Differential effects of basolateral and apical iron supply on iron transport in Caco-2 cells.

Iron homeostasis in the human body is maintained primarily through regulation of iron absorption in the duodenum. The liver peptide hepcidin plays a central role in this regulation. Additionally, expression and functional control of certain components of the cellular iron transport machinery can be influenced directly by the iron status of enterocytes. The significance of this modulation, relative to the effects of hepcidin, and the comparative effects of iron obtained directly from the diet and/or via the bloodstream are not clear. The studies described here were performed using Caco-2 cell monolayers as a model of intestinal epithelium, to compare the effects of iron supplied in physiologically relevant forms to either the apical or basolateral surfaces of the cells. Both sources of iron provoked increased cellular ferritin content, indicating iron uptake from both sides of the cells. Supply of basolateral transferrin-bound iron did not affect subsequent iron transport across the apical surface, but reduced iron transport across the basolateral membrane. In contrast, the apical iron supply led to subsequent reduction in iron transport across the apical cell membrane without altering iron export across the basolateral membrane. The apical and basolateral iron supplies also elicited distinct effects on the expression and subcellular distribution of iron transporters. These data suggest that, in addition to the effects of cellular iron status on the expression of iron transporter genes, different modes and direction of iron supply to enterocytes can elicit distinct functional effects on iron transport.

The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.

BACKGROUND: The Ras/RAF/MEK/ERK pathway is frequently deregulated in cancer and a number of inhibitors that target this pathway are currently in clinical development. It is likely that clinical testing of these agents will be in combination with standard therapies to harness the apoptotic potential of both the agents. To support this strategy, it has been widely observed that a number of chemotherapeutics stimulate the activation of several intracellular signalling cascades including Ras/RAF/MEK/ERK. The MEK1/2 inhibitor selumetinib has been shown to have anti-tumour activity and induce apoptotic cell death as a monotherapy. METHODS: The aim of this study was to identify agents, which would be likely to offer clinical benefit when combined with selumetinib. Here, we used human tumour xenograft models and assessed the effects combining standard chemotherapeutic agents with selumetinib on tumour growth. In addition, we analysed tumour tissue to determine the mechanistic effects of these combinations. RESULTS: Combining selumetinib with the DNA-alkylating agent, temozolomide (TMZ), resulted in enhanced tumour growth inhibition compared with monotherapies. Biomarker studies highlighted an increase in γH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by TMZ alone. In several models we observed that continuous exposure to selumetinib in combination with docetaxel results in tumour regression. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib. CONCLUSION: The data presented suggests that MEK inhibition in combination with several standard chemotherapeutics or an Aurora B kinase inhibitor is a promising clinical strategy.

Impaired endothelial function in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients suffer from excess cardiac deaths due to accelerated atherosclerosis. Endothelial dysfunction is a marker of early atherosclerosis. We tested the hypothesis that SLE patients have impaired endothelial function and assessed the relationship between endothelial function and clinical outcome over the subsequent five years. Thirty-six female SLE patients were compared with 22 healthy age and sex matched controls. Endothelial dependent vasodilatation (EDD) was assessed at the brachial artery in response to shear stress. Endothelium-independent dilatation induced by glyceryl trinitrate was also measured. Patients were followed for up to five years and the development of damage in the cardiovascular and other systems recorded. SLE patients showed significantly impaired endothelial function (median EDD 5.6%, IQR 3.1-7.2%) compared with healthy controls (median EDD 8.0%, IQR 6.3-9.3%; P = 0.001). Endothelium independent dilatation did not differ between the two groups. Endothelial function was significantly worse in postmenopausal compared with premenopausal women (median EDD 6.6%, IQR 3.9-7.8% versus 3.1%, IQR 2.6-5.1%; P = 0.016). Total cholesterol was inversely correlated with endothelial function in SLE patients (Spearman correlation r = -0.422, P = 0.025). There was no relationship between endothelial function and the development of damage in any organ system, including the cardiovascular system during patient follow-up. Patients with SLE have impaired endothelial Lupus (2007) 16, 84-88.

Ultrasound guidance allows accurate needle placement and aspiration from small joints in patients with early inflammatory arthritis.

OBJECTIVES: To compare the accuracy of palpation-guided and high frequency ultrasound-guided needle placement in small joints and to develop a technique to obtain synovial fluid from these joints for diagnosis and research. METHODS: The accuracy of needle placement during palpation-guided proximal interphalangeal (PIP) or metacarpophalangeal (MCP) joint injection was assessed. This was compared with the accuracy of ultrasound-guided needle placement. A joint lavage technique was developed to obtain synovial fluid from these joints. RESULTS: Needle positioning was intra-articular in 59% of palpation-guided injections (6/12 PIP and 4/5 MCP joints). No fluid could be aspirated prior to injection. With ultrasound guidance, initial needle placement was intra-articular in 96% of cases (24/26 PIP and 27/27 MCP joints). Synovial fluid cells were lavaged from 63% of joints (19/25 PIP and 14/27 MCP joints). In only one case was a large effusion seen and this was aspirated directly. CONCLUSIONS: The use of high frequency ultrasound to guide needle placement within a small joint allows for significantly greater accuracy than a palpation-guided approach. When followed by lavage, synovial fluid cells and diluted synovial fluid can be obtained from the majority of small joints. This has important clinical and research implications.

Cardiovascular risk in systemic lupus erythematosus--evidence of increased oxidative stress and dyslipidaemia.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with severe and premature cardiovascular disease, which is not explained by traditional risk factors alone. This study aimed to investigate markers of oxidative stress, lipid metabolism and inflammation as potential cardiovascular risk factors in women with SLE. METHODS: Venous blood samples were taken from 53 female Caucasian patients with SLE and from healthy age- and sex-matched controls. Samples were analysed for markers of oxidative stress, lipid metabolism [including low-density lipoprotein (LDL) subfraction profile] and C-reactive protein (CRP). RESULTS: Female SLE patients had an atherogenic lipid profile characterized by raised total cholesterol and triglycerides, and the presence of small, dense LDL subfractions compared with healthy controls. These changes were associated with increased oxidative damage and a moderately raised CRP. CONCLUSIONS: The results provide evidence for free radical and inflammatory activity in SLE and suggest potential targets to reduce the risk of cardiovascular disease in these patients.

Development and assessment of a World Wide Web site for systemic lupus erythematosus patient information.

Patient education is an important component of the management of chronic diseases such as SLE. We have investigated the value of the World Wide Web as a medium for delivery of SLE patient information. Volunteers recruited from the clinic and from the website completed interviews and questionnaires aimed at defining their information needs. A new website was then established and its impact on users tested using knowledge questionnaires. The new website was used extensively (20-30 users each day) over the 24 month period of study until April 2001. A total of 510 participants completed an online questionnaire that showed that for some users it was their first use of the internet to gather lupus information, but the majority (58.9%) accessed it at least monthly for this purpose. We also found that, while most users (56.9%) found current disease information was at an appropriate level, 37.5% thought it was too basic. Knowledge questionnaires from 42 participants before and after using the site showed a significant rise in users' knowledge of the areas covered by the site. As far as we are aware this study is the first to show that a patient-oriented website can have a positive effect on disease knowledge. The relative ease with which good quality information can be disseminated via the web suggests that this medium is likely to be less costly and perhaps more educationally effective than printed information, and so is likely to become a primary vehicle for patient education. The website tested can be found at: www.rheumatology.bham.ac.uk/lupus/intro.html.

The Test of Everyday Attention for Children (TEA-Ch): patterns of performance in children with ADHD and clinical controls.

The present study explores the utility of the Test of Everyday Attention for Children (TEA-Ch) as a measure of the attentional impairments displayed by children with Attention Deficit Hyperactivity Disorder (ADHD). Sixty-three children with ADHD and 23 non-ADHD Clinical Control children were compared on subtests of the TEA-Ch reflecting three attentional domains: sustained, selective, and attentional control. Results show that children with ADHD performed significantly worse than clinical controls on subtests of sustained attention and attentional control. The groups did not differ, however, on subtests of selective attention. These findings suggest that the TEA-Ch is sensitive to attentional deficits unique to ADHD and holds promise as a useful tool in the assessment of ADHD. Performance patterns and future directions are discussed.

Older patients with schizophrenia: challenges in the coming decades.

The number and proportion of older adults with schizophrenia will increase considerably in the coming decades. Although a vast literature on schizophrenia among younger adults exists, much less is known about late-life schizophrenia and its treatment. The authors describe two potential scenarios for 2011, the year that the first baby boomers will turn 65. To ensure that the more favorable scenario becomes a reality, the authors suggest four goals: decrease medical comorbidity and mortality among younger patients with schizophrenia and improve their access to health care so that they can live longer and more productive lives; improve our understanding of the neurobiological and psychosocial factors underlying late-life schizophrenia, as well as the health care and social service needs of such patients; develop more effective and safer pharmacologic, psychosocial, and cognitive behavioral treatments; and improve rehabilitation of older people with schizophrenia. Specific strategies to foster these goals include establishing a consortium for studies of late-life schizophrenia; conducting multicenter studies of treatment effectiveness; and forming interdisciplinary collaborations among researchers, clinicians, government and industry representatives, and patient advocacy groups.

Schizoaffective disorder: a form of schizophrenia or affective disorder?

BACKGROUND: The diagnostic status of schizoaffective disorder continues to be controversial. Researchers have proposed that schizoaffective disorder represents a variant of schizophrenia or affective disorder, a combination of the 2, or an intermediate condition along a continuum between schizophrenia and affective disorder. METHOD: We compared outpatients aged 45 to 77 years with DSM-III-R diagnosis of schizoaffective disorder (N = 29), schizophrenia (N = 154), or nonpsychotic mood disorder (N = 27) on standardized rating scales of psychopathology and a comprehensive neuropsychological test battery. A discriminant function analysis was used to classify the schizoaffective patients based on their neuropsychological profiles as being similar either to schizophrenia patients or to those with nonpsychotic mood disorder. RESULTS: The schizoaffective and schizophrenia patients had more severe dyskinesia, had a weaker family history of mood disorder, had been hospitalized for psychiatric reasons more frequently, were more likely to be prescribed neuroleptic and anticholinergic medication, and had somewhat less severe depressive symptoms than the mood disorder patients. The schizophrenia patients had more severe positive symptoms than the schizoaffective and mood disorder patients. The neuropsychological performances of the 2 psychosis groups were more impaired than those of the nonpsychotic mood disorder patients. Finally, on the basis of a discriminant function analysis, the schizoaffective patients were more likely to be classified as having schizophrenia than a mood disorder. CONCLUSION: These findings suggest that schizoaffective disorder may represent a variant of schizophrenia in clinical symptom profiles and cognitive impairment.

The use of Bacillus diarrhoeal enterotoxin (BDE) detection using an ELISA technique in the confirmation of the aetiology of Bacillus-mediated diarrhoea.

A commercially available ELISA kit was used for the detection of Bacillus diarrhoeal enterotoxin (BDE) in a variety of foods and faeces. The ability of isolates of Bacillus spp., including Bacillus cereus, to produce BDE in Brain Heart Infusion broth containing 0.1% glucose was also checked by use of the kit. Results show that 29 out of 31 B. cereus isolates were enterotoxigenic. Foods positive for performed BDE were always contaminated with > 10(5) B. cereus cfu g-1, but not all foods contaminated with large numbers of B. cereus were positive for BDE. Bacillus sp., other than one isolate which closely resembled B. subtilis, were negative for BDE production. Criteria for the confirmation of Bacillus-mediated diarrhoea should now include reports of symptoms and incubation periods consistent with the diarrhoeal form of food-poisoning by Bacillus spp., together with the results of tests for enterotoxigenicity of the Bacillus isolate, and detection of BDE in either the food and/or faeces.

Validity of specific subscales of the positive and negative symptom scales in older schizophrenia outpatients.

We investigated the construct validity of subscales of the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) along with other measures of psychopathology in 109 schizophrenia outpatients aged 45-84 years. Scores on subscales of the SAPS, SANS and Brief Psychiatric Rating Scale (BPRS) and on the Hamilton Depression Scale (HAM-D) were subjected to a principal components analysis and orthogonal rotation followed by an extension analysis. In both analyses, three of four SAPS subscales had their highest loading on the positive symptom factor and four of five SANS subscales had their highest factor loading on the negative symptom factor. The SAPS bizarre behavior subscale, however, had a much higher loading on the depressive symptom factor than on the positive symptom factor, and the SANS avolition-apathy subscale had moderate loadings on both the negative symptom factor and the depressive symptom factor. The use of SAPS and SANS subscales to represent two constructs was largely (but not entirely) validated among middle-aged and elderly schizophrenia outpatients. The SAPS bizarre behavior subscale and, to a lesser extent, the SANS avolition-apathy subscale appear to represent in this older population a separate construct which may be related to depressive symptoms.

Clinical and neuropsychological comparison of psychotic depression with nonpsychotic depression and schizophrenia.

OBJECTIVE: This study compared the clinical and neuropsychological characteristics of patients with psychotic depression to those of patients with nonpsychotic depression and patients with schizophrenia. METHOD: Two hundred eighteen patients over the age of 45, including 30 who met the DSM-III-R criteria for unipolar major depression with psychotic features, 28 with nonpsychotic unipolar major depression, and 160 with schizophrenia, were examined. Subjects were evaluated on several clinical measures as well as on neuropsychological tests of attention, learning, memory (retention), psychomotor speed, and motor skills. RESULTS: The three groups were comparable in age and education. The severity of depressive symptoms in the depressed patients with and without psychosis was similar. The patients with psychotic depression were comparable to those with schizophrenia on the neuropsychological measures; they were more impaired than the patients with nonpsychotic depression on the measures of psychomotor speed, motor skills, attention, and learning. The cognitive deficits seemed to be trait-related. CONCLUSIONS: The findings provide additional support for the validity of psychotic depression as a diagnostic category distinct from nonpsychotic depression.

Dietary exposure of mink to carp from Saginaw Bay, Michigan: 2. Hematology and liver pathology.

The effects of consumption of environmental contaminants contained in carp (Cyprinus carpio) from Saginaw Bay, Michigan on various hematological parameters and liver integrity of adult female mink (Mustela vision) were determined. Mink were fed diets that contained 0 (control), 10, 20, or 40% carp prior to and throughout the reproductive period (182 days). The diets contained 0.015, 0.72, 1.53, and 2.56 mg polychlorinated biphenyls (PCBs)/kg diet and 1.0, 19, 40, and 81 pg 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQs)/g diet, respectively. Mink fed the diets containing carp showed a general dose-dependent occurrence of clinical signs commonly associated with chlorinated hydrocarbon toxicity, including listlessness, nervousness when approached, anorexia, and melena. Erythrocyte counts were less in mink exposed to Saginaw Bay carp than in controls, while the number of white blood cells was greater than in controls. Significant differences (p < 0.05) in the concentrations of neutrophils, lymphocytes, monocytes, and eosinophils were also found between the control and carp-fed groups, but are considered to be of limited clinical or biological importance. Hematocrit values for the mink fed the 20 and 40% carp diets were significantly less than those of mink in the control and 10% carp groups. There were no significant differences in hemoglobin concentrations among the groups. Necropsies revealed enlarged yellowish livers in many of the carp-fed mink, especially those fed the 40% carp diet. Liver, spleen, and lung weights of carp-fed mink were significantly greater than those of control mink.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary exposure of mink to carp from Saginaw Bay, Michigan. 1. Effects on reproduction and survival, and the potential risks to wild mink populations.

Carp (Cyprinus carpio) collected from Saginaw Bay, Michigan, containing 8.4 mg total polychlorinated biphenyls (PCBs)/kg and 194 ng of 2,3,7,8-tetrachloro-dibenzo-p-dioxin equivalents (TEQs)/kg, were substituted for marine fish at levels of 0, 10, 20, or 40% in the diets of adult ranch mink (Mustela vison). The diets, containing 0.015, 0.72, 1.53, and 2.56 mg PCBs/kg diet, or 1.03, 19.41, 40.02, and 80.76 ng TEQs/kg diet, respectively, were fed to mink prior to and throughout the reproductive period to evaluate the effects of a naturally-contaminated prey species on their survival and reproductive performance. The total quantities of PCBs ingested by the mink fed 0, 10, 20, or 40% carp over the 85-day treatment period were 0.34, 13.2, 25.3, and 32.3 mg PCBs/mink. respectively. The corresponding quantities of TEQs ingested by the mink over the same treatment period were 23, 356, 661, and 1,019 ng TEQs/mink, respectively. Consumption of feed by mink was inversely proportional to the PCB and TEQ content of the diet. The diet containing Saginaw Bay carp caused impaired reproduction and/or reduced survival of the kits. Compared to controls, body weights of kits at birth were significantly reduced in the 20 and 40% carp groups, and kit body weights and survival in the 10 and 20% carp groups were significantly reduced at three and six weeks of age. The females fed 40% carp whelped the fewest number of kits, all of which were stillborn or died within 24 hours. Lowest observable adverse effect levels (LOAEL) of 0.134 mg PCBs/kg body weight/day or 3.6 ng TEQs/kg body weight/day for adult female mink were determined. The potential effects of exposure of wild mink to contaminated Great Lakes fish were assessed by calculating "maximum allowable daily intakes" and "hazard indices" based on total concentrations of PCB residues in several species of Great Lakes fish and mink toxicity data derived from the study.

Chromophore-enhanced laser-tumor tissue photothermal interaction using an 808-nm diode laser.

A diode laser was used to irradiate tumor tissue, with indocyanine green as the chromophore. The 808-nm wavelength radiation falls within the absorption peak of the chromophore (about 780 nm). The preliminary results in this report revealed clear and significant coupling of this laser and indocyanine green in laser-tissue photothermal interaction. The chromophore targeted tissue showed laser damage while peripheral tissues remained intact. Without the chromophore, this laser inflicted no apparent tissue damage in the non-contact mode with irradiance up to 1755 J/cm2.

Contaminants in fishes from Great Lakes-influenced sections and above dams of three Michigan rivers. I: Concentrations of organo chlorine insecticides, polychlorinated biphenyls, dioxin equivalents, and mercury.

Fishes of the Great Lakes contain hazardous chemicals such as synthetic halogenated hydrocarbons and metals. These fish can move from the lakes into the Great Lakes tributaries of Michigan. In doing so, they transport concentrations of contaminants which may represent a risk to wildlife. Concentrations of mercury (Hg), total polychlorinated biphenyls (PCBs), 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQ), total DDT complex, aldrin, endrin, dieldrin, heptachlor, heptachlor epoxide, lindane, hexachlorobenzene, cis-chlordane, oxychlordane, endosulfan-I, methoxychlor, trans-chlordane, and trans-nonachlor were determined in composite samples of fishes from above and below Michigan hydroelectric dams, which separate the fishes which have access to the Great Lakes from fishes that do not. Mean concentrations of total PCBs, TCDD-EQ, DDT, and most of the other pesticides were greater in composite samples of six species of fishes from below than above the dams on the Au Sable, Manistee, and Muskegon Rivers. Concentrations of mercury, were the same or greater above the dams than below. However, this difference was statistically significant only on the Au Sable. Mercury concentrations ranged from less than 0.05 mg/kg to 0.73 mg Hg/kg, ww. Total concentrations of PCBs ranged from 0.02 to 1.7 mg/kg, ww. Concentrations of 2,3,7,8-tetrachlordibenzo-p-dioxin equivalents varied among fishes and locations. The concentrations of TCDD-EQ ranged from 2.4 to 71 micrograms/kg, ww, with concentrations in carp being the greatest. Concentrations of TCDD-EQ were greater than the concentrations which would be expected to occur, due solely to the presence of polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and technical mixtures of PCBs.

Contaminants in fishes from Great Lakes-influenced sections and above dams of three Michigan rivers. II: Implications for health of mink.

Populations of mink (Mustela vison) have declined in many areas of the world. Such declines have been linked to exposures to synthetic, halogenated hydrocarbons. In the Great Lakes region, mink are fewer in areas along the shore of the Great Lakes and their tributaries where mink have access to fish from the Great Lakes. Recently, there has been discussion of the relative merits of passage of fishes around hydroelectric dams on rivers in Michigan. A hazard assessment was conducted to determine the potential for adverse effects on mink, which could consume such fishes from above or below dams on the rivers. Concentrations of organochlorine insecticides, polychlorinated biphenyls (PCBs), 2,3,7,8-tetrachlordibenzo-p-dioxin equivalents (TCDD-EQ), and total mercury were measured in composite samples of fishes from above or below hydroelectric dams on the Manistee and Muskegon Rivers, which flow into Lake Michigan, and the Au Sable River, which flows into Lake Huron. Concentrations of organochlorine insecticides, PCBs, and TCDD-EQ were all greater in fishes from below the dams than those from above. Concentrations of neither organochlorine insecticides nor mercury in fishes are currently a risk to mink above or below the dams. All of the species of fishes collected from downstream of the dams contained concentrations of PCBs and TCDD-EQ, which represent a hazard to mink. The hazard index for PCBs was less than one for the average of all species from the upstream reaches of the Manistee and Au Sable Rivers, but not the Muskegon. The hazard index (concentration in fish/NOAEC) was greater than 1 for all of the species collected from below the dams, in all three rivers. The greatest hazard index was observed for carp (Cyprinus carpio) downstream on the Muskegon River. Because the concentrations of PCBs used in the hazard assessment were corrected for relative toxic potencies, the hazard ratios based on PCBs should be similar to those based on TCDD-EQ. This was found to be true. Thus, either total PCBs or TCDD-EQ could be used as the critical toxicant in the hazard assessment. However, if uncorrected concentrations of PCBs, expressed as Aroclors, were used in the hazard assessment, the toxicity of the weathered mixture would have been underestimated by approximately five-fold, and, in that instance, TCDD-EQ would be the critical contaminant for the hazard assessment.(ABSTRACT TRUNCATED AT 400 WORDS)

A staff development plan for the graying of America's hospital patients.

In this article, the authors describe a program created by a nursing inservice department to address the graying of America's hospital patients. The increased number of aging patients presents a challenge that hospitals must confront. Elderly patients who take longer to get well and consume more resources make unprecedented demands on nursing staff members. Because basic nursing education programs fail to address the problem, the task of preparing nursing personnel to care for aging patients falls to the hospital's department of staff development.

Negative symptoms in late-life schizophrenia.

The authors assessed the relationship of negative symptoms to demographic, other clinical, and neuropsychological variables to investigate and, to an extent, validate the assessment of individual negative symptoms in older schizophrenic patients. Sixty-four subjects meeting DSM-III-R criteria for schizophrenia, including 39 with onset before age 45 (early-onset schizophrenia, or EOS) and 25 diagnosed with late-onset schizophrenia (LOS) were recruited, along with 35 normal comparison (NC) subjects. All the subjects were assessed, using Scales for the Assessment of Negative Symptoms, other psychiatric rating scales, and a comprehensive neuropsychological evaluation. The prevalence of alogia and anhedonia/asociality was comparable in EOS and LOS groups. The prevalence of affective blunting and avolition/apathy was greater in EOS than in LOS. The authors propose a three-factor model of negative symptoms in older, ambulatory, neuroleptic-treated schizophrenic patients. Limitations of the study, as well as possible implications of findings are discussed.