bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolving spinal analgesia practice in palliative care
Authors: Baker Lisa , Lee Mark , Regnard Claud , Crack Lindsay , Callin Sarah
Published: August 2004

Intraspinal analgesia can be helpful in some patients with intractable pain. Over 15 years palliative care professionals evolved their spinals policy through a repeated series of evaluations, discussions and literature reviews. One hundred intraspinal lines were then reviewed. Notable changes in policy were the switch from epidurals to intrathecals, and the insertion of lines during working hours rather than as emergencies. Our efficacy, and frequency of adverse effects, is equal or better to published studies. Key issues in reducing adverse effects were the improved care of the spinal line exit site, a change from bolus administration to continuous infusions, and modifying line insertion techniques. Current policy is to use continuous infusions of diamorphine and bupivacaine in a 1:5 ratio through externalized intrathecal lines. The lines are effective in approximately two thirds of patients and can be kept in place for up to 18 months. The policy continues to be updated and common documentation is now in place.
Thoughts of patients with advanced heart failure on dying
Authors: Willems D L , Hak A , Visser F , Van der Wal G
Published: August 2004

Objective: To explore, over a one-year period, the ideas and attitudes of patients with end-stage cardiac failure concerning dying. Design: Prospective longitudinal multiple case study using qualitative interview techniques. Participants: Thirty-one patients from two hospitals who fulfilled one or more of the following criteria: NYHA III or IV, ejection fractionB >25%, at least one hospitalization for heart failure. Main outcomes: Statements of patients with advanced heart failure, expressed in semi-structured interviews, concerning the quality of dying and medical decisions at the end of life. Results: Many respondents only thought about death during exacerbations. Mentioned aspects of appropriate dying include: a degree of usefulness, prognostic knowledge, appropriate duration and mental awareness. Few respondents were in favour of euthanasia or suicide, but all wanted life-prolonging treatment to be withheld or withdrawn when appropriate. Conclusions: Our study found some elements of ‘appropriate dying’ that differ from other studies and that are relatively specific for advanced heart failure. The tendency of patients not to think about death raises ethical concerns.
Methods for assessment of cognitive failure and delirium in palliative care patients: implications for practice and research
Authors: Hjermstad Marianne J , Loge Jon H , Kaasa Stein
Published: August 2004

The most commonly encountered clinical conditions presenting with cognitive failure (CF) are delirium, dementia and amnestic disorders. Of these, delirium is probably the most prevalent in palliative care, and it is potentially reversible. Thus, improvement in diagnostics seems warranted. The objectives of this review were to examine the methods for assessment of CF and delirium in palliative care.

Twenty-two studies were reviewed: 64% were published in 2000 or later. Twelve reports focused on delirium, six on CF, while the remaining four assessed confusion (2), hallucinations and general psychological morbidity. Median sample size was 100 (20–393). Ten different instruments were used: The Mini Mental State Exam was used in 13 studies. Five studies were validation reports of new or existing instruments.

The term CF is an imprecise description of a loss in one or more of the cognitive functions. The interchangeable use of CF as a description of specific diagnoses should be avoided, as this contributes to prevalence rates that are not representative. Assessment tools that discriminate between the different diagnostic entities presenting with CF should be used in future studies.
Systematic review of the problems and issues of accessing specialist palliative care by patients, carers and health and social care professionals
Authors: Ahmed N , Bestall J E , Ahmedzai S H , Payne S A , Clark D , Noble B
Published: August 2004

Objectives: To determine the problems and issues of accessing specialist palliative care by patients, informal carers and health and social care professionals involved in their care in primary and secondary care settings. Data sources: Eleven electronic databases (medical, health-related and social science) were searched from the beginning of 1997 to October 2003. Palliative Medicine (January 1997–October 2003) was also hand-searched. Study selection: Systematic search for studies, reports and policy papers written in English. Data extraction: Included papers were data-extracted and the quality of each included study was assessed using 10 questions on a 40-point scale. Results: The search resulted in 9921 hits. Two hundred and seven papers were directly concerned with symptoms or issues of access, referral or barriers and obstacles to receiving palliative care. Only 40 (19%) papers met the inclusion criteria. Several barriers to access and referral to palliative care were identified including lack of knowledge and education amongst health and social care professionals, and a lack of standardized referral criteria. Some groups of people failed to receive timely referrals e.g., those from minority ethnic communities, older people and patients with nonmalignant conditions as well as people that are socially excluded e.g., homeless people. Conclusions: There is a need to improve education and knowledge about specialist palliative care and hospice care amongst health and social care professionals, patients and carers. Standardized referral criteria need to be developed. Further work is also needed to assess the needs of those not currently accessing palliative care services.
A prospective study to determine the association between physical symptoms and depression in patients with advanced cancer
Authors: Lloyd-Williams Mari , Dennis Mick , Taylor Fiona
Published: August 2004

Depression is a common symptom in patients with advanced cancer and patients who are depressed may also have physical symptoms which are difficult to palliate and which improve as their depression is appropriately treated. This study was carried out to determine if there was an association between depression and physical symptoms in patients with advanced cancer and to establish whether a seven-item verbal rating scale asking patients to verbally rate the severity of physical symptoms together with low mood could be used to screen for depression. The scale was validated against a semi-structured clinical interview according to DSM IV criteria. Seventy-four patients participated with an age range of 28–92 years. All patients had an ECOG performance status of two or three. The prevalence of major depression in this study was found to be 27% (95% C.I. 17–37%). The mean score on the verbal rating scale was 28.77 (median score 29.5) (95% C.I., 26.23–31.31; range 0–65). A cut-off of ≥30 gave a sensitivity of 65% and specificity of 59%, with positive and negative predictive values of 37% and 82% respectively. The verbal mood item alone had an optimal cut-off point of 3, with a sensitivity of 80% and specificity of 43%. Patients diagnosed as being depressed according to psychiatric interview rated each symptom higher than nondepressed patients. The verbal mood item and total verbal rating score correlated with a high significance (rs=0.607, P<0.01), implying a relationship between a patient's subjective mood state and other symptoms. Both using the verbal scale and asking patients to verbally rate their mood alone had poor efficacy as a screening tool. However, there is a close association between physical symptoms and the presence of depression in palliative care patients.
Topical benzydamine cream and the relief of pressure pain
Authors: Prentice W M , Roth L J , Kelly P
Published: August 2004

Objective: To determine whether topical benzydamine hydrochloride 3% cream is more effective than placebo in reducing pain related to pressure areas in palliative care patients. Design: Randomized double-blind, placebo-controlled trial. Setting: Three specialist palliative care units in the north of England, with local ethical committee approval for all sites. Subjects: Hospice in-patients with pain related to pressure areas. Interventions: A single application of either benzydamine hydrochloride 3% cream or placebo cream to the painful pressure area. Main outcome measures: Pain assessed using 100 mm VAS, an 11 point numerical pain score and a five-point pain relief score. Results: There was no statistically significant difference between topical benzydamine hydrochloride 3% cream and placebo cream in reducing pain related to pressure areas in palliative care patients. Conclusions: This study does not demonstrate a statistically significant difference between the two treatments. However the study does provide reliable information with respect to the use of different pain measurement tools in late-stage palliative patients. It also provides information regarding the baseline characteristics of this group of patients which may be useful in the planning of any future similar studies.
A case series of inferior vena cava stenting for lower limb oedema in palliative care
Authors: McGee H , Maudgil D , Tookman A , Kurowska A , Watkinson A F
Published: August 2004

Inferior vena caval obstruction (IVCO) is an occasional cause of lower limb oedema in palliative care patients with metastatic malignancy. We present five cases who underwent IVC stenting for symptomatic relief. Four of the five cases had significant reduction in their oedema but three of these four patients died within two weeks of the procedure. The procedure itself is described and the appropriateness of this intervention in patients with end-stage disease is discussed.
Numerical modelling of landscape evolution: geomorphological perspectives
Authors: Martin Yvonne , Church Michael
Published: August 2004

A resurgence of interest in landscape evolution has occurred as computational technology has made possible spatially and temporally extended numerical modelling. We review elements of a structured approach to model development and testing. It is argued that natural breaks in landscape process and morphology define appropriate spatial domains for the study of landscape evolution. The concept of virtual velocity is used to define appropriate timescales for the study of landscape change. Process specification in numerical modelling requires that the detail incorporated into equations be commensurable with the particular scale being considered. This may entail a mechanistic approach at small (spatial) scales, whereas a generalized approach to process definition may be preferred in large-scale studies. The distinction is illustrated by parameterizations for hillslope and fluvial transport processes based on scale considerations. Issues relevant to model implementation, including validation, verification, calibration and confirmation, are discussed. Finally, key developments and characteristics associated with three approaches to the study of landscape modelling:(i) conceptual; (ii) quasi-mechanistic; and (iii) generalized physics, are reviewed.
Antineutrophil autoantibodies and their target antigens in systemic lupus erythematosus
Authors: Chen M , Zhao M-H , Zhang Y , Wang H
Published: August 2004

Various autoantibodies have been identified in sera from patients with systemic lupus erythematosus (SLE) and autoantibodies against neutrophil have been reported. It was suggested that antineutrophil autoantibodies might be involved in the pathogenesis of neutrocytopenia; however, the role of autoantibodies against neutrophil precursors and their specific target autoantigen(s) remained further characterized. The objective was to investigate the target antigens and clinical associations of autoantibodies against neutrophils and neutrophil precursors in patients with SLE. Sera were collected from 92 patients with SLE and renal biopsy proven lupus nephritis. Cell lysates of peripheral neutrophils (as mature neutrophils) from a normal blood donor and white blood cells from a patient with blast crisis of chronic granulocytic leukemia (CGL) (as neutrophil precursors) were used as antigens in Western blot analysis to detect autoantibodies in sera from patients with SLE. The clinical significance of antineutrophil autoantibodies that recognized different antigens were further analysed. Using normal peripheral neutrophils as antigens, two bands could be blotted: 64 kD (33/92, 35.9%) and 50 kD (13/92, 14.1%). The prevalence of anti-64 kD autoantibody in patients with positive rheumatic factor was significantly higher than that in patients without (54.5 versus 18.8%, P, 0.05). Using CGL white cells as antigen, five bands could be blotted: 60 kD (34/92, 37.0%), 50 kD (32/92, 34.8%), 29 kD (27/92, 29.3%), 42 kD (19/92, 20.7%) and 18 kD (16/92, 17.4%). The prevalence of anti-60 kD autoantibody was significantly higher in patients with neutrocytopenia than that in patients without neutrocytopenia (100 versus 48.3%, P, 0.01). The prevalence of anti-29 kD autoantibody was significantly higher in patients with alopecia than that in patients without alopecia (45.8 versus 20.8%, P, 0.05). Furthermore, the prevalences of anti-60 kD, anti-50 kD and anti-42 kD autoantibodies were significantly higher in patients with anti-Ro autoantibody than those in patients without; the prevalences of anti-29 kD and anti-18 kD autoantibodies were significantly higher in patients with anti-Sm autoantibody than those in patients without. We conclude that there are heterogeneous autoantibodies against both neutrophils and their precursors in sera from patients with SLE. Different autoantibodies may have different clinical significance.
The basement membrane zone in patients with systemic lupus erythematosus: immunofluorescence studies in the skin, kidney and amniochorion
Authors: Alahlafi A M , Wordsworth P , Lakasing L , Davies D , Wojnarowska F
Published: August 2004

Histological studies suggest that the basement membrane zone (BMZ) is the main target of tissue pathology in cutaneous lupus erythematosus (LE). The BMZ is characteristically thickened and is the site of deposition of autoantibodies in LE. Alteration of some (BMZ) macromolecules is implicated in the pathology of several bullous skin diseases. A major component of BMZ is heparan sulphate proteoglycan (HSPG) which was found reduced in the skin of some patients with systemic lupus erythematosus (SLE) and in the kidney of mice with lupus nephritis. Similar to the skin, amnion is derived from the ectodermal germ layer during embryogenesis and expression of BMZ components of amniochorion was not previously studied in SLE. The aim of the present study was to investigate the expression of major BMZ macromolecules in the skin, kidney and amnioplacentae obtained from patients with SLE and compare these findings with organ biopsies from unaffected individuals. In addition, determining whether the differences in composition and distribution of BMZ macromolecules in these organs correlate with certain patterns of deposition of immunoreactants could contribute to our understanding of the mechanism of deposition of immunoreactants in SLE. In some patients with SLE, reduced expression of HSPG in nonlesional skin was reported previously. These changes of heparan sulphate might be important in the pathogenesis of LE. Therefore, the aims of this study are to confirm the previous finding and to compare HSPG expression between lesional and nonlesional LE skin. The unique features of each BMZ could contribute to the deposition or binding of positively charged immune complexes and explain the different patterns of immunofluorescence. Frozen sections of skin, kidney and amniochorion obtained from patients with SLE were investigated by indirect immunofluorescence technique using monoclonal antibodies (Moab) to determine the expression of major components of the BMZ. Heparan sulfate expression is reduced in the skin and, to a lesser extent, in the kidney in patients with SLE. There was no correlation between the kidney and skin heparan sulfate expression within the same patient. The BMZ composition in amniochorionic membrane of placentae from women with SLE was normal. Heparan sulfate may be one of the major targets for immunoglobulin deposition in the skin of patients with SLE. The processes of immunoglobulin deposition in SLE may be more complex in that there was no correlation between heparan sulfate expression in the skin and kidney of the same patient.
Susac’s syndrome or catastrophic antiphospholipid syndrome?
Authors: Bucciarelli S , Cervera R , Martínez M , Latorre X , Font J
Published: August 2004

Susac’s syndrome is a microangiopathic disorder of unknown pathogenesis presenting with encephalopathy, hearing loss and branch retinal artery occlusions. The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to define a subset of the APS characterized by thrombotic microangiopathy with clinical evidence of three or more organ involvement developed in a short period of time. We describe a patient with typical features of Susac’s syndrome, that appeared in less than a week, in whom aPL were detected, thus fulfilling criteria for ‘probable’ catastrophic APS.
IL-1RA in refractory systemic lupus erythematosus
Authors: Moosig F , Zeuner R , Renk C , Schröder J O
Published: August 2004

There is evidence from animal and human studies that IL-1 might play an important role in the development and maintainence of inflammation in systemic lupus erythemathosus (SLE). We hypothesized that, in SLE, there might be a relative deficiency in the physiologic antagonist of IL-1, IL-1 receptor antagonist (IL-1RA). We therefore treated three patients with active SLE in whom conventional therapy has failed with the human IL-1RA, Anakinra. In two of the three patients there was a transient effect on muscle pain and/or polyarthritis. In one patient with lupus myositis there was no effect at all. The therapy was well tolerated and the only significant side effect was a transient drop in complement levels (C3 and C4) without clinical or laboratory signs of increased SLE activity in all three patients.
Relationship between adherence to study and clinic visits in systemic lupus erythematosus patients: data from the LUMINA cohort
Authors: Uribe A G , Ho K T , Agee B , McGwin G , Fessler B J , Bastian H M , Reveille J D , Alarcón G S
Published: August 2004

The aim of this study was to examine the relationship between nonadherence with study visits and with regularly scheduled clinic visits after adjusting for other patient and disease characteristics. One hundred and forty-one LUMINA patients with appointment data in the institutions’ computerized systems (UAB and UTH) were studied. ‘No shows’ were assessed as the percentage of appointments not attended for either rheumatology, other clinics and LUMINA visits (from zero to 100%). Eighty-nine percent of the patients were women, 40% were Caucasians, 55% African-Americans and 5% Hispanics. ‘No shows’ to rheumatology were associated with non-Caucasian ethnicity, younger age, single marital status, lack of home ownership, ‘no shows’ to other clinics and to the LUMINA study, greater disease activity and to some disease manifestations (serositis, renal involvement, positive anti-dsDNA antibodies). In multivariable analyses, features predictive of rheumatology ‘no shows’ were lack of home ownership, ‘no shows’ to LUMINA study visits, renal involvement and serosal manifestations. Nonadherence with study visits and with regularly scheduled care at rheumatology clinics were associated. Other factors predictive of nonadherence to recommended care were lack of home ownership (a measurement of low socioeconomic status) and the presence of disease manifestations (i.e., renal or serosal involvement). These data should be considered when caring for patients with SLE.
Risk of ovarian failure and pregnancy outcome in patients with lupus nephritis treated with intravenous cyclophosphamide pulse therapy
Authors: Park M-C , Park Y-B , Jung S Y , Chung I H , Choi K H , Lee S-K
Published: August 2004

This study was designed to investigate the risk of ovarian failure and the pregnancy outcomes in women treated with intravenous cyclophosphamide (IVCYC) pulse therapy for lupus nephritis. Sixty-seven women with proliferative lupus nephritis were studied. The clinical and laboratory data, SLEDAI and damage indices at IVCYC initiation, doses and numbers of IVCYC pulses, pregnancy and fetal outcomes were evaluated. During a follow-up of 74.4 + 20.6 months, amenorrhea occurred in 25 (37.3%) and was sustained permanently in 10 patients (14.9%). Thirteen women became pregnant with a total of 19 pregnancies. Seventeen pregnancies ended without complications and all babies were born healthy without any congenital anomalies or perinatal illnesses. Two pregnancies were terminated by induced abortion but no congenital anomaly was noted in these cases. Logistic regression analysis showed that old age, high damage index at the initiation of IVCYC pulse therapy and high cumulative dosage of IVCYC were the independent risk factors of ovarian failure, and that the presence of amenorrhea, regardless of its duration, was the risk factor of pregnancy failure. Pregnancy was possible with a favorable outcome after the withdrawal of IVCYC pulse therapy, unless amenorrhea develops.
Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus
Authors: Tam L-S , Li E K , Wong C-K , Lam C WK , Szeto C-C
Published: August 2004

Twelve systemic lupus erythematosus (SLE) patients with mild to moderate disease activity (SLEDAI of ≥6 and on prednisolone, 0.5 mg/kg/day) were included in a prospective, randomized, double-blind, placebo-controlled pilot study for 24 weeks. Six were randomized to receive oral leflunomide and six received placebo. Primary outcome of this study included the mean change of SLEDAI at 24 weeks. Secondary outcomes included the changes in proteinuria, complement levels, anti ds-DNA binding, and prednisolone dosage. The mean age of the 12 patients was 41 + 9 years, and the mean disease duration was 8.5 + 5.8 years. All were female except one patient. The disease activity of both groups of patients decreased significantly after six months of treatment (14.7 + 6.0 to 3.7 + 2.3 in leflunomide group, P 1/4 0.028, and 9.7 + 3.4 to 5.2 + 4.1 in placebo group, P 1/4 0.027). Reduction in the SLEDAI from baseline to 24 weeks was significantly greater in the leflunomide group than the placebo group (11.0 + 6.1 in the leflunomide group and 4.5 + 2.4 in the placebo group respectively, P 1/4 0.026). Minor adverse events included transient elevation in ALT, hypertension and transient leucopenia. In summary, leflunomide was more effective than placebo in treating SLE patients with mild to moderate disease activity and was safe and well-tolerated.
Analysis of molecular heterogeneity of prolactin in human systemic lupus erythematosus
Authors: García M , Colombani-Vidal M E , Zylbersztein C C , Testi A , Marcos J , Arturi A , Babini J , Scaglia H E
Published: August 2004

Hyperprolactinemia without clinical manifestations has been reported in some patients with systemic lupus erythematosus (SLE) because an increase of prolactin (PRL) is produced due to the BIG/BIG molecular variant (molecular variant, 150 kD). This research project aimed to determine levels of PRL: its bioactive form, the little nonglycosylated form (NGPRL) and variants with decreased bioactivity such as the BIG/BIG and the little glycosylated (GPRL), in 29 women and five men with SLE. PRL was assayed by IRMA with a kit from Immunotech Laboratory, the BIG/BIG form by precipitation with polyethyleneglycol 6000, and the NGPRL and GPRL by chromatography on Concanavalin-A-Sepharose. Increased PRL was detected in seven patients (20.6%) of whom three had increased BIG/BIG, six had increased GPRL and only four had increased NGPRL. The three cases with increased BIG/BIG were contrasted by chromatography on Sephadex G-100. No increased PRL or any of the other variants assayed were found in men. Results were similar when PRL was evaluated in the same blood samples by a different IRMA (DPC Laboratory). The etiology of the hyperprolactinemia in some of these patients is unknown, but their lack of symptoms (galactorrhea or amenorrhea) could be due to the BIG/BIG forms and basically to the glycosylation of the hormone. As for the relation between PRL and SLE activity, we found that hyperprolactinemic patients were younger, had a shorter history of illness, although it was not statistically significant, and a higher SLEDAI score. This would indicate a relation between hyperprolactinemia and lupus activity. The patients with increased BIG/BIG form also had a very active illness at the time of the study.
Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus
Authors: Obermoser G , Emberger M , Wieser M , Zelger B
Published: August 2004

Nephrogenic fibrosing dermopathy (NFD) is a novel fibrosing disorder of the skin with characteristic histopathology. It affects patients with impaired renal function and appears to be independent from the type of kidney disease. Its aetiopathology is unknown and presently no standard therapy exists. We report a patient with systemic lupus erythematosus (SLE) and glomerulonephritis who developed diffuse indurated erythematous plaques covering nearly the entire legs and trunk. She had never received dialysis. The second patient suffered from SLE and antiphospholipid syndrome related thrombotic glomerulopathy. After 10 weeks of haemodialysis she developed the same skin condition. To the best of our knowledge, these are the first reports of NFD occurring in patients with SLE.
Impaired brachial artery endothelium dependent flow mediated dilation in systemic lupus erythematosus: preliminary observations
Authors: Johnson S R , Harvey P J , Floras J S , Iwanochko M , Ibanez D , Gladman D D , Urowitz M
Published: August 2004

Our objective was to compare brachial artery endothelium dependent and independent vasodilation in lupus patients and healthy females, by means of high-resolution noninvasive brachial artery ultrasound. Endothelially mediated vasodilation was estimated noninvasively by examination of brachial artery responses to postischemic reactive hyperemia and endothelial independent vasodilation from response to sublingual glycerlynitrate (GTN) using high-resolution external vascular ultrasound. Five patients with known coronary artery disease (CAD), five with subclinical CAD, five with no CAD and five control subjects were assessed. Endothelium dependent vasodilation was significantly blunted in lupus patients with CAD as compared with healthy female controls (0.11 versus 11.1%, P 1/4 0.018). Corresponding values for lupus patients with subclinical CAD and no CAD were 11 and 9.6%, respectively. For each subject, endothelium dependent vasodilation (EDV) was related to endothelium independent vasodilation (EIV) to adjust for varying vascular smooth muscle responses to GTN in individual subjects. This ratio was markedly depressed in lupus patients with CAD as compared with control subjects (0.12 versus 1.15). The corresponding EDV/EIV ratios for patients with subclinical CAD and no CAD were similar at 0.69 and 0.65, respectively. The conclusion was that flow mediated vasodilation in lupus patients with coronary artery disease is markedly depressed as compared to healthy subjects.
Systemic lupus erythematosus in Kuwaiti children: organ system involvement and serological findings
Authors: Alsaeid K , Kamal H , Haider M Z , Al-Enezi H M , Malaviya A N
Published: August 2004

The course and severity of systemic lupus erythematosus (SLE) in children is generally similar to the adult form with potential serious organ system involvement, there are, however, factors that influence the prevalence and clinical behavior of the disease. Our objective was to analyse the organ system involvement and immunological findings in Kuwaiti children with SLE in relation to gender and age of onset and compare these findings to that in published reports. Organ system involvement and serologic profiles were analysed in 35 children with SLE. The major organ systems studied were: renal, hematological, cardiac, pulmonary, hepatic and the central nervous system. The prevalence of ANA, anti-dsDNA, anti-Sm, SSA, SSB and anti-cardiolipin antibodies were studied in addition to complement C3 and C4 levels. The results showed that a high percentage of children had hematological involvement (34%); thrombocytopenia (23%) and hemolytic anemia (20%). Renal involvement was proven by biopsy in only 10 children (29%). Neuropsychiatric manifestations were seen in five (14%) of patients. Males had a tendency for major organ involvement relative to females. All patients had positive ANA tests. All males had positive anti-dsDNA tests compared to 86% of female patients. The most significant finding in this study is the high frequency of hematological manifestations and the relatively low incidence of renal disease and neuropsychiatric abnormalities in Kuwaiti children with SLE.
Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis
Authors: Feng Juan , Misu Tatsuro , Fujihara Kazuo , Sakoda Saburo , Nakatsuji Yuji , Fukaura Hikoaki , Kikuchi Seiji , Tashiro Kunio , Suzumura Akio , Ishii Naoto , Sugamura Kazuo , Nakashima Ichiro , Itoyama Yasuto
Published: August 2004

We investigated the immunoregulatory effects of ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4- cells revealed that the ibudilast monotherapy significantly reduced tumour necrosis factor-a and interferon (IFN)-g mRNA and the IFN-g/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.
Modulation of Adipoinsular Axis in Prediabetic Zucker Diabetic Fatty Rats by Diazoxide
Authors: Alemzadeh Ramin , Tushaus Kathryn M.
Published: August 2004

Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to β-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg·d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced β3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet β3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced β-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented β-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing β-cell failure and progression to diabetes in humans.
Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro
Authors: Leong Gary M. , Moverare Sofia , Brce Jesena , Doyle Nathan , Sjögren Klara , Dahlman-Wright Karin , Gustafsson Jan-Åke , Ho Ken K. Y. , Ohlsson Claes , Leung Kin-Chuen
Published: August 2004

Suppressors of cytokine signaling (SOCS) are important negative regulators of cytokine action. We recently reported that estrogen stimulates SOCS-2 expression and inhibits GH signaling in kidney cells. The effects of estrogen on SOCS expression in other tissues are unclear. The aim of this study was to investigate in vivo and in vitro whether estrogen affected SOCS expression in the liver, a major target organ of GH. The in vivo hepatic effects of estrogen on ovariectomized mice lacking estrogen receptor (ER)-α, ERβ, or both and their wild-type littermates were examined by DNA microarray analysis. In vitro, the effects of estrogen on SOCS expression in human hepatoma cells were examined by reverse transcription quantitative PCR. Long-term (3 wk) estrogen treatment induced a 2- to 3-fold increase in hepatic expression of SOCS-2 and -3 in wild-type and ERβ knockout mice but not in those lacking ERα or both ER subtypes. Short-term treatment (at 24 h) increased the mRNA level of SOCS-3 but not SOCS-2. In cultured hepatoma cells, estrogen increased SOCS-2 and -3 mRNA levels by 2-fold in a time- and dose-dependent manner (P < 0.05). Estrogen induced murine SOCS-3 promoter activity by 2-fold (P < 0.05) in constructs containing a region between nucleotides −1862 and −855. Moreover, estrogen and GH had additive effects on the SOCS-3 promoter activity. In summary, estrogen, via ERα, up-regulated hepatic expression of SOCS-2 and -3, probably through transcriptional activation. This indicates a novel mechanism of estrogen regulation of cytokine action.
Genistein Acutely Stimulates Nitric Oxide Synthesis in Vascular Endothelial Cells by a Cyclic Adenosine 5′-Monophosphate-Dependent Mechanism
Authors: Liu Dongmin , Homan Laurie L. , Dillon Joseph S.
Published: August 2004

Genistein may improve vascular function, but the mechanism of this effect is unclear. We tested the hypothesis that genistein directly regulates vascular function through stimulation of endothelial nitric oxide synthesis. Genistein activated endothelial nitric oxide synthase (eNOS) in intact bovine aortic endothelial cells and human umbilical vein endothelial cells over an incubation period of 10 min. The maximal eNOS activity was at 1 μm genistein. Consistent with this activation pattern, 1 μm genistein maximally stimulated the phosphorylation of eNOS at serine 1179 at 10 min of incubation. The rapid activation of eNOS by genistein was not dependent on RNA transcription or new protein synthesis and was not blocked by a specific estrogen receptor antagonist. In addition, inhibition of MAPK or phosphatidylinositol 3-OH kinase/Akt kinase had no affect on eNOS activation by genistein. Furthermore, the genistein effect on eNOS was also independent of tyrosine kinase inhibition. However, inhibition of cAMP-dependent kinase [protein kinase A (PKA)] by H89 completely abolished the genistein-stimulated eNOS activation and phosphorylation, suggesting that genistein acted through a PKA-dependent pathway. These findings demonstrated that genistein had direct nongenomic effects on eNOS activity in vascular endothelial cells, leading to eNOS activation and nitric oxide synthesis. These effects were mediated by PKA and were unrelated to an estrogenic effect. This cellular mechanism may underlie some of the cardiovascular protective effects proposed for soy phytoestrogens.
Cardiovascular Effects of Long-Term Central and Peripheral Administration of Urocortin, Corticotropin-Releasing Factor, and Adrenocorticotropin in Sheep
Authors: Weisinger R. S. , Blair-West J. R. , Burns P. , Denton D. A. , Purcell B. , Vale W. , Rivier J. , Weisinger H. S. , May C. N.
Published: August 2004

The neuroendocrine hormones ACTH and corticotropin- releasing factor (CRF), which are involved in the stress response, have acute effects on arterial pressure. New evidence indicates that urocortin (UCN), the putative agonist for the CRF type 2 receptor, has selective cardiovascular actions. The responses to long-term infusions of these hormones, both peripherally and centrally, in conscious animals have not been studied. Knowledge of the long-term effects is important because they may differ considerably from their acute actions, and stress is frequently a chronic stimulus. The present experiments investigated the cardiovascular effects of CRF, UCN, and ACTH in conscious sheep. Infusions were made either into the lateral cerebral ventricles (icv) or iv over 4 d at 5 μg/h. UCN infused icv or iv caused a prolonged increase in heart rate (HR) (P < 0.01) and a small increase in mean arterial pressure (MAP) (P < 0.05). CRF infused icv or iv progressively increased MAP (P < 0.05) but had no effect on HR. Central administration of ACTH had no effect, whereas systemic infusion increased MAP and HR (P < 0.001). In conclusion, long-term administration of these three peptides associated with the stress response had prolonged, selective cardiovascular actions. The striking finding was the large and sustained increase in HR with icv and iv infusions of UCN. These responses are probably mediated by CRF type 2 receptors because they were not reproduced by infusions of CRF.
Antiapoptotic Effects of Estrogen in Normal and Cancer Human Cervical Epithelial Cells
Authors: Wang Qifang , Li Xin , Wang Liqin , Feng Ying-Hong , Zeng Robin , Gorodeski George
Published: August 2004

The present study investigated the antiapoptotic effects of estrogen in normal and cancer human cervical cells and the mechanisms involved. Baseline apoptosis in human cervical epithelial cells is mediated predominantly by P2X7-receptor-induced, Ca2+-dependent activation of the mitochondrial (caspase-9) pathway. Treatment with 10 nm 17β-estradiol blocked apoptosis induced by the P2X7-receptor ligands ATP and 2′,3′-0-(4-benzoylbenzoyl)-ATP in normal human cervical epithelial cells (hECEs) and attenuated the effect in hECEs immortalized with human papillomavirus-16 (ECE16–1) and the cancer cervical cells HT3 and CaSki. Diethylstilbestrol and to a lesser degree estrone could mimic the effects of 17β-estradiol, whereas actinomycin-D and cycloheximide attenuated the response. The antiapoptotic effect of estrogen did not depend on cell cycle phase, and in both normal and cancer cervical cells, it involved attenuation of activation of caspase-9 and the terminal caspase-3. However, involvement of cascades upstream to the caspase-9 differed in normal vs. cancer cervical cells. In the normal hECEs estrogen blocked P2X7-receptor-induced calcium influx. In contrast, in the cancer CaSki cells, estrogen up-regulated expression of Bcl-2 and attenuated Ca2+-induced mitochondrial swelling (i.e. formation of mitochondrial permeability transition pores). Estrogen had no effect on P2X7-receptor-induced apoptosis in the anaplastic SiHa and Hela cells. These results point to a novel antiapoptotic effect of estrogen in the cervix that is independent of its mitogenic function. The results also suggest that cancer cervical cells evolved antiapoptotic mechanisms that enable the cells to evade apoptosis and could therefore promote tumor progression.
The CRE-Like Element Inside the 5′-Upstream Region of the Rat Sodium/Iodide Symporter Gene Interacts with Diverse Classes of b-Zip Molecules that Regulate Transcriptional Activities through Strong Synergy with Pax-8
Authors: Chun J. T. , Di Dato V. , D’Andrea B. , Zannini M. , Di Lauro R.
Published: August 2004

We previously demonstrated that transcription of the rat sodium/iodide symporter (NIS) gene is regulated by NUE, an upstream enhancer located between nucleotides −2264 and −2495 of the 5′-flanking region. To elucidate the mechanism of TSH/cAMP-mediated regulation of NIS gene expression, we have characterized the putative cAMP response element (CRE)/activator protein (AP)-1 site (termed NUC) that is closely located between the two Pax-8 (paired box domain transcription factor-8) binding sites within NUE. In two different approaches using either gel supershift analyses or dominant-negative inhibitors of b-Zip molecules, we have shown that NUC can be recognized by several members of the AP-1 and CREB family transcription factors that modulate the transcriptional activity of NUE. Using tethered dimers of b-Zip molecules, we have also demonstrated that specific homo- or heterodimers of AP-1 can synergistically stimulate NUE activity in concert with Pax-8. To demonstrate further that NUC is a bona fide CRE, we made an artificial promoter with the five-time tandem repeat of this sequence (5xNUC). In comparison to the canonical CRE (5xCRE), 5xNUC manifested greater transcriptional activity and broader response to cAMP signaling. Hence, we postulate that the significance of this evolutionally conserved CRE-like site may lie in its broader cell type specificity.
Herpes simplex virus infection of the central nervous system in human immunodeficiency virus-type 1-infected patients
Authors: Grover D. , Newsholme W. , Brink N. , Manji H. , Miller R.
Published: August 2004

We report clinical, radiological and virological data from nine consecutive HIV-infected patients with herpes simplex virus (HSV) infection of the central nervous system (CNS). Three patients presented with confusion, two with fever and headache, two with anxiety and depression, one with slow mentation and memory loss and one with expressive dysphasia. Five patients had previous AIDS-defining diagnoses: four of these five patients had previous cutaneous HSV infection. HSV DNA was detected by the polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) in seven patients. HSV infection was diagnosed by brain biopsy (after negative PCR on CSF) in one patient and at autopsy in one patient (after negative CSF PCR and brain biopsy). Seven patients received specific anti-viral therapy; two died of unrelated causes and the other five recovered. Two patients were not treated, in one the diagnosis was made at autopsy and the other recovered spontaneously. HIV-infected patients with CNS HSV infection have a varied presentation. Diagnosis by PCR on CSF identified the majority of cases. With specific treatment the outcome was good.
High-risk sexual behaviours among drug users in Pakistan: implications for prevention of STDs and HIV/AIDS
Authors: Haque N. , Zafar T. , Brahmbhatt H. , Imam G. , ul Hassan S. , Strathdee S. A.
Published: August 2004

Our objective was to describe HIV/STD risk behaviours and awareness among a community-based sample of drug users in Pakistan. Drug users contacted through street outreach by a non-governmental organization in Quetta, Peshawar and Rawalpindi underwent interviewer-administered questionnaires. Descriptive statistics were used to characterize sexual behaviours by city, marital status and the use of injection drugs. Logistic regression was used to identify correlates of ever having an STD. Of 608 drug users studied, all but one was male; median age was 32 years and 45% had no formal education. Half were married, of whom 25% were living with their wives. Sexual behaviours were reported as follows: 14% had sex with other males, 28% reported sex with both males and females, 49% had paid money to have sex and only 10% had ever used condoms. One-fifth reported having had an STD and about 40% reported having suffered from either one or more STD-related symptoms. Only 41% had heard about HIV/AIDS, of whom 17% knew that HIV/AIDS could be transmitted through sexual contact. In conclusion, high-risk sexual behaviours are prevalent among male drug users in Pakistan, and awareness of transmission risks is low. These data attest to the urgent need for effective and specific interventions in Pakistan to prevent transmission of HIV and STDs among drug users and their sex partners.
Training in genitourinary medicine from the specialist registrar's point of view: opportunities and facilities available across the UK and plans for future working
Authors: Kingston M.A. , Browning M.R.
Published: August 2004

In recent years training for specialist registrars (SpRs) in GU medicine has undergone a number of changes. In addition, the speciality in general is undergoing modernization and change and issues of workforce planning and consultant job availability have been of particular importance to SpRs. In March 2003 a postal survey of SpRs in the UK was undertaken to evaluate training, future career plans and working patterns. A 59% (69/117) response rate was achieved and overall most SpRs expressed satisfaction with their training. However, a number of concerns were raised with aspects of training, which are discussed in this paper. Nearly half of SpRs will consider working part time in the future and almost two-thirds are interested in job sharing. This is the first survey of its kind in GU medicine and the results are informative to all involved with SpR training programmes and workforce planning in the speciality.
How do clients access their HIV test results from genitourinary medicine services in the UK? A time for change!
Authors: Wright Simon , Kell Philip , Tobin Rose
Published: August 2004

With the changes in the nation's sexual health needs and the introduction of the Government's Sexual Health Strategy, GU services need to review their operational policies to accommodate the inevitable increase for service. There had been a long-standing practice of anyone having an HIV test to return in person to collect his or her result. As more and more people, many of whom are considered to be low risk, are testing for HIV as part of a routine sexual health check-up, the question is, do they really need to return in person for these results? The national survey shows that while the majority of clinics are insisting that everyone having an HIV test returns in person, there are some services that have already adopted other approaches. It is also evident that many service providers are also considering a change in policy.
Osteomyelitis complicating pyomyositis in HIV disease
Authors: Buckland Matthew S. , Longhurst Hilary J. , Murphy Maurice
Published: August 2004

Pyomyositis has previously been described in association with human immunodeficiency virus (HIV) and as a discrete entity in HIV seronegative patients from tropical climates (tropical pyomyositis). Pyomyositis and osteomyelitis are usually considered a late complication of advanced HIV disease. We describe a patient with well-controlled HIV and both types of musculoskeletal infection. The case highlights an unusual presentation, the utility of MRI in soft tissue infection and an excellent outcome from prolonged antimicrobial therapy following surgical debridement.