″-O-E feruloyl)-sophorotrioside (4) and quercetin-3-O-β-D-glucopyranoside (5). The isolated compounds were quantified in PE, using a validated HPLC method and the nutritional composition of pea by-product was also investigated. Our results suggest that pea by-product contained biologically active constituents which can be utilised to obtain high value added products for nutraceutical use.


Selection of Arabidopsis mutants overexpressing genes driven by the promoter of an auxin-inducible glutathione S-transferase gene.
Transgenic arabidopsis plants were isolated that contained a T-DNA construct in which the promoter of an auxin-inducible glutathione S-transferase (GST) gene from tobacco was fused to the kanamycin resistance (nptII) as well as to the beta-glucuronidase (gusA) reporter gene. Subsequently, seeds were treated with EMS to obtain mutants in which both reporter gene fusions were up-regulated. Northern analysis showed that the mRNA level of a related, endogenous auxin-inducible GST gene of Arabidopsis was increased in some of these mutants as well. Two of the gup (GST up-regulated) mutants were characterized in more detail and roughly mapped. Both had epinastic cotyledons and leaves, a phenotype that turned out to be linked to the gup mutation.


Sludge reduction using aquatic worms under different aeration regimes.
Adding aquatic worms to a wastewater treatment system can reduce sludge production through predation. The aeration level is crucial for success. To evaluate aeration impacts on sludge reduction and determine an optimal aeration regime, this study investigated the processes of in-situ sludge reduction, using aquatic worms exposed to different aeration levels. The experiment also compared treatment results between a conventional reactor and an aquatic worm reactor (WR). Results indicated that the recommended concentration of dissolved oxygen (DO) was 2.5 mg L-1. The removal rate of chemical oxygen demand remained steady at 80% when the DO concentration was higher than 2.5 mg L-1, while the removal rate of ammonia nitrogen continued to moderately increase. Increasing the DO concentration to 5 mg L-1 did not improve sludge reduction, and consumed more power. With a DO concentration of 2.5 mg L-1 and a power of 0.19 kWh t-1 water, the absolute sludge reduction and relative sludge reduction rates in the WR were 60.0% and 45.7%, respectively, and the daily aquatic worm growth rate was 0.150 d-1 during the 17-d test. Therefore, at the recommended aeration regime, aquatic worms reduced the sludge without increasing the power consumption or deteriorating the effluent.


"Eat your lunch!" - controversies in the nutrition of the acutely, non-critically ill medical inpatient.
There is no doubt about the strong association of malnutrition and adverse medical outcomes including mortality, morbidity and quality of life. Particularly in the elderly and frail medical inpatient population, loss of appetite due to the acute illness further aggravates nutritional status. In fact, this relationship between acute disease and eating behaviour / nutritional status may well be bidirectional, with not only illness affecting nutritional status, but also dietary factors influencing the course of illness. Whether loss of appetite associated with acute illness is indeed a protective physiological response or a therapeutic target needing early corrective nutritional therapy is a matter of current debate and can only be resolved within a large and well-designed randomised controlled trial comparing early nutritional therapy with "appetite-guided" nutrition in this patient population. Apart from in critical care, where various large trials have recently been published, there is an important lack of high quality data from large randomised trials in unselected acutely ill medical inpatients to support the early use of nutritional therapy, to shed light on the optimal type, caloric amount and timing of nutritional therapy and to answer ultimately the question as to which patient population will in fact benefit from nutritional interventions. Currently, the EFFORT trial is enrolling patients and aims to fill these literature gaps. The aim of this review is to discuss the current evidence regarding nutritional therapy in acutely ill medical inpatients, and to recommend whether or not, based on today's available evidence, physician should indeed encourage their malnourished patients to "…finish their lunch".


Equal care ensures equal survival for African-American women with cervical carcinoma.
[corrected] It was the purpose of this study to investigate whether race is an independent prognostic factor in the survival of patients with cervical carcinoma in a health care system with minimal racial bias, and few barriers to access to care. Records for patients with a diagnosis of invasive cervical carcinoma from 1988 to 1999 were obtained from the Automated Central Tumor Registry for the United States Military Health Care System. Clinical data including race, age at diagnosis, histology, grade, stage, socioeconomic status, treatment modality, and survival also were obtained. Survival analysis was performed with Kaplan-Meier survival curves. One thousand five hundred fifty-three patients were obtained for review. Sixty-five percent of patients were Caucasian, and 35% were minorities. Of the minorities, 29% were African Americans (AAs). Mean age of diagnosis was similar among AAs and Caucasians, 44 and 42 years, respectively. There was no statistically significant difference between the distribution of age, stage, grade, or histology between Caucasians and AAs. Forty-six percent of patients were treated with surgery and 56% with radiation therapy, with no difference in type of treatment between the Caucasian and AA groups. Five- and 10-year survival rates for Caucasians and AAs were 75%, and 76%, and 64% 65% (P = 0.59), respectively. In an equal access, unbiased, nonracial environment, race is not an independent predictor of survival for patients with cervical carcinoma. This study has shown, for the first time to the authors' knowledge, that when they receive equal treatment for cervical carcinoma, AA women's survival can approach that of their nonminority counterparts (75% at 10 years).


Oxidative stress and aging.
Free radical-derived reactive oxygen species (ROS) are constantly generated in most living tissue and can potentially damage DNA, proteins and lipids. "Oxidative stress" occurs if ROS reach abnormally high concentrations. Harman was the first to propose that the damaging effects of ROS may play a key role in the mechanism of aging. Genetic studies of such distantly related species as C. elegans, Drosophila melanogaster, and mice support this hypothesis. However, ROS are not only a cause of structural damage, but also physiologically important mediators in biological signaling processes. Abnormally high levels of ROS may therefore lead to dysregulation of redox-sensitive signaling pathways. The redox-sensitive targets in these pathways are often signaling proteins with redox-sensitive cysteine residues which are oxidized to sulfenic acid moieties and mixed disulfides, thereby altering the signaling function of the protein. Because the formation of these mixed disulfides can also occur through a prooxidative shift in the intracellular thiol/disulfide redox status (REDST), the respective signaling pathways respond not only to ROS but also to changes in REDST. Information about the concentration of ROS in living tissue is scarce, but aging-related changes in REDST are well documented. Several studies with cell cultures or experimental animals have shown that the oxidative shift in the intracellular glutathione REDST is typically associated with cellular dysfunction. Complementary studies in humans have shown that oxidative changes in the plasma (i.e., extracellular) REDST are correlated with aging-related pathophysiological processes. The available evidence suggests that these changes play a key role in various conditions which limit the human life span. Several attempts have been made to ameliorate the consequences of aging by thiol-containing antioxidants, but this approach requires a detailed knowledge of the effects of thiol-containing antioxidants on cysteine homeostasis, REDST, and redox-sensitive signaling pathways of the host.


[Infestation of Pseudopiazurus papayanus (Marshall) (Coleoptera: Curculionidae) on Carica spp. and Vasconcella spp. genotypes].
The papaya borer weevil, Pseudopiazurus papayanus (Marshall), is generally considered a secondary pest, but it has been reported in high infestations in Northeast Brazil. This work aimed at evaluating the occurrence of P. papayanus and reporting its infestation level in papaya genotypes kept at the germplasm bank of Embrapa Cassava & Tropical Fruits (Cruz das Almas, Bahia, Brazil). The number of larvae, pupae and adults found in each plant of 65 Carica spp. genotypes and of three Vasconcella spp. genotypes was registered in three to five plants of each genotype, by cutting the exsudating trunks lenghtwise. Papaya borer weevil was found in C. papaya and V. cauliflora but not in those of V. quercifolia. Among the evaluated genotypes, 52.4% of those belonging to the Solo group were infested, against 25.0% of the Formosa group. Larval infestation was the best criterion for sorting out genotypes concerning this insect infestation. This is also the first occurrence of the papaya borer weevil on V. cauliflora.


The response pattern of patients with chronic airway obstruction to bronchodilators.
To investigate the response pattern of patients with chronic airway obstruction (CAO) to bronchodilators, 128 subjects consisting of 80 men and 48 women with a mean age of 52.6 years were randomly tested with three inhalant bronchodilators: a non-selective beta-agonist (isoproterenol), a beta 2-selective agonist (terbutaline) and an anticholinergics (ipratropium) plus placebo. All patients had a baseline FEV/FVC of less than 65% and their clinical diagnosis were classified as either COPD or bronchial asthma according to the criteria of the ACCP-ATS Joint Committee on Pulmonary Nomenclature. The drugs were delivered to the patient via a metered dose inhaler (MDI) using the conventional inhalation technique. Spirometry was measured at regular intervals with a computerized pulmonary function analyzer CHESTAC-65(Japan). A more than 15% increase in FEV1 and/or FVC after treatment was regarded as responsive. While 108 patients were tested with a single drug, the remaining 20 patients were tested sequentially with terbutaline, ipratropium and placebo in a randomized cross-over manner for studying additivity. Our results showed that the response rates of asthmatic patients to isoproterenol, terbutaline and ipratropium were 50%, 87% and 67%, respectively. Only 27% of COPD patients responded to isoproterenol and 60% to terbutaline. On the other hand, ipratropium possessed a 61% response rate in the treatment of COPD and showed a bronchodilator effect independent to that of terbutaline. Combined use of both drugs resulted in additional improvement. Once patients responded to the drugs, apparent changes in FEV1 and/or FVC occurred within 30 minutes and reached the maximum usually at 60 minutes post-inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)


Pregabalin in the discontinuation of long-term benzodiazepines' use.
Tolerance, dependence, and adverse effects on cognitive functions are well-known consequences of long-term use of benzodiazepines (BDZ), especially at high doses, raising thorny therapeutic problems in their discontinuation. One promising pharmacological agent in BDZ discontinuation might be the newer anti-epileptic pregabalin, already successfully tested in the treatment of anxiety disorders. We report on a sample of 15 patients with long-term, mostly high-dose dependence from BDZ, treated with pregabalin in an open-label study at doses 225-900 mg. All patients discontinued successfully BDZ in 3-14 weeks, moreover with a significant reduction of their previous anxiety levels under BDZ. In addition, patients showed also a significant amelioration in their cognitive functioning. Pregabalin's side-effects were mild and transient, lasting only during the first 2 weeks of treatment. Although preliminary, our findings suggest that pregabalin may be one new promising agent in the treatment of BDZ dependence.


Identification and sequence analysis of six new members of the NIMA-related kinase family in Chlamydomonas.
The NIMA kinases are an evolutionarily conserved protein family with enigmatic roles in the regulation of mitosis. We report six new members of this family in Chlamydomonas, in addition to the previously identified NIMA-related kinase, Fa2p. Chlamydomonas NIMA-related kinases (CNKs) 1-6 were sequenced from subclones generated by RT-PCR using information from EST libraries and the recently sequenced Chlamydomonas genome. Phylogenetic and bioinformatic approaches were used to determine the relationships of the six new members with known members of the NIMA-related kinase family. Although humans express at least eleven NIMA-related kinases, the eukaryotic microbes that have been studied to date express only one or two members of the family. Thus, the discovery that Chlamydomonas expresses a total of at least seven NIMA-related kinases is intriguing. Our analyses suggest that members of this family may play roles in the assembly and function of cilia.


Hypnocyclicus thermotrophus gen. nov., sp. nov. isolated from a microbial mat in a hydrothermal vent field.
The bacterial strain, IR-2T, was isolated from a microbial mat sampled near a hydrothermal vent in the Greenland Sea. Phylogenetic analysis, based on the 16S rRNA gene, showed that the closest relatives of IR-2T were Ilyobacter tartaricus, Ilyobacter insuetus, Propionigenium modestum and Fusobacterium varium (91 % 16S rRNA gene sequence similarity). The cells of the novel strain were Gram-stain-negative and pleomorphic; changing from long motile rods to non-motile ring structures during the growth cycle. Growth occurred at 20-55 °C (optimally at 48 °C), with 1-6 % (w/v) NaCl (optimally with 2 %), and at pH 5.3-8.0 (optimally at pH 6.0-8.0). The strain had obligate fermentative growth on various sugars and yeast extract. The DNA G+C content of strain IR-2T was 25.7 mol%. The cell sugars comprised mainly ribose, mannose and glucose, while the main polar lipids were glycolipids, phospholipids, phosphatidylglycerol and diphosphatidylglycerol. The fatty acid content of strain IR-2 was dominated by saturated and unsaturated iso-branched or anteiso-branched forms. Strain IR-2 represents a novel genus and species, for which the name Hypnocyclicus thermotrophus gen. nov., sp. nov. is proposed. The type strain is IR-2T ( = DSM 100055 = JCM 30901).


Spontaneous, bilateral intraocular lens dislocation in a patient with exfoliation syndrome.
Exfoliation syndrome (XFS) is a relatively common age-related disorder characterized by the production and progressive accumulation of a fibrillar extracellular material in numerous ocular tissues and throughout the body. XFS is a known identifiable cause of open-angle glaucoma. However, because of its widespread distribution, other structures in the eye are affected. Because of weakening of the zonular apparatus and posterior capsule, and subsequent loss of support for the lens or posterior chamber intraocular lenses (IOLs), its presence must be factored into the pre- and postoperative management of persons undergoing cataract surgery. An 89-year-old white female presented with the sudden onset of decreased vision in her left eye. She had a history of uncomplicated cataract extraction and posterior chamber IOL implantation in each eye about 10 years previously. She was also known to have XFS. Examination found XFS, a dislocated posterior chamber IOL, anterior uveitis, and markedly elevated intraocular pressure. After stabilizing the eye medically, the patient presented 5 months later with the same condition in the right eye. This eye was also stabilized medically. The patient refused further treatment. It is imperative that the comanaging optometrist and cataract surgeon be cognizant of the presence of XFS when planning cataract surgery. However, the effects of XFS may not be seen for many years after apparently successful cataract surgery.


Shift report: improving a complex process to enhance patient safety.
This article focuses on the shift change process, which is a time for communication of critical patient information. It identifies the multitude of variables that can interfere with that communication process and introduce the potential for error to occur. Human factors include the variability of staff, variability of processes, fatigue, environmental factors and the complexity of systems. The article also discusses methods to improve current processes with the intent to prevent error and improve patient outcomes.


Genetic polymorphism of manganese superoxide dismutase (MnSOD) and breast cancer susceptibility.
Within mitochondria, manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species (ROS). An alanine-9valine (Ala-9Val) polymorphism in the mitochondrial targeting sequence of MnSOD has been described and has recently been associated with risk of human breast cancer. Our present case-control study was performed to explore the association between MnSOD genetic polymorphism and individual susceptibility to breast cancer. Ala-9Val polymorphism in the signal sequence of the protein for MnSOD was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a study population. There was no significant difference in risk for breast cancer development between patients positive and negative for the MnSOD Ala allele with adjusted odds ratio (OR): 0.86 (95% confidence interval (CI(0.43 to 1.72). When MnSOD Ala was combined with either cytochrome P450 1B1 CYP1B1*1 and catechol O-methyltransferase COMT-L (V158M) genotypes, the risk for developing breast cancer was significantly increased in patients with a body mass index (BMI) greater than 24 kg m(-2) (OR: 1.42 (95%CI=1.04-1.93)).


High-field, high-resolution MR imaging of the human indusium griseum.
The human indusium griseum (IG), the paired dorsal continuation of the hippocampus, was investigated with high-field (3.0T) MR imaging. The IG was clearly visible in 16 out of 20 healthy volunteers. The most common pattern was a single lateralized strip. The classical neuroanatomic pattern of paired symmetric strips along the midline was found in one case. The study clearly demonstrates that diminutive, hitherto overlooked structures such as the IG now can be readily investigated in vivo by non-invasive high-field MR imaging.


Late-Onset Cystoid Macular Edema Associated With Small-Incision Cataract Surgery and Inadvertent Entry of Chloramphenicol Ointment into the Anterior Chamber.
The authors report the long-term outcome of a 78-year-old man who experienced inadvertent entry of chloramphenicol ointment into the anterior chamber following small-incision sutureless cataract surgery. The chloramphenicol initially formed a single spherical mass on the interior aspect of the corneal section with no discernable effect on visual acuity. However, in the following 6 years the vision deteriorated with the development of multiple fine droplets within the anterior chamber and cystoid macular edema. An anterior chamber washout and removal of the ointment was performed with a subsequent improvement in vision. The authors discuss risks associated with unsutured corneal wounds and the use of ocular ointments.


[Molecular epidemiology of diarrhea among children with Norwalk-like virus in a hospital of Guangzhou in autumn and winter].
To explore the epidemiological characteristics of Norwalk-like virus (NLVs) infection in children with diarrhea and to study the genotype and predominant cluster at a hospital in Guangzhou city. Fecal specimens from 358 children with acute gastroenteritis from October 2003 to January 2004 and information about the cases were collected. NLVs was detected from the specimens by reverse transcription-polymerase chain reaction (RT-PCR) and the PCR products were purified and sequenced. Forty-two positive specimens were detected from the 358 fecal specimen with a positive rate of 11.73% (42/358). Of these, 40 specimens were obtained from infants younger than 3 years of age. The youngest infant infected with NLVs in this study was only 25 days. The positive rate in November (17.27%) was the highest. Eleven positive PCR products were selected and sequenced. Nucleotide sequence analysis revealed that 11 strains all belong to genogroup II (G II), and of these, 5 strains belonged to G II-3 cluster, with another 5 strains belonged to G II-4 cluster. However, one strain with its cluster could not be determined. NLVs served as one of the important pathogens causing sporadic acute gastroenteritis among children at a hospital in Guangzhou. The predominant strains were identified as G II-3 and G II-4 cluster.


Partial characterization of vitellin and localization of vitellogenin production in the terrestrial isopod, Armadillidium vulgare.
Vitellins were purified separately from ovaries and eggs of the isopod, Armadillidium vulgare. Ovarian vitellin consisted of at least six proteins with relative molecular masses of 205, 200, 185, 180, 122 and 112 kDa. The larger four proteins disappeared in eggs within a week after oviposition and a 59-kDa protein appeared thereafter. The amino-terminal amino acid sequences of these vitellin proteins were identical except for the ovarian 112 kDa, egg 112 kDa and 59 kDa proteins, and showed considerable similarity to those of known vitellogenins from other animals. Comparison of tryptic peptide maps of the 122 and 112 kDa proteins from eggs on reversed-phase HPLC and sequence identification of two randomly selected peaks having the same retention times indicated that two peptides were mostly similar in sequence. PCR-assisted cloning of the 5' region of a cDNA (591 bp) encoding vitellogenin revealed the presence of a signal peptide consisting of 16 amino acid residues and clarified the structural relationship among the protein components except for the ovarian 112 kDa and the egg 59 kDa proteins. Northern blot analysis revealed that the fat body is the main vitellogenin producing organ.


[Bronchial cytology of "occult" lung cancers (author's transl)].
Having underlined the value of bronchial cytology for the early diagnosis of lung cancers, the authors report 7 observations concerning a particular clinical form: the "occult" lung cancer with a malignant cytological precession more or less in advance in relation with the radiological or fibroscopical data. Malignant cells can be found in sputum from 9 months to 8 years beforehand. All histological types can be seen but no cancer of the anaplasic type with small cells was identified either in this series or in the literature. The authors insist also on the difficulty in localizing these cancers in situ at a very early stage. They set apart the insufficiencies of the X-ray results in several observations and the limits of other investigating techniques (bronchography, scintigraphy, echotomography, ...). These tumours seem to have a mild evolutivity.


Emigration and remigration of Okinawans settled in the lowlands of eastern Bolivia in relation to background characteristics of their place of origin.
Post-war Okinawans emigrated to the lowlands of Bolivia in an attempt of pioneer agricultural colonization were studied with regard to behavioral patterns of the adjustment process in terms of permanency in the newly created colony. The uniqueness of the post-war emigration to Bolivia by Okinawans is discussed in comparison with pre-war emigration and the inter-regional migratory flow. The permanency of Okinawan emigrants in Bolivia is analyzed in relation to background characteristics of their regional origin in Okinawa using Spearman's rank correlations between each pair of selected variables; the number of emigrants by municipality in Okinawa Prefecture, rate of persons who settled in the colony, rate of population engaged in the primary sector of economy in 1965 in Okinawa Prefecture, and rate of area for U.S. military use. The permanency of the migrants in colonization is related to the background characteristics in the place of their origin before emigration. The likelihood of emigrants settling in the colony is thus greater for those from less urbanized municipalities, the size of migrants from one municipality of the rural area signifying the permanency in the pioneer colonization project.


Some patients with multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and can be treated effectively with MVD: report of five cases.
The role of trigeminal ganglion percutaneous injection and radio-frequency lesioning procedures for the treatment of trigeminal neuralgia (TGN) in multiple sclerosis (MS) is well established. There is general acceptance that microvascular decompression (MVD) cannot be an appropriate treatment due to the view that the underlying aetiology is a demyelinating plaque affecting the root entry zone of the trigeminal pathway. Recently, MR-imaging has been used in the preoperative investigation of this group of patients demonstrating that neurovascular compression can occasionally be the responsible mechanism and that MVD can be the treatment of choice. We present five cases with MS and TGN. All the patients had failed to respond to medical treatment or percutaneous procedures. Magnetic resonance imaging demonstrated evidence of neurovascular compression in four cases. All the patients underwent MVD. Postoperatively four of the five patients made an uncomplicated recovery, were pain-free and fully satisfied with the result (mean follow-up 38.75 months; range 8-59 months). One patient developed recurrent pain 1 week following surgery and went on to have a total sensory rhizotomy. TGN in MS can be caused by neurovascular compression, which may be identified on MR-imaging. MVD has offered satisfactory short-term outcome for at least 2 years and does not inflict sensory loss. Longer follow-up will determine whether the outcome in MS patients will be as successful as in the TGN patients who do not suffer from MS.


Energy consumption during prosthetic walking and wheelchair locomotion by elderly hip disarticulation amputees.
To investigate the differences in energy consumption by patients with hip disarticulation between prosthetic walking and wheelchair locomotion. : The subjects consisted of seven amputees, all older than 60, with unilateral hip disarticulation. Energy consumption when walking with prosthesis and when propelling a wheelchair, each at the respective comfortable movement speed, was measured by means of a portable telemetric system. The average comfortable movement speed for prosthetic walking was 30.5 m/min, which was much slower than the 63.1 m/min average for wheelchair locomotion (P < 0.01). The average oxygen cost value for prosthetic walking was 0.639 ml/kg/m, and the average for wheelchair locomotion was 0.175 ml/kg/m, indicating that oxygen cost was significantly higher for prosthetic walking than for wheelchair locomotion (P < 0.01). The results of this research clearly showed that the efficiency of prosthetic walking for elderly hip disarticulation amputees was very low. When the subject is judged not to be a candidate for practical prosthetic walking after a careful multidisciplinary evaluation, wheelchair locomotion may be an alternative to prosthetic walking as a realistic goal.


Metagenomic Characterization of Bacterial Communities in Drinking Water Supply System of a Mega City.
Supplying safe water to consumers is vital for protection of public health. With population of > 15 million, Karachi is the main economical hub of Pakistan. Lake Keenjhar serves as the main source of fresh water while Hub dam is the secondary water reservoir for Karachi. In this study, bacterial community of the drinking water supply system (DWSS) of Karachi was studied from source to tap using metagenomics approach. For this purpose, we collected 41 water samples from different areas of the city (n = 38) and water reservoirs (n = 3). 16S rDNA metagenomic sequencing of water samples revealed that 88% sequences were associated with Proteobacteria (52%), Planctomycetes (15%), Becteroidetes (12%), and Verrucomicrobia (6%). On the class level, α-proteobacteria (6-56%) were found to be the most abundant followed by β- (8-41%) and γ-proteobacteria (6-52%). On the genus level, substantial diversity was observed among the samples. Bacterial communities in water from Hub dam was found to be distantly related while among the residential towns, Lyari was highly distant from the others. Twenty-four bacterial genera were found to be exclusively present in residential area samples in comparison to the source waters which is suggestive of their resistance against treatment procedures and/or contamination. Metagenomic analysis revealed abundance of Pseudomonas, Legionella, Neisseria, Acinetobacter, Bosea, and Microcystis genera in residential areas water samples. The present metagenomic analysis of DWSS of Karachi has allowed the evaluation of bacterial communities in source water and the water being supplied to the city. Moreover, measurement of heavy metals in water samples from Karachi revealed arsenic concentration according to WHO standards which is in contrast of recent study which reported extensive arsenic contamination in aquifers in the Indus valley plain. To the best of our knowledge, this is the first metagenomic study of DWSS of Karachi.


2-hydroxycaproate predicts cardiovascular mortality in patients with atherosclerotic disease.
We aimed to identify novel biomarkers for cardiovascular mortality through a non-targeted metabolomics approach in patients with established atherosclerotic disease from the Tor Vergata Atherosclerosis Registry (TVAR). We compared the serum baseline metabolome of 19 patients with atherosclerosis suffering from cardiovascular death during follow-up with the baseline serum metabolome of 20 control patients matched for age, gender, body mass index (BMI) and atherosclerotic disease status, who survived during the observation period. Three metabolites were significantly different in the cardiovascular mortality (CVM) group compared to controls: 2-hydroxycaproate, gluconate and sorbitol. 2-hydroxycaproate (otherwise known as alpha hydroxy caproate) was also significantly correlated with time to death. The metabolites performed better when combined together rather than singularly on the identification of CVM status. Our analysis led to identify few metabolites potentially amenable of translation into the clinical practice as biomarkers for specific metabolic changes in the cardiovascular system in patients with established atherosclerotic disease.


Mathematical modeling and physical reality in noncovalent interactions.
The Hellmann-Feynman theorem provides a straightforward interpretation of noncovalent bonding in terms of Coulombic interactions, which encompass polarization (and accordingly include dispersion). Exchange, Pauli repulsion, orbitals, etc., are part of the mathematics of obtaining the system's wave function and subsequently its electronic density. They do not correspond to physical forces. Charge transfer, in the context of noncovalent interactions, is equivalent to polarization. The key point is that mathematical models must not be confused with physical reality.


Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment.
Temozolomide dry powder formulations for inhalation, performed with no excipient or with a lipid or lactose coating, have been evaluated. The particle size of raw temozolomide in suspension was reduced by a high-pressure homogenizing technique, and the solvent was evaporated by spray-drying to obtain a dry powder. The physicochemical properties of this powder were evaluated and included its crystalline state, thermal properties, morphology, particle size and moisture and drug content, and these properties were determined by X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, laser light scattering, thermogravimetric analysis and high-performance liquid chromatography, respectively. The aerodynamic properties and release profiles were also evaluated using a multistage liquid impinger and a modified USP type 2 dissolution apparatus adapted for inhaler products, respectively. The dry powder inhalation formulations had a high temozolomide content that ranged from 70% to 100% in the crystalline state and low moisture content. Aerodynamic evaluations showed high fine-particle fractions of up to 51% related to the metered dose. The dissolution profile revealed a similarly fast temozolomide release from the formulations. Dry temozolomide powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion properties, represent an attractive alternative for use in local lung cancer therapy.


Phospholipase D in cultured rat vascular smooth muscle cells and its activation by phorbol ester.
We determined the phospholipase D (PLD) activity in rat vascular smooth muscle cells by the formation of phosphatidylethanol in cells prelabeled with [3H] myristic acid. The enzyme was markedly activated by a phorbol ester (TPA). Down regulation of protein kinase C (PKC) resulted in almost complete inhibition indicating PKC-dependent mechanism of its activation. Depletion of calcium by EGTA and TMB-8 caused 53% inhibition. Chelator-stable association of PKC to membrane by TPA was observed in the absence of extracellular Ca2+. The mitogenic peptide PDGF also caused a marked stimulation of PLD. These results indicate that PLD in vascular smooth muscle cells is stimulated by TPA through the activation of PKC both by calcium-dependent and independent mechanisms.


Effect of ultrasound on adherent microbubble contrast agents.
An investigation into the effect of clinical ultrasound exposure on adherent microbubbles is described. A flow phantom was constructed in which targeted microbubbles were attached using biotin-streptavidin linkages. Microbubbles were insonated by broadband imaging pulses (centred at 2.25 MHz) over a range of pressures (peak negative pressure (PNP) = 60-375 kPa). Individual adherent bubbles were observed optically and classified as either being isolated or with a single neighbouring bubble. It is found that bubble detachment and deflation are two significant effects, even during low amplitude ultrasound exposure. Specifically, while at very low acoustic pressure (PNP < 75 kPa) 95% of the bubbles were not affected, at medium pressure (151 kPa < P < 225 kPa) 53% of the bubbles detached and at higher pressures (301 kPa < P < 375 kPa) 96% of the bubbles detached. In addition, more than 50% of the bubbles underwent deflation at pressures between 301 and 375 kPa. At pressures between 226 and 300 kPa, more adherent bubbles detached when there was a neighbouring bubble, suggesting the role of multiple scattering and secondary Bjerknes force on bubble detachment. The flow shear, primary and secondary Bjerknes forces exerted on each bubble were calculated and compared to the estimated forces acting on the bubble due to oscillations. The oscillation force is shown to be much higher than other forces. The mechanisms of bubble detachment are discussed.


Note: Vector reflectometry in a beam waveguide.
We present a one-port calibration technique for characterization of beam waveguide components with a vector network analyzer. This technique involves using a set of known delays to separate the responses of the instrument and the device under test. We demonstrate this technique by measuring the reflected performance of a millimeter-wave variable-delay polarization modulator.


High-throughput methods for detection of genetic variation.
Understanding human genetic variation is currently believed to reveal the cause of individual susceptibility to disease and the large variation observed in response to treatment. In this review, we will focus on different approaches to identify and visualize genetic alterations. The various approaches for allele discrimination are formally systematically divided into (i) enzymatic approaches, in which the properties of different enzymes to discriminate between nucleotides are used (restriction enzymes type II, Cleavase and Resolvase, DNA polymerase, and ligase); (ii) electrophoretic methods, in which the allele discrimination is based on the difference in mobility in polymeric gels or capillaries (single- and double-stranded conformation assays, heteroduplex analysis, and DNA sequencing); (iii) solid-phase determination of allelic variants, including high-density oligonucleotide arrays for hybridization analysis, minisequencing primer extension analysis, and fiberoptic DNA sensor array; (iv) chromatographic methods such as denaturing high-performance liquid chromatography (DHPLC); (v) other physical methods of discrimination of allelic variants such as mass spectrometry (mass and charge) or fluorescence exchange-based techniques; and (vi) in silico methods such as high-throughput analysis of expressed sequence tag data. The most frequently used techniques and instrumental settings applied in different combinations are described, and other methods that are less broadly used but have interesting potentials are discussed.


Evaluation of a night respite community palliative care service.
A three-phase project was undertaken to develop and evaluate a community night respite palliative care service for patients and family carers. An assessment tool to identify those most in need of night respite was developed and tested. The tool was reliable and feasible for use in practice. Care aides were trained to provide night respite. Fifty-three patients participated over 11 months. Findings revealed the types of patients and families most in need of night respite, the amount of respite needed, and location of death. There is evidence that patients who would have been transferred to an inpatient setting for end-of-life care were able to die at home with the support of the night respite service. Families were extremely appreciative of the service and a limited cost comparison suggested costs were lower than if patients had been transferred to hospital and/or inpatient hospice care. Recommendations for practice are offered.


Proteomic analysis of striatal proteins in the rat model of L-DOPA-induced dyskinesia.
L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lacking. In the present study, we investigated the changes occurring at the protein level in striatal samples obtained from the unilaterally 6-hydroxydopamine-lesion rat model of PD treated with saline, L-DOPA or bromocriptine using two-dimensional difference gel electrophoresis and mass spectrometry (MS). Rats treated with L-DOPA were allocated to two groups based on the presence or absence of LID. Among the 2000 spots compared for statistical difference, 67 spots were significantly changed in abundance and identified using matrix-assisted laser desorption/ionization time-of-flight MS, atmospheric pressure matrix-assisted laser desorption/ionization and HPLC coupled tandem MS (LC/MS/MS). Out of these 67 proteins, LID significantly changed the expression level of five proteins: alphabeta-crystalin, gamma-enolase, guanidoacetate methyltransferase, vinculin, and proteasome alpha-2 subunit. Complementary techniques such as western immunoblotting and immunohistochemistry were performed to investigate the validity of the data obtained using the proteomic approach. In conclusion, this study provides new insights into the protein changes occurring in LID.


Neurogenic continence. Part 2: Neurogenic bladder management.
This article addresses physical and psychosocial issues in neurogenic bladder management. The impact of neurogenic bladder and its assessment will be discussed. There are a wide range of treatment options available to manage neurogenic bladder dysfunction and this article offers an overview of key management techniques, including non-invasive techniques, self-intermittent and suprapubic catheters, medication and surgical management. The importance of the nursing role in assessment, teaching and supporting patients by enabling them to make informed choices about their bladder management is addressed.


Characterization and health risks of criteria air pollutants in Delhi, 2017.
Severe air pollution events were observed frequently in north India in recent years especially at its capital, Delhi. Criteria air pollutants data at 10 sites for 2017 in Delhi were analyzed. The results show annual fine particulate matter (PM2.5) concentrations exceeded the National Ambient Air Quality Standards (NAAQS) of 60 μg/m3 at all sites from 105.51 (site 10) to 143.23 μg/m3 (site 7). Sub-urban sites (site 8, 9 and 10) had lower PM2.5 concentrations than urban sites. Coarse PM (PM10) and ozone (O3) were also important with annual averages of 399.56 μg/m3 and 75.69 ppb, respectively. Peak PM2.5 occurred at the Diwali in early November and Christmas. Only PM10 showed a significant weekly difference with a weekdays/weekends ratio of ∼1.5. PM2.5/PM10 ratio in episode days with PM2.5 of >60 μg/m3 was higher than non-episode days. Pearson correlation coefficients show O3 was negatively related with CO, SO2, and NO2, while PM2.5 was positively related to these pollutants. Analysis of two extreme events from Nov. 6th to Nov. 14th and Dec. 18th to Dec. 26th shows that meteorological conditions with low wind speed and warm temperature kept PM2.5 concentrations at a high level during these events. Backward trajectory and cluster analysis show the wind coming from northwest of Delhi, where massive anthropogenic emissions were generated, led to high concentrations of air pollutants to Delhi. Health risk analysis reveals that PM2.5 and PM10 were the two major pollutants threatening public health among the six criteria pollutants.


Protective effect of melatonin on photo-damage to lysozyme.
The behavior of melatonin in the riboflavin-sensitized photo-oxidation of lysozyme was monitored. Melatonin was found to prevent aggregation of protein and the decrease of enzyme activity induced by photo-oxidation. Electron spin resonance experiments showed that photo-oxidation of lysozyme in the presence of riboflavin resulted in formation of protein radicals, and melatonin was highly effective in reducing the formation of protein radicals. Direct evidence of melatonin's ability for quenching the triplet state of riboflavin and singlet oxygen was presented. A mechanism of the protective effect of melatonin on photo-oxidation of protein was proposed and the physiological relevance was discussed.


Ketoprofen, paracetamol and placebo in the treatment of episodic tension-type headache.
The aim of the study was to assess the efficacy and tolerability of a single oral dose of ketoprofen 25 mg in comparison with single doses of ketoprofen 2 x 25 mg, paracetamol 500 mg and 1,000 mg, and placebo in the treatment of episodic tension-type headache. The study was conducted as a single centre, double-blind, randomized, placebo-controlled, five-period, within-patient comparative trial in outpatients with episodic tension-type headache according to the International Headache Society's diagnostic criteria. Each patient had to treat five attacks of episodic tension-type headache with a single dose of each of the tested medications with a minimum interval of 72 h between two attacks. Details of the attack and response to treatment were recorded on a diary card. Altogether 30 patients treated 5 attacks and 2, 3, 1 and 4 patients treated 4, 3, 2 and 1 attack, respectively. The primary variable was decrease in headache pain intensity from baseline to 2 h after intake, evaluated by means of a 100 mm visual analogue scale. Ketoprofen 50 mg was significantly better than placebo and paracetamol for this main criterion. Neither of the paracetamol groups differed from the placebo group. Only a few adverse events were reported, usually of mild or moderate severity, with no difference between the treatments. Ketoprofen 50 mg may be considered an effective and well tolerated analgesic in the treatment of episodic tension-type headache of moderate or severe intensity.


Electrophysiological correlates of attentional orientation in humans to strong intensity deviant nociceptive stimuli, inside and outside the focus of spatial attention.
Laser evoked potentials (LEPs) are electrical brain responses to nociceptive heat stimuli. In a recent study [Legrain, V., Guérit, J.M., Bruyer, R. and Plaghki, L., Pain, 99 (2002) 21-39.], we found that amplitude at approximately 400 ms was increased by rare intensity deviant nociceptive stimuli (P400 effect). In that study, laser stimuli were randomly delivered on both hands, and subjects were focusing attention on one hand in order to detect rare stimuli. As the P400 effect was found for rare stimuli when spatial attention was directed both towards and away from the stimulated hand, it was postulated to represent a P3a component reflecting an involuntary orientation of attention to unexpected deviant stimuli. However LEPs to strong and weak intensity stimuli were averaged together and some effects could have been underestimated. So, we present a new interpretation of the P400 effect based on separate analyses of strong and weak intensity deviant stimuli. Indeed, the P400 effect was only observed for strong stimuli, and again on both attended and unattended hands. Thus, if the P400 effect reflects P3a, only strong deviant stimuli provided enough signals to induce attentional switching even when they were delivered outside the focus of spatial attention. It is suggested that attentional switching could have been triggered by neural systems having detected sharp increase of intensity. Weak deviant stimuli were not salient enough to induce attentional switching.


The impact of body composition parameters on severe toxicity of nivolumab.
The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.


Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling.
Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.


Straddling care and education: Developing interprofessional collaboration through a hotspotting service learning project.
Interprofessional (IP) team work has been shown to decrease burnout and improve care and decrease costs. However, institutional barriers have challenged adoption in practice and education. Faculty and students are turning to IP service-learning projects to help students gain experience and provide needed services. This paper highlights a "hotspotting" program where students from different health professions work collaboratively to improve high utilizing patients' health. Benefits, challenges and preliminary results including cost savings and student efficacy are shared. Institutions should surmount barriers that make hotspotting service-learning challenging as IP team-based experiences prepare students for the workplace and can help mitigate burnout.


MoFi: A Software Tool for Annotating Glycoprotein Mass Spectra by Integrating Hybrid Data from the Intact Protein and Glycopeptide Level.
Hybrid mass spectrometry (MS) is an emerging technique for characterizing glycoproteins, which typically display pronounced microheterogeneity. Since hybrid MS combines information from different experimental levels, it crucially depends on computational methods. Here, we describe a novel software tool, MoFi, which integrates hybrid MS data to assign glycans and other post-translational modifications (PTMs) in deconvoluted mass spectra of intact proteins. Its two-stage search algorithm first assigns monosaccharide/PTM compositions to each peak and then compiles a hierarchical list of glycan combinations compatible with these compositions. Importantly, the program only includes those combinations which are supported by a glycan library as derived from glycopeptide or released glycan analysis. By applying MoFi to mass spectra of rituximab, ado-trastuzumab emtansine, and recombinant human erythropoietin, we demonstrate how integration of bottom-up data may be used to refine information collected at the intact protein level. Accordingly, our software reveals that a single mass frequently can be explained by a considerable number of glycoforms. Yet, it simultaneously ranks proteoforms according to their probability, based on a score which is calculated from relative glycan abundances. Notably, glycoforms that comprise identical glycans may nevertheless differ in score if those glycans occupy different sites. Hence, MoFi exposes different layers of complexity that are present in the annotation of a glycoprotein mass spectrum.


Magnetic resonance imaging of bone destruction in rheumatoid arthritis: comparison with radiography.
Bony changes in forty-four knees of patients with clinically established rheumatoid arthritis (RA) were examined using magnetic resonance imaging (MRI) and plain film radiography. In all cases MRI was clearly superior to radiographs, demonstrating 25 marginal erosions and 42 subchondral cysts, while the number seen on radiographs was 3 and 8, respectively. These results emphasize the problems in visualizing bone erosions in large joints using plain films. MRI is the method of choice for detecting early changes in RA, not only because of its high sensitivity, but also because of the ability of contrast-enhanced MRI to provide physiological characterization of these lesions.


Association of hospitalization for infection in childhood with diagnosis of autism spectrum disorders: a Danish cohort study.
To investigate the association between hospitalization for infection in the perinatal/neonatal period or childhood and the diagnosis of autism spectrum disorders (ASDs). A population-based cohort study. Denmark. All children born in Denmark from January 1, 1980, through December 31, 2002, comprising a total of 1 418 152 children. Infection requiring hospitalization. The adjusted hazard ratio (HR) for ASDs among children hospitalized for infection compared with other children. A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]). The association between hospitalization for infection and ASDs observed in this study does not suggest causality because a general association is observed across different infection groups. Also, the association is not specific for infection or for ASDs. We discuss a number of noncausal explanatory models.


Effects of materials containing antimicrobial compounds on food hygiene.
Surfaces with microorganisms may transfer unwanted microorganisms to food through cross-contamination during processing and preparation. A high hygienic status of surfaces that come in contact with food is important in order to reduce the risk of cross-contamination. During the last decade, products containing antimicrobial compounds, such as cutting boards, knives, countertops, kitchen utensils, refrigerators, and conveyor belts, have been introduced to the market, claiming hygienic effects. Such products are often referred to as "treated articles." Here we review various aspects related to treated articles intended for use during preparation and processing of food. Regulatory issues and methods to assess antibacterial effects are covered. Different concepts for treated articles as well as their antibacterial activity are reviewed. The effects of products with antimicrobials on food hygiene and safety are discussed.


Cytochrome P450 2D6 (CYP2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results.
Debrisoquine hydroxylase (CYP2D6) is involved in the metabolism of many toxicologically important drugs. The gene encoding for this enzyme displays a polymorphic distribution in all populations examined. We report a study on 46 cases, where analyses of the CYP2D6 gene were conducted on postmortem femoral blood in order to investigate the occurrence of poor metabolizers (PM). A polymerase chain reaction (PCR) method, designed and routinely used for therapeutic drug monitoring, was employed, only slightly modified. Samples from 22 cases, where the parent drug to metabolite ratio was unexpectedly high were analyzed as well as samples from 24 control cases. Genotyping could be carried out in all but one case. Previous freezing or addition of potassium fluoride as preservative did not prevent analysis. Only one PM (from the control group) was discovered, implying an occurrence of only 2.2% as compared to the reported frequency of approx. 7% in Sweden. Among the extensive metabolizers (EM), however, a number of individuals with mutated genes were identified. Although it seems reasonable to suspect a PM genotype in cases with a high concentration of a drug metabolized by CYP2D6, but without suspicion of acute overdose, our study does not support the opinion that this interpretation pitfall is particularly common. This study rather indicates that drug interactions in EMs constitute a more frequent and important problem.


Quantitative determination of elastic and inelastic attenuation coefficients by off-axis electron holography.
Off-axis electron holography is a well-established transmission electron microscopy technique, typically employed to investigate electric and magnetic fields in and around nanoscale materials, which modify the phase of the reconstructed electron wave function. Here, we elaborate on a detailed analysis of the two characteristic intensity terms that are completing the electron hologram, the conventional image intensity and the interference fringe intensity. We show how both are related to elastic and inelastic scattering absorption at the sample and how they may be separated to analyze the chemical composition of the sample. Since scattering absorption is aperture dependent, a quantitative determination of the corresponding attenuation coefficients (reciprocal mean free path lengths) requires the use of holographic image modi with well-defined objective aperture stops in the back-focal plane of the objective lens. The proposed method extends quantitative electron holography to a correlated three-in-one characterization of electric and magnetic fields, Z-contrast and dielectric losses in materials.


Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study.
The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 +/- 114 vs 443 +/- 54 ms [mean +/- SD], P < 0.01), a larger precordial QT dispersion (50 +/- 74 vs 27 +/- 26 ms, P < 0.05), and a lower T wave amplitude (0.12 +/- 0.21 vs 0.24 +/- 0.16 mV, P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 +/- 26 vs 489 +/- 74 ms, P < 0.001), a larger QT dispersion in precordial (82 +/- 7 vs 54 +/- 52 ms, P < 0.01) and extremity leads (163 +/- 0 vs 40 +/- 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.


Molecular characterization of the major outer membrane protein of Haemophilus somnus.
The major outer membrane protein (MOMP) of Haemophilus somnus shows antigenic and molecular mass diversity that forms the basis of a preliminary grouping system for H. somnus strains. In this study, the gene encoding MOMP of H. somnus strain 8025 was cloned in three overlapping fragments by PCR techniques, and then sequenced. The gene consists of a 1164-bp open reading frame encoding a deduced 380-amino acid protein with a 19-amino acid signal sequence, giving a mature protein with a calculated molecular mass of 39,913 Da. Significant homology was found between MOMP and porin protein sequences of bacteria in Pasteurellaceae species. When expressed in Escherichia coli, the protein from the MOMP gene directed by the T7 promoter was identical in size (approximately 40 kDa) to native MOMP and reacted with MOMP-specific antibodies. Comparisons of the MOMP gene sequences from six unrelated strains of H. somnus to that of strain 8025 revealed that the genes of three MOMP type 1 strains were highly conserved with that of strain 8025 in length and sequence. However, two MOMP type 3c strains and one MOMP type 3a strain differed markedly from the MOMP of strain 8025 in their 3'-terminal halves. Their deduced MOMP amino acid sequences differed in sequence (3c, 80.5 and 82.7% identity; 3a, 62.4% identity) and in length (3c, 384 and 376; 3a, 316), indicating that the molecular differences are the basis of antigenicity and molecular mass differences of H. somnus MOMP. In the predicted MOMP secondary structure, the variable sequences primarily mapped to putative surface-exposed loops, and a variable and surface-exposed epitope of MOMP-specific antibody was identified in the seventh-largest loop. These findings are useful for understanding the structural and immunological characteristics of H. somnus.


A complex case of hepatitis in a patient with systemic lupus erythematosus.
Liver involvement in patients with systemic lupus erythematosus (SLE) is considered rare. Previous treatment with potentially hepatotoxic drugs or viral hepatitis have usually been implicated as the main causes of liver disease in SLE patients. On the other hand, even after careful exclusion of these aetiologies, the problem remains whether to classify the patient as having a primary liver disease with associated autoimmune clinical and laboratory features resembling SLE, such as autoimmune hepatitis, or as having liver disease as a manifestation of SLE. We report the case of an elderly woman who presented with acute hepatitis, who had been diagnosed with SLE 14 years ago and who also had Sjögren's syndrome and anti-phospholipid's syndrome for several years. The histology depicted chronic active hepatitis and, after drug-induced hepatitis and viral hepatitis were excluded, the serological and clinical features were shown to be typical of liver damage caused by SLE. The patient was treated with azathioprine 100 mg/d and prednisone 30 mg/d. The clinical symptoms resolved in 10 days and the laboratory values were normal at the end of the first month of therapy. Prednisone was progressively reduced, during a period of 4 months, to 10 mg/d but azathioprine was kept to the same dose. One year after the diagnoses the patient is still in remission. Although uncommon, hepatic involvement is well recognised in SLE. The interest of this case lies in the differential diagnosis and recognition of this condition, which deserves an aggressive treatment.


[Short-term care after hospitalization: influencing factors for discharge to the patient's own home environment].
A special short-term care (KZP) in a nursing home is offered to patients who are not yet able to live independently after hospitalization. It was institutionalized in 1989. But its basic conditions changed in 1996 with the new Pflegeversicherungsgesetz (nursing insurance law): the maximal stay was limited to 4 weeks and cost were turned over to the new insurance system. The paper analyzes the part KZP plays in health care maintenance. It addresses the questions which kind of patients is referred to KZP and what factors influence discharge at home vs admission to end-term nursing homes.A total of 325 patient's records (female: 80.3%) from 5 KZP institutions in the city of Bremen were analyzed (nearly 50% of all clients, who were formerly hospitalized). Patient's mean age was 82.9 years. Hospitalization lasted three weeks with men staying 27.6 days and women staying 20.1 days. Nervous disorders (especially apoplexy) and cardiovascular diseases are very common. After the stay in KZP, 39.1% moved to nursing homes, 36.0% returned home. Predictors for nursing home admission are long-lasting hospitalization, predicted need of long-term care by physicians, and nervous disorders. The results show that short-term care is a useful concept in health care maintenance of patients with special diseases und complicates re-convalescence.


Comparison of four immunohistochemical tests and FISH for measuring HER2 expression in gastric carcinomas.
: Accurate testing for HER2 is essential to identify patients who are likely to benefit from trastuzumab therapy. Although comparative studies on the performance of commercially available immunohistochemistry (IHC) antibodies for HER2 have been performed in breast cancer, similar studies have not been done in gastric carcinoma (GC) thus far. : Quadruplicate tissue microarrays (TMAs) of 289 advanced GCs were immunostained with HercepTest, A0485, 4B5 and CB11, and the results were compared to those of gene amplification by fluorescence in situ hybridisation (FISH). : HER2 was amplified by FISH in 38 (13.2%) GCs. HER2 overexpression (2+ or 3+) was observed in 40 (13.8%) cases by HercepTest, 46 (15.9%) by A0485, 40 (13.8%) by 4B5 and 27 (9.3%) by CB11. The sensitivity and specificity of IHC compared to FISH was 78.9%/96% for HercepTest, 86.5%/94.4% for A0485, 76.3%/95.6% for 4B5 and 60.5%/98.4% for CB11. Focal HER2 gene amplification was more common in GCs with no (0 and 1+) or low (2+) HER2 expression. Discordant IHC results were seen in 23 cases (8.0%) with the four antibodies. All HER2 3+ cases (n = 22) by HercepTest were positive with A0485 and 4B5, while one was negative with CB11. CB11 was found to be negative in 10 HercepTest 2+ and FISH+ cases. : Focal HER2 gene amplification is more common in GCs with no or low expression of HER2. Although the specificity and positive predictive value of CB11 for FISH is highest, it lacks sufficient sensitivity to be used as a first line screening test to assess HER2 status in GCs.


Titanium balanitis with phimosis.
We report the 2nd case of titanium balanitis reported in the world literature. Clinically the patient presented with phimosis: histologically the titanium was surrounded by a mixed granulomatous inflammatory reaction. Topical titanium preparations may lead to phimosis and therefore we thought it important to bring this potential iatrogenic complication to further notice.


Cardiac adaptation and its limitation in an experimental model of congestive heart failure.
To elucidate mechanisms of adaptation and maladaptation in heart failure, abnormalities of left ventricular function and their relationships to myocardial contractile protein were studied in the Syrian hamster Bio 14.6. Left ventricular and heart weights were both increased in 20-week-old cardiomyopathic hamsters, indicating cardiac hypertrophy as a compensatory mechanism to the disease process of cardiomyopathy. However further increase in the left ventricular weight was not observed in older (40-week-old) cardiomyopathic hamsters. On the other hand left ventricular volume and volume/mass ratio were increased progressively. Correspondingly, V3 type myosin was increased and myosin sliding velocity was decreased. Left ventricular function of cardiomyopathic hamsters evaluated using an isovolumically beating perfused heart preparation was depressed, and this functional impairment was also progressive. Chronic administration of metoprolol, a beta-blocking agent, induced further increase in left ventricular volume and mass without changing left ventricular function and myosin isozyme pattern. Thus in cardiomyopathic hamsters, left ventricular function progressively deteriorates in spite of a variety of adaptive mechanisms, and remodeling occurs.


Genotoxicity testing of 3,4,5-trimethylfuran-2(5H)-one, a compound from plant-derived smoke with germination inhibitory activity.
Plant-derived smoke and certain smoke compounds improve seed germination and enhance seedling growth of many species. Thus, smoke-infused water and the active smoke-derived compounds have the potential to be used in different agricultural and horticultural applications. However, despite these interesting and potentially practical properties, it should also be ascertained whether such compounds may pose a health risk, particularly if they are to be used in the production of food or fodder crops. Amongst some of the aspects that would be important to understand are any possible genotoxic properties that the compounds may possess due to potential carry-over effects. Here, we report on a genotoxicity study of 3,4,5-trimethylfuran-2(5H)-one, a compound from plant-derived smoke previously shown to have germination inhibitory activity. Using two in vitro tests, namely the bacterial VITOTOX® test (with/without S9 metabolic activation) and the cytome assay on human C3A cells, no genotoxicity or toxicity was found. Furthermore, these results support a previous study where a related smoke-derived compound with germination promoting properties was investigated.


Painful athletic injuries of the shoulder.
Pain in the athlete's shoulder is likely to have a mechanical origin, because the athlete performs repetitive high-stress activity. Proper treatment is based on understanding the biomechanics and physiology of the tissues, as well as the demands of the patient's specific athletic activity. Correct rehabilitation is the key to successful conservative and surgical management. A return to previous activity depends on restoring the normal biomechanics, either through conservative management or surgery. Some of these problems are unsolved and remain fruitful areas for future research.


Direct analysis of VLDL by TOF-MS allows rapid definition of Apo E genotypes and facilitates characterisation of post translational changes.
Apolipoprotein E (Apo E) is a glycoprotein which acts as a ligand facilitating the uptake of lipids. Three common isoforms of Apo E are recognised, E2, E3 and E4. E2 and E4 are associated with altered lipid metabolism and increased cardiovascular risk. We report a novel variant of Apo E (c.382G>A) predicting 110Asp→Asn identified by genotyping, we were prompted to investigate this further as the amino acid substitution produced a prospective N-glycosylation site in this novel variant. We present a new rapid approach to genotyping Apo E performed by electrospray TOF-MS, on the same sample analysed by ultracentrifugation. The analysis can be performed in <10min and requires minimal sample volume. Control samples were used to verify the analysis. Spectra showed the expected mass for the E3 isoform at 34,237Da, E2 and E4 isoforms were identifiable by peaks at -53Da and +53Da respectively. Post translational glycosylation of the protein can also be identified. The novel isoform had a mass of 34,237Da without evidence of N-glycosylation. No significant effect on lipid metabolism was identified. The electrospray TOF-MS approach potentially provides a rapid alternative method for genotyping Apo E and for the investigation of novel isoforms.


Intermolecular potential energy surface of Ar-NO.
Rotational spectra of an open-shell complex, Ar-NO, in the electronic ground state have been analyzed by employing an analysis using a free-rotor model, where previously observed data by Mills et al. [J. Phys. Chem. 90, 3331 (1986); 90, 4961 (1986)] and additional transitions observed by Fourier-transform microwave spectroscopy in the present study are simultaneously analyzed with a standard deviation of the least-squares fit to be 27.5 kHz. A two-dimensional intermolecular potential energy surface for Ar-NO has been determined from the analysis. The determined potential energy surface is compared with those of Ar-OH and Ar-SH, which are also complexes containing an open-shell species with the 2Pi ground electronic state.


Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion.
Dehydroepiandrosterone sulfate (DS) concentration was measured in the sera of premature and full-term infants and in children throughout puberty. Panhypopituitary, Addisonian, and virilized children were also studied. DS decreased slowly during the first weeks of life from a high level in neonates to the low levels observed between one to five years. After five years of age, DS concentration started to rise. A steeper increase was observed with the onset of puberty, and adult DS concentrations were reached in late puberty. There was no sex difference in DS concentration at any pubertal stage or bone age. Day-to-day variations were small in childhood and during puberty, but were considerable in premature infants. DS concentrations measured at 0900 h were not significantly different from those at 1700 h. There was a positive correlation of serum DS concentrations with the excretion of urinary 17-ketosteroids in boys and girls (r=0.789). Premature infants had DS concentration in or above the late pubertal range. Five panhypopituitary patients and five Addisonian patients had DS concentrations below normal. DS was markedly elevated in patients with congenital adrenal hyperplasia and in one girl with adrenal carcinoma, and was suppressible with dexamethasone in the former. The ease of measurement and the small amount of blood required make serum DS determination a useful guide for adrenal androgen secretion.


Determining neutrino mass from the cosmic microwave background alone.
Distortions of cosmic microwave background temperature and polarization maps caused by gravitational lensing, observable with high angular resolution and high sensitivity, can be used to measure the neutrino mass. Assuming two massless species and one with mass m(nu), we forecast sigma(m(nu))=0.15 eV from the Planck satellite and sigma(m(nu))=0.04 eV from observations with twice the angular resolution and approximately 20 times the sensitivity. A detection is likely at this higher sensitivity since the observation of atmospheric neutrino oscillations requires Deltam(2)(nu) greater, similar (0.04 eV)(2).


[Phase II clinical trial of MCNU].
MCNU is a new derivative of nitrosourea and experimental studies have shown equal or superior activity to known nitrosourea compounds. Twenty one cases were entered into our clinical studies with a phase II study. Nineteen cases have had a several courses of prior chemotherapy. Four out of 21 cases achieved a partial response (each one of lymphoepithelioma, parotid gland cancer, recurrent uterine cancer and recurrent breast cancer). The major toxicity encountered during treatment was myelosuppression. Full recovery of myelosuppression was delayed and was seen six to eight weeks after each injections. These initial results justify further clinical investigations with MCNU.


Determination of carbon disulfide at the workplace by sampling on charcoal tubes--problems and solutions.
The aim of the study was to check the reliability and comparability of different analytical methods for ambient monitoring of carbon disulfide (CS2). A stationary sampling system, consisting of a charcoal sampling tube and pump, and two personal sampling systems, consisting of a charcoal sampling tube and a portable pump and of a diffusive charcoal sampler have been compared. The limits of quantification, within-series precision, between-series precision, recovery, and comparability of the methods were investigated. For passive sampling the recovery was determined by three different techniques. For a sampling time of 6 hours the limit of quantification was 0.2 ppm for the personal sampling and 0.01 ppm for the stationary sampling system. The within-series precision was between 5 and 8%. For personal sampling the between-series precision was between 9 and 12% using a passive sampler. The recovery ranged between 45 and 85% depending on the quotient of eluent volume and charcoal mass. The comparison of the two personal sampling methods in a field study using linear regression demonstrated with statistical certainty an excellent concordance of the methods. The study shows that particularly the method for determining air levels of carbon disulfide by passive sampling is associated with high systematic errors. If these errors are unknown or ignored they will result in highly underestimated exposure data for carbon disulfide.


The nursing programme 'Coping with itch': a promising intervention for patients with chronic pruritic skin diseases.
To examine the feasibility of the nursing programme 'Coping with Itch' and the effect of the programme on the frequency and intensity of itching and scratching, itch-related coping, skin-related psychosocial morbidity and quality of life. Itch is a major symptom of many chronic skin diseases and has a considerable impact on the quality of life. Therefore, the nursing programme 'Coping with Itch' has been developed and implemented at the outpatient departments of dermatology of one university and one general hospital in the Netherlands. The programme is intended to reduce itch and to help the patient cope with his or her itch. The feasibility of the programme has been determined by interviewing the nurses who carried out the programme, dermatologists and one medical social worker and by counting the number of visits and specific interventions. The effect of the nursing care programme 'Coping with Itch' was evaluated in 32 patients with pruritic skin diseases. Paired t-tests were used to determine its effect after three and nine months. The nursing programme 'Coping with Itch' proved to be practically feasible. It leads to a significant reduction of the frequency and intensity of itching and scratching, to a significant reduction of catastrophizing and helpless coping and to a significant reduction of skin-related psychosocial morbidity in the short term. These results stabilized at nine months. No changes were found in the quality of life. The nursing programme 'Coping with Itch' is a promising intervention for patients with chronic pruritic skin diseases.


[Gd-BOPTA enhanced excretory MR urography without administration of diuretics].
To evaluate the feasibility and clinical utility of Gd-BOPTA enhanced excretory magnetic resonance urography without additional administration of diuretics in correlation with conventional urography. 15 preoperative patients with pelvic tumors were examined at 1.5 T using a breath-hold high-resolution 3D-FLASH sequence during first-pass as well as 5, 10, 15 minutes after i.v. injection of 0.05 mmol/kg BW Gd-BOPTA (MultiHance) without administration of diuretics. Post-processed coronal and multiplanar MIP reconstructions were compared to conventional excretory urography with regard to morphologic accuracy, anatomic variability, filling defects, cause and level of obstruction or compression, tumor visibility, and time-effectiveness by two independent radiologists. Visualization of the urinary tract by MRU was comparable to conventional excretory urography in 14 of 15 cases. Caliceal fornices were better delineated on conventional urographies, whereas MRU was considered superior in the assessment of the inferior ureter sections, the urinary bladder and obstructive tumors, whose extents could be clearly marked out. Examination times of both techniques were comparable. These first results show that non-diuretic Gd-BOPTA enhanced MRU is comparable to conventional excretory urography for the preoperative diagnosis of pelvic tumors. Further improvements of this technique seem possible by optimization of examination intervals and injection doses.


β-amyloid model core peptides: Effects of hydrophobes and disulfides.
The mechanism by which a disordered peptide nucleates and forms amyloid is incompletely understood. A central domain of β-amyloid (Aβ21-30) has been proposed to have intrinsic structural propensities that guide the limited formation of structure in the process of fibrillization. In order to test this hypothesis, we examine several internal fragments of Aβ, and variants of these either cyclized or with an N-terminal Cys. While Aβ21-30 and variants were always monomeric and unstructured (circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMRS)), we found that the addition of flanking hydrophobic residues in Aβ16-34 led to formation of typical amyloid fibrils. NMR showed no long-range nuclear overhauser effect (nOes) in Aβ21-30, Aβ16-34, or their variants, however. Serial 1 H-15 N-heteronuclear single quantum coherence spectroscopy, 1 H-1 H nuclear overhauser effect spectroscopy, and 1 H-1 H total correlational spectroscopy spectra were used to follow aggregation of Aβ16-34 and Cys-Aβ16-34 at a site-specific level. The addition of an N-terminal Cys residue (in Cys-Aβ16-34) increased the rate of fibrillization which was attributable to disulfide bond formation. We propose a scheme comparing the aggregation pathways for Aβ16-34 and Cys-Aβ16-34, according to which Cys-Aβ16-34 dimerizes, which accelerates fibril formation. In this context, cysteine residues form a focal point that guides fibrillization, a role which, in native peptides, can be assumed by heterogeneous nucleators of aggregation.


Prostate specific antigen bounce phenomenon after external beam radiation for clinically localized prostate cancer.
We characterize the prostate-specific antigen (PSA) bounce in patients who underwent external beam radiation therapy for prostate cancer and correlate the PSA bounce with the development of biochemical disease progression. In this study 964 patients received full dose radiation therapy alone. Followup PSA values were obtained 3 months after completion of radiotherapy and every 3 to 6 months thereafter. Median followup of the entire study group was 48 months. All time intervals were calculated from the completion date of radiation therapy. PSA bounce was defined as an initial increase in serum PSA of at least 0.5 ng./ml., followed by a decrease to pre-bounce baseline serum PSA values no more than 60 months after external beam radiation therapy. Of the 964 patients 119 (12%) had a PSA bounce. PSA bounce was unrelated to age, race, pretreatment PSA, Gleason score, clinical T stage or radiation dose. Mean time to PSA bounce was 9 months from the time of therapy. The respective 1 and 5-year biochemical disease-free survival rates were 100% and 82.1% for patients with PSA bounce and 93.9% and 57.7% for those without PSA bounce (p = 0.0001). Of men with prostate cancer treated with external beam radiation therapy 12% experienced a transient increase in PSA (PSA bounce) followed by a return to pre-bounce levels after radiation. The PSA bounce phenomenon was not predictive of time to biochemical recurrence.


Symptomatic radiation necrosis in brain metastasis patients treated with stereotactic radiosurgery and immunotherapy.
The association of symptomatic radiation necrosis (RN) with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs) in brain metastases patients has been incompletely explored. We aim to discuss the incidence, risk factors, and prognosis of symptomatic RN in patients treated with these modalities. We retrospectively evaluated the incidence of symptomatic RN among all patients with brain metastases treated with both SRS and an ICI at a single academic center. Risk factors for the development of symptomatic RN were determined, along with median overall survival (OS) stratified by the development of RN. Between 2010 and 2016, 57 brain metastases patients were treated with both SRS and an ICI. Only 4 (7%) developed symptomatic RN. Symptomatic RN lesions were more likely to be located in the cerebral cortex (p = 0.019) and be associated with a primary renal cell carcinoma (p = 0.032). Median OS was 32 months for those who developed symptomatic RN and 29 months for all other patients (p = 0.16). Treatment of brain metastases with both SRS and an ICI is an effective modality that poses mild risk for developing symptomatic RN when compared to the risk of RN from SRS alone.


[Development of a gas chromatographic column system for the on-line analysis of trace tetrahydrofuran in hexane].
A gas chromatographic system using home-made 7 microns thick cross-linked dimethylpolysiloxane columns for the on-line analysis of trace tetrahydrofuran in hexane in a rubber production facility was developed. The experimental parameters of the column system, including the temperature, flow rate as well as the back-flushing and heart-cutting program were investigated. The total column-switching program was suggested. The system has been successfully operated for more than one year with good resolution, stability and precision (RSD < 5%) in analyzing trace tetrahydrofuran (0-250 x 10(-6), V/V) for industrial process control in the rubber production facility.


Single-channel and whole-cell currents in rat cerebellar granule cells.
The patch-clamp technique was used to study both whole-cell and single-channel currents in cultured rat cerebellar granule cells. In whole-cell recordings under voltage-clamp conditions 3 types of current were found; a transient inward sodium current and a transient and a sustained outward potassium current. Single-channel currents were recorded from both inside-out and outside-out membrane patches. Three types of potassium channel were identified; two non-inactivating channels with unit conductances of 160 and 60 pS and one inactivating channel of 20 pS. No calcium currents were detected.