bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette‐Guérin
Authors: Esin Semih , Batoni Giovanna , Pardini Manuela , Favilli Flavia , Bottai Daria , Maisetta Giuseppantonio , Florio Walter , Vanacore Renato , Wigzell Hans , Campa Mario
Published: April 2004

The kinetics of activation and induction of several effector functions of human natural killer (NK) cells in response to Mycobacterium bovis bacille Calmette‐Guérin (BCG) were investigated. Owing to the central role of monocytes/macrophages (MM) in the initiation and maintenance of the immune response to pathogens, two different experimental culture conditions were analysed. In the first, monocyte‐depleted nylon wool non‐adherent (NW) cells from healthy donors were stimulated with autologous MM preinfected with BCG (intracellular BCG). In the second, the NW cells were directly incubated with BCG, which was therefore extracellular. In the presence of MM, CD4+ T lymphocytes were the cell subset mainly expressing the activation marker, CD25, and proliferating with a peak after 7 days of culture. In contrast, in response to extracellular BCG, the peak of the proliferative response was observed after 6 days of stimulation, and CD56+ CD3– cells (NK cells) were the cell subset preferentially involved. Such proliferation of NK cells did not require a prior sensitization to mycobacterial antigens, and appeared to be dependent upon contact between cell populations and bacteria. Following stimulation with extracellular BCG, the majority of interferon‐γ (IFN‐γ)‐producing cells were NK cells, with a peak IFN‐γ production at 24–30 hr. Interleukin (IL)‐2 and IL‐4 were not detectable in NK cells or in CD3+ T lymphocytes at any time tested. IL‐12 was not detectable in the culture supernatant of NW cells stimulated with extracellular BCG. Compared to the non‐stimulated NW cells, the NW cells incubated for 16–20 hr with BCG induced the highest levels of expression of apoptotic/death marker on the NK‐sensitive K562 cell line. BCG also induced expression of the activation marker, CD25, and proliferation, IFN‐γ production and cytotoxic activity, on negatively selected CD56+ CD3− cells. Altogether, the results of this study demonstrate that extracellular mycobacteria activate several NK‐cell functions and suggest a possible alternative mechanism of NK‐cell activation as the first line of defence against mycobacterial infections.
Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic properties with protein structure?
Authors: Gentile Fabrizio , Conte Marisa , Formisano Silvestro
Published: April 2004

Autoantibodies against human thyroglobulin are a hallmark of autoimmune thyroid disease in humans, and are often found in normal subjects. Their pathogenic significance is debated. Several B‐cell epitope‐bearing peptides have been identified in thyroglobulin. They are generally located away from the cysteine‐rich regions of tandem sequence repetition. It is possible that our current epitopic map is incomplete because of the difficulty that proteolytic and recombinant approaches have in restituting conformational epitopes based upon proper pairing between numerous cysteinyl residues. Furthermore, the homology of cysteine‐rich repeats with a motif occurring in several proteins, endowed with antiprotease activity, suggests that these regions may normally escape processing and presentation to the immune system, and brings attention to the mechanisms, such as oxidative cleavage, by which such cryptic epitopes may be exposed. A number of T‐cell epitope‐bearing peptides, endowed with thyroiditogenic power in susceptible mice, were also identified. None of them was dominant, as none was able to prime in vivo lymph node cells that would proliferate or transfer autoimmune thyroiditis to syngeneic hosts, upon stimulation with intact thyroglobulin in vitro. More than half of them are located within the acetylcholinesterase‐homologous domain of thyroglobulin, and overlap B‐cell epitopes associated with autoimmune thyroid disease, while the others are located within cysteine‐rich repeats. The immunopathogenic, non‐dominant character of these epitopes also favours the view that the development of autoimmune thyroid disease may involve the unmasking of cryptic epitopes, whose exposure may cause the breaking of peripheral tolerance to thyroglobulin. Further research in this direction seems warranted.
Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T‐cell subset
Authors: Somerset David A. , Zheng Yong , Kilby Mark D. , Sansom David M. , Drayson Mark T.
Published: April 2004

CD4+ CD25+ T regulatory cells (TReg), suppress antigen‐specific immune responses and are important for allograft tolerance. During pregnancy the mother tolerates an allograft expressing paternal antigens (the fetus) requiring substantial changes in immune regulation over a programmed period of time. We analysed whether immune‐suppressive TReg cells were altered during pregnancy and therefore might play a part in this tolerant state. The presence of TReg cells was assessed in the blood of 25 non‐pregnant, 63 pregnant and seven postnatal healthy women by flow cytometry. We observed an increase in circulating TReg cells during early pregnancy, peaking during the second trimester and then a decline postpartum. Isolated CD25+ CD4+ cells expressed FoxP3 messenger RNA, a marker of TReg cells, and suppressed proliferative responses of autologous CD4+ CD25– T cells to allogeneic dendritic cells. These data support the concept that normal pregnancy is associated with an elevation in the number of TReg cells which may be important in maintaining materno‐fetal tolerance.
The use of dextromethorphan to treat repetitive self‐directed scratching, biting, or chewing in dogs with allergic dermatitis
Authors: Dodman N. H. , Shuster L. , Nesbitt G. , Weissman A. , Lo W.‐Y. , Chang W.‐W. , Cottam N.
Published: April 2004

Objective:  To evaluate the efficacy of oral dextromethorphan in dogs with a repetitive behavior problem (self‐licking, self‐chewing, and self‐biting associated with chronic allergic dermatitis).

Animals:  Fourteen dogs with chronic allergic dermatitis were enrolled in the study. Twelve dogs completed the study.

Procedure:  The dogs were treated for 2 weeks each with dextromethorphan (2 mg/kg BID) and placebo in a randomized, double blind, crossover designed study. A dermatology score, including an assessment of affected areas of the integument and the level of self‐directed behavior, was generated before and following each 2‐week phase of the study. Owners were required to record daily the amount of time they spent with their dog and the amount of time that the dog was observed to be engaged in any of the specified self‐directed behaviors.

Results:  The percent of the observed time that the dogs were reported to be involved in self‐directed behaviors was significantly less during the 2‐week active drug treatment phase. The pruritus score component of the dermatology score also was significantly less during the active treatment phase. In addition, a dermatologist‐rated global assessment was more favorable in 11 of 12 dogs following the active treatment phase.

Conclusions:  Dextromethorphan significantly reduces the percentage of time that allergic dogs spend self‐licking, self‐chewing, and self‐biting.

Clinical relevance:  Dextromethorphan may be a useful adjunct in the management of self‐directed behaviors associated with allergic dermatitis and possibly in other repetitive behaviors as well.
Pharmacokinetics of flunixin in the cat: enterohepatic circulation and active transport mechanism in the liver
Authors: Horii Y. , Ikenaga M. , Shimoda M. , Kokue E.
Published: April 2004

The plasma and urine pharmacokinetics of flunixin‐meglumine (FNX) in cats were examined using a total of 12 adult animals. After an intravenous injection of FNX (2 mg/kg), the plasma concentration time curves showed a profile of a two‐compartment open model with an elimination half‐life of 6.6 h. In spite of high plasma protein binding (>99%), theVdβwas unusually large, 0.7 L/kg. Although the recovery of FNX from urine was only 0.4% of the dose, the estimated inherent renal clearance closely corresponded to the renal plasma flow rate, indicating that a renal active tubular secretion was involved in the pharmacokinetics of FNX. Cholestyramine (ChSA), an anion exchanger, was orally administered immediately before the FNX injection in order to determine the involvement of enterohepatic circulation in FNX pharmacokinetics. The elimination phase of the profile of FNX was prevented by the concomitant administration of ChSA, so it was concluded that the drug undergoes enterohepatic circulation in cats. Pravastatin (PV) is a specific substrate of the type‐2 organic anion transporting polypeptide transporter (OATP‐2) in human liver cells. The effect of a concomitant intravenous injection of PV with FNX was examined in order to determine the involvement of OATP‐2 like transporter in the pharmacokinetics. The V1 and total body clearance were decreased after the injection of PV. In conclusion, at least two active transport mechanisms are involved in the pharmacokinetics of FNX in cats. One pathway is renal tubular secretion and the other is sinusoidal active uptake by liver cells. The latter may be responsible for the enterohepatic circulation of FNX in cats.
Functional integrity of precision‐cut liver slices from deer and cattle
Authors: Sivapathasundaram S. , Howells L. C. , Sauer M. J. , Ioannides C.
Published: April 2004

Precision‐cut bovine and cervine liver slices were incubated in RPMI 1640 media for up to 72 h, and cellular integrity was assessed utilizing the leakage of lactate dehydrogenase (LDH) and the formation of the formazan metabolite of 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazolium bromide (MTT). Leakage of LDH (80%) from the bovine and cervine slices was noted only following 10 h of culture, and similarly, the generation of MTT‐formazan declined. Metabolic viability was determined using 7‐ethoxycoumarin as the model substrate, which was metabolized by slices from both animal species in a time‐dependent manner for at least 6 h to generate 7‐hydroxycoumarin, which was secreted into the media primarily as glucuronide and sulphate conjugates. With both cervine and bovine slices metabolic activity decreased markedly after a 4‐h preincubation as assessed following a further 2‐h incubation in the presence of 7‐ethoxycoumarin. Subsequently, ethoxycoumarin metabolism by bovine slices did not decrease further until 24 h and was still detectable at 72 h. In the case of cervine slices, activity declined gradually after 8 h, with no activity being detectable at 72 h. It may be concluded that cervine and bovine slices may be maintained metabolically active for 8–10 h, which should prove sufficient for xenobiotic metabolism studies to be performed.
Tissue distribution of clenbuterol in the horse
Authors: Soma L. R. , Uboh C. E. , Guan F. , Luo Y. , Teleis D. , Runbo L. , Birks E. K. , Tsang D. S. , Habecker P.
Published: April 2004

Plasma and tissue concentrations of clenbuterol (CLB) were determined following oral (p.o.) administration of 1.6 μg/kg twice daily (b.i.d.) for 2 weeks. Horses were administered the last dose on morning of day 15, killed at 0.25, 24, 48, and 72 h post‐administration. At 0.25 h, the highest tissue concentrations of CLB were found in the liver (16.21 ng/g), lung (6.48 ng/g), left ventricle (4.99 ng/g), kidney (3.35 ng/g), bronchi (2.56 ng/g), right ventricle (2.08 ng/g), and eye fluids (1.09 ng/g) all of which were higher than that of plasma (1.10 ng/mL). The elimination half‐lives (t1/2k) for CLB in tissues ranged from 21.2 to 56.3 h, the longest were in the eye fluids (56.9 h), spleen (21.2 h), cerebrum (27.1 h), cerebellum (21.5) and cecum (23.7 h). The t1/2k for plasma was 10.9 h. Tissue/plasma ratios of liver (14.7), lung (5.9), left ventricle (4.6), kidney (3.1), bronchi, (2.3) and right ventricle (1.9) were high at 0.25 h and remained elevated up to 72 h. Accumulation and sustained high concentration of CLB relative to plasma in these tissues contributed to the prolonged elimination and the ability to quantify CLB in plasma and urine for a prolonged period.
Influence of concomitant quinidine administration on dextromethorphan disposition in rats
Authors: Marier J. F. , Pope L. E. , Yakatan G. J. , Berg J. E. , Stiles M. , Vachon P.
Published: April 2004

High doses of dextromethorphan (DM) have been clinically investigated for the treatment of multiple neuronal disorders including neuropathic pain. Several authors have suggested the concomitant administration of DM and a CYP2D6 reversible inhibitor in order to enhance the exposure of DM and limit the exposure to total dextrorphan (DX). The present study proposes to determine whether or not a single dose of quinidine is sufficient to enhance the plasma concentrations of DM in rats and keep those of DX at a minimal level. Oral doses of DM (50 mg/kg) were administered with increasing dose levels of quinidine (0, 2, 20, and 50 mg/kg) to male Sprague–Dawley rats and blood samples were collected over 24 h. Plasma concentrations of DM and total DX were determined using ESI‐LC/MS/MS. Quinidine coadministration resulted in a more than twofold increase in the area under the curve of DM with an ED50 of approximately 2 mg/kg whereas those of total DX were only increased by 21%. These results support the working hypothesis that a single dose of quinidine may enhance the plasma concentrations of DM relative to those of total DX and may therefore improve the treatment of neuropathic pain.
Glucoprivation increases expression of neuropeptide Y mRNA in hindbrain neurons that innervate the hypothalamus
Authors: Li Ai‐Jun , Ritter Sue
Published: April 2004

The hypothalamus is jointly innervated by hindbrain and hypothalamic neuropeptide Y (NPY) cell bodies. While the specific roles of these distinct sources of innervation are not known, NPY neurotransmission within the hypothalamus appears to contribute to glucoregulatory feeding. Here we examine the involvement of hindbrain NPY neurons in glucoregulation using in situ hybridization to assess their responsiveness to glucoprivation. The hindbrain NPY innervation of the hypothalamus is derived from cell bodies that coexpress norepinephrine or epinephrine. Therefore, we quantified NPY mRNA hybridization signal in hindbrain catecholamine cell groups 90 min after subcutaneous administration of the glycolytic inhibitor 2‐deoxy‐d‐glucose (2DG, 250 mg/kg) to male rats. Catecholamine cell groups A1, A1/C1 and C2 (that provide the major NPY innervation of the hypothalamus) showed a basal level of NPY mRNA hybridization signal that was dramatically increased by 2DG. In C1 and C3, where basal NPY mRNA expression was close to or below our detection threshold, the hybridization signal was also significantly increased by 2DG. In cell groups A2, A5, A6 and A7, neither basal nor 2DG‐stimulated NPY mRNA expression was detected. Hypothalamic microinjection of the retrogradely transported catecholamine immunotoxin saporin conjugated to anti‐dopamine‐β‐hydroxylase destroyed hindbrain catecholamine/NPY neurons and abolished basal and 2DG‐stimulated increases in NPY expression in hindbrain cell groups. The responsiveness of hindbrain NPY neurons to glucose deficit suggests that these neurons participate in glucoprivic feeding or other glucoregulatory responses.
Thrombin reduces MuSK and acetylcholine receptor expression along with neuromuscular contact size in vitro
Authors: Faraut Brice , Ravel‐Chapuis Aymeric , Bonavaud Sylvie , Jandrot‐Perrus Martine , Verdière‐Sahuqué Martine , Schaeffer Laurent , Koenig Jeanine , Hantaï Daniel
Published: April 2004

In the course of studies on thrombin and its inhibitor(s) in synaptic plasticity, we addressed the question of their roles in the formation of neuromuscular junctions (NMJ) and used a model of rat neuron–myotube cocultures. We report that the size of acetylcholinesterase (AChE) patches used as a marker of neuromuscular contacts was decreased in the presence of either thrombin or SFLLRN, the agonist peptide of the thrombin receptor PAR‐1, whereas it was increased with hirudin, a specific thrombin inhibitor. In an attempt to relate these neuromuscular contact size variations to molecular changes, we studied muscle‐specific tyrosine kinase receptor (MuSK), acetylcholine receptor (AChR) and rapsyn expression in the presence of thrombin. We showed that thrombin did not change rapsyn gene and protein expression. However, the expression of MuSK and surface AChR proteins was diminished in both myotube cultures and neuron–myotube cocultures. These reductions in protein expression were associated with a decrease in MuSK and AChR α‐subunit gene expression in myotube cultures but not in neuron–myotube cocultures. Moreover, the expression of the AChR ε‐subunit gene, specifically enhanced by neuron‐released factors, was not modified by thrombin in neuron–myotube cocultures. This suggests that thrombin did not affect the expression of synaptic AChRs enhanced by neuron‐released factors but rather reduced the level of extrasynaptic AChRs. Taken together, these results indicate that thrombin in balance with its inhibitor(s) could modulate the formation of neuromuscular contacts in vitro by affecting the expression of two essential molecules in NMJ postsynaptic differentiation, MuSK and AChR.
Photoreceptor cell dysplasia in two Tippler pigeons
Authors: Moore P. A. , Munnell J. F. , Martin C. L. , Prasse K. W. , Carmichael K. P.
Published: April 2004

Two 12‐week‐old Tippler pigeons were evaluated for ocular abnormalities associated with congenital blindness. The pigeons were emaciated and blind. Biomicroscopy and direct and indirect ophthalmoscopy findings of the Tippler pigeons were normal with the exception of partially dilated pupils at rest. Scotopic (blue stimuli) and photopic monocular electroretinograms were extinguished in the blind Tippler pigeons. Histological and electron microscopy studies revealed reduced numbers of rods and cones, and an absence of the double cone complex. The photoreceptor cells’ outer segments were absent, and the inner segments were short and broad. The number of cell nuclei in the outer and inner nuclear layers was decreased, and the internal and external plexiform layers were reduced in width. Photoreceptor cell endfeet with developing synaptic ribbons were present in the external plexiform layer. Inflammatory cell and subretinal debris was not seen. The electroretinographic, histopathological, and ultrastructural findings of the blind Tippler pigeons support the diagnosis of a photoreceptor cell dysplasia.
Periocular sarcoid in a horse
Authors: Komáromy András M. , Andrew Stacy E. , Brooks Dennis E. , Detrisac Carol J. , Gelatt Kirk N.
Published: April 2004

A periocular nodular sarcoid of the right upper and lower eyelids was diagnosed in an 11‐year‐old Thoroughbred mare. Computed tomography scan revealed the extent of the tumor. The mass was surgically debulked under general anesthesia, and the affected periocular region was injected intralesionally withBacillusof Calmette and Guerin (BCG). An emulsion of cell wall fractions was used, which has been modified to reduce the toxic and allergic effect, but retain the antitumor activity. In total, five injections were performed at 2‐week intervals. At follow‐up 7 months after the last BCG injection, the tumor was completely resolved. Two years after the last treatment, the horse remains tumor‐free.
Haematocrit and risk of development of Type 2 diabetes mellitus in middle‐aged Japanese men
Authors: Nakanishi N. , Suzuki K. , Tatara K.
Published: April 2004

Aims To investigate the association between haematocrit and risk of development of diabetes.

Methods The study enrolled 2953 normoglycaemic [fasting plasma glucose (FPG) < 6.1 mmol/l and taking no hypoglycaemic medication] Japanese men aged 35–59 years and free of medication for hypertension and history of cardiovascular disease. FPG was measured at periodic annual health examinations from May 1994 through May 2001. Men in whom Type 2 diabetes mellitus (FPG ≥ 7.0 mmol/l or receiving hypoglycaemic medication) was found during repeated surveys were classified as having Type 2 diabetes.

Results The estimated incidence rates for Type 2 diabetes during 7 years of follow‐up were 3.1%[95% confidence interval (CI) 1.6, 4.6], 4.6% (2.8, 6.4), 5.0% (3.2, 6.9), 6.4% (4.4, 8.5), and 11.5% (8.9, 14.2) for respective haematocrit levels of < 42.6, 42.6–44.0, 44.1–45.3, 45.4–46.8, and ≥ 46.9% (the log‐rank test:P < 0.001). After controlling for potential predictors of diabetes, the respective relative risks for Type 2 diabetes were 1.0 (reference), 1.52 (95% CI 0.81, 2.86), 1.24 (0.66, 2.31), 1.57 (0.86, 2.88), and 2.30 (1.30, 4.08) (Pfor trend = 0.002). From stratified analyses by presence or absence of a risk factor, a linear association of haematocrit level with risk of development of Type 2 diabetes was also observed.

Conclusion These results indicate that haematocrit contributes to the risk of developing Type 2 diabetes.
Long‐term effects of self‐management education for patients with Type 2 diabetes taking maximal oral hypoglycaemic therapy: a randomized trial in primary care
Authors: Goudswaard A. N. , Stolk R. P. , Zuithoff N. P. A. , De Valk H. W. , Rutten G. E. H. M.
Published: April 2004

Aims  Education is an essential part of the management of patients with Type 2 diabetes, but the long‐term effects are unclear and not well investigated in primary care.

Methods  Fifty‐four patients (39–75 years) treated with maximal dosages of oral hypoglycaemic agents, needing to start insulin (HbA1c≥ 7.0%), were randomly allocated to a 6‐month educational programme by a diabetes nurse (DN group) or usual care (UC group). Main outcome measures were HbA1c, number of patients with HbA1c < 7.0%, and number of patients treated with insulin 18 months after baseline.

Results  Six weeks after the intervention HbA1c levels had improved from 8.2 (1.1) to 7.2 (1.3) in the DN group, and from 8.8 (1.5) to 8.4 (1.7) in the UC group. Adjusted for baseline values, at 6 weeks HbA1c improved 0.7% (95% confidence interval 0.1, 1.4) more in DN than in UC. Of the patients in DN, 60% reached HbA1c < 7.0% compared with 17% in UC (P < 0.01). However, at 18 months there were no significant differences for HbA1c, number of patients with HbA1c < 7.0%, or number treated with insulin.

Conclusions  Education was effective in improving glycaemic control and in delaying the need for insulin therapy in patients treated with maximal oral hypoglycaemic therapy. The reduced effect after 1 year was probably due to the discontinuation of the educational programme. Short‐term education should not be offered without regular reinforcements integrated into standard diabetes care.
Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance
Authors: Bennett S. M. A. , Agrawal A. , Elasha H. , Heise M. , Jones N. P. , Walker M. , Wilding J. P. H.
Published: April 2004

Aims  To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT).

Methods  Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24‐h ambulatory blood pressure was monitored.

Results  Rosiglitazone significantly improved the insulin sensitivity index by 2.26 µg/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2‐h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126).

Conclusions  Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.
Acute, local effects of iontophoresed insulin and C‐peptide on cutaneous microvascular function in Type 1 diabetes mellitus
Authors: Delaney C. , Shaw J. , Day T.
Published: April 2004

Aim  The aim of the present study was to demonstrate acute, local vasodilatatory effects of insulin and C‐peptide on cutaneous microvascular function in Type 1 diabetic subjects. There are no published data available examining physiological effects of C‐peptide delivered in this way.

Methods  The study included 20 participants with C‐peptide‐deficient Type 1 diabetes mellitus. Cutaneous microvascular function was assessed on the forearm using laser Doppler velocimetry. Insulin, C‐peptide, acetylcholine (ACh), sodium nitroprusside (SNP) and saline were delivered through the skin using iontophoresis. The response was measured as percentage increase in flux above baseline.

Results  C‐peptide delivered by iontophoresis produced a vasodilatatory response greater than the response to saline (289.5 ± 265.9% vs. 105.1 ± 163.6%, P = 0.003). The response to C‐peptide was also shown to be dose dependent. Further, the size of the response to C‐peptide correlated well with the size of the response to the endothelium‐dependent vasodilatator ACh (r = 0.666, P = 0.001) but not with the size of the response to the endothelium‐independent vasodilator SNP (r = 0.345, P > 0.05).

Conclusions  Physiological effects of C‐peptide on cutaneous microvascular function could be demonstrated in individuals with Type 1 diabetes. The results support both physiological activity of C‐peptide and an endothelium‐dependent mechanism similar to that of ACh. The technique reported may be useful in investigating vasoactive actions of C‐peptide in a safe and non‐invasive way.
Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in Type 1 diabetes
Authors: Schölin A. , Törn C. , Nyström L. , Berne C. , Arnqvist H. , Blohmé G. , Bolinder J. , Eriksson J. W. , Kockum I. , Landin‐Olsson M. , Östman J. , Karlsson F. A. , Sundkvist G. , Björk E.
Published: April 2004

Aim To identify clinical, immunological and biochemical factors that predict remission, and its duration in a large cohort of young adults with Type 1 diabetes mellitus (DM).

Methods In Sweden, 362 patients (15–34 years), classified as Type 1 DM were included in a prospective, nation‐wide population‐based study. All patients were followed at local hospitals for examination of HbA1cand insulin dosage over a median period after diagnosis of 5 years. Duration of remission, defined as an insulin maintenance dose ≤ 0.3 U/kg/24 h and HbA1cwithin the normal range, was analysed in relation to characteristics at diagnosis.

Results Remissions were seen in 43% of the patients with a median duration of 8 months (range 1–73). Sixteen per cent had a remission with a duration > 12 months. Among patients with antibodies (ab+), bivariate analysis suggested that adult age, absence of low BMI, high plasma C‐peptide concentrations, lack of ketonuria or ketoacidosis at diagnosis and low insulin dose at discharge from hospital were associated with a high possibility of achieving remission. Multiple regression showed that normal weight (BMI of 20–24.9 kg/m2) was the only factor that remained significant for the possibility of entering remission. In survival analysis among ab+remitters, a low number of islet antibodies, one or two instead of three or four, were associated with a long duration of remissions.

Conclusion In islet antibody‐positive Type 1 DM, normal body weight was the strongest factor for entering remission, whilst a low number of islet antibodies was of importance for the duration.

Diabet. Med. (2004)
The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study
Authors: Rachmani R. , Slavachevsky I. , Amit M. , Levi Z. , Kedar Y. , Berla M. , Ravid M.
Published: April 2004

Objective  The effect of spironolactone, cilazapril and their combination on albuminuria was examined in a randomized prospective study in female patients with diabetes and hypertension.

Patients and methods  Sixty female diabetic patients aged 45–70 years with blood pressure (BP) 140–180/90–110 mmHg, serum creatinine (sCr) ≤ 160 µmol/l, HbA1c ≤ 10%, and albuminuria were treated by atenolol 12.5–75 mg/d and hydrochlorothiazide 6.25–25 mg/d. Titration‐to‐target helped to reach BP values ≤ 135/85 mmHg in 46 patients after 12 weeks. These patients were randomized to spironolactone 100 mg/d or cilazapril 5 mg/d for 24 weeks. Then both groups received spironolactone 50 mg/d and cilazapril 2.5 mg/d for 24 weeks. BP was stabilized by tapering the dose of the initial agents. Urinary albumin/creatinine ratio (ACR), BP, K+. sCr and HbA1c were assessed at baseline and at weeks 12, 16, 36 and 60.

Results  The average BP at week 12 was 128 ± 4/81 ± 3 mmHg and remained constant, in both groups, throughout the study. ACR declined on spironolactone from a median value (range) of 452 (124–1571) to 216 (64–875) mg/g (P = 0.001), and on cilazapril to 302 (90–975) mg/g (P = 0.001). The difference between spironolactone and cilazapril was significant (P = 0.002). Combined treatment resulted in a further modest decline in ACR. Serum creatinine was unaltered by spironolactone and rose slightly (121 to 126 µmol/l, P = 0.02) on cilazapril.

Conclusion  At the doses tested, spironolactone was superior to cilazapril in reducing albuminuria. Combined administration was more effective than either drug alone. These effects were independent of BP values. Hyperkalaemia was the main side‐effect.
Managerial Technologies, Ethics and Managing
Authors: Townley Barbara
Published: April 2004

ABSTRACT  This paper engages with a key element of Legge's work: the relationship between the technical and the moral in the application of managerial technologies, and how managers manage these different layers of meaning. Taking business planning and performance measurement as an example of managerial technologies, these are analysed for the extent to which they allow for an engagement with an ethical position, using Legge's (1978) characterization of the role of managerial technologies originally identified in Power, Innovation and Problem Solving in Personnel Management. The inter‐related elements of the technical, the ethical and the practical are then used to explore how managers construct the meaning of management and their implications for Legge's more recent deontological and teleological ethical framework.
For the Sake of Argument: Towards an Understanding of Rhetoric as Process
Authors: Carter Pippa , Jackson Norman
Published: April 2004

ABSTRACT  This paper seeks to respond to two particular aspects of Legge's work, her development of the concept of rhetoric and her commitment to the educative process. Legge has been drawing attention to the concept of rhetoric for a long time (e.g. Gowler and Legge, 1981, 1996 [originally 1983]; Legge, 1989, 1995a). However, despite its popularity as an epithet, the process of rhetoric remains largely unexplored. Locating rhetoric within a poststructuralist view of language, this paper utilizes and explores the contribution of ‘The New Rhetoric’ to such an understanding, focusing on issues of style and context. This is used to illustrate a characterization of rhetoric which emphasizes its quality as a closed system with an important role in maintaining the status quo of ‘managerialism’. Highlighting the key concept within ‘The New Rhetoric’ of audience, we suggest that to achieve change it is necessary to intervene in the closed cycle of the relationship between producers and consumers of management knowledge.
Double-Blind Clinical Trials of Oral Triptans Vs Other Classes of Acute Migraine Medication — A Review
Authors: Lipton RB , Bigal ME , Goadsby PJ
Published: April 2004

Although the migraine clinical trials literature is enormous, we identified only nine published double-blind studies which compare an oral triptan with a non-triptan acute treatment. Of the nine comparative trials that met inclusion criteria for this review, six compared sumatriptan with other drugs, zolmitriptan was studied in two trials and eletriptan in one trial. In seven of the nine studies reviewed herein, differences between active treatments on the primary endpoints were not dramatic. Experience in clinical practice suggests that, for many patients, oral triptans are superior to non-specific acute treatments, creating a discrepancy between clinical trials results and clinical practice experience. Four possible explanations for the disparities between clinical trials and clinical practice are likely: (i) statistically significant differences may not have emerged because the studies lack adequate statistical power; (ii) patients treated with triptans in clinical practice may be relatively more responsive to triptans and relatively less responsive to other agents than those who participate in clinical trials (patient selection); (iii) headache response at 2 h, as measured in clinical trials, may not fully capture the benefits of triptans relative to other therapies, as assessed in clinical practice; (iv) waiting until pain is moderate or severe, as required in clinical trials, may disadvantage triptans relative to comparators.
Short Migraine Attacks of less than 2 h Duration in Children and Adolescents
Authors: Abu-Arafeh I , Callaghan M
Published: April 2004

We studied the duration of migraine attacks among children and adolescents who reported headache attacks lasting <2 h. Among the 720 children who attended our specialist headache clinic, over a period of 6 years, 231 children had migraine with or without aura fulfilling the International Headache Society (IHS) criteria for the diagnosis of migraine. A further 15 children reported headache attacks typical of migraine, but of duration <2 h. They were asked to fill prospective headache diaries in order to determine with accuracy the duration of their headache attacks. Ten (67%) of these children provided prospective fully analysable headache diaries and recorded a total of 120 headache attacks, 66 attacks (55%) lasting for <1 h each, 30 attacks (25%) lasting between 1 and 2 h, and 24 attacks (20%) lasting >2 h. Patient-based analysis of the headache diaries showed that only three children consistently had headache attacks lasting <1 h. Seven children had some of their headache attacks lasting for at least 1 h and four had some of their headache attacks lasting at least 2 h. This study shows that headache attacks in children with migraine can be variable, and brief attacks are rare. A combination of short (<1 h) and long (>2 h) attacks of headache can coexist in the same patient. The HIS diagnostic criteria of 1988 for migraine in children should therefore acknowledge such variation and allow reduction of the duration of migraine attacks to 1 h.
Patterns of Functional Brain Organization and Migraine
Authors: Endicott NA
Published: April 2004

The purpose of this study was to examine the relationship between the patterns of functional organization of the brain, as evaluated by the number of anomalous brain conditions or phenomena (ABCP), and the prevalence of migraine in a group of 434 women with lifetime major depressive disorder. ABCP are conditions or phenomena which are clearly related to brain function whose prevalence significantly deviates from the statistical mean for the general population. Eighteen ABCP (e.g. mixed or left handedness, enuresis after age 5, learning and speech disorders) were used in this study as ‘markers’ for their associated patterns of functional brain organization. The relationship between the number of ABCP and the prevalence of migraine was highly significant. The correlation between the number of ABCP and the prevalence of migraine was 0.36 ( P < 0.0001, confidence interval 0.26, 0.43). The prevalence of migraine in patients with no ABCP ( n = 11) was 9%, while that of those with eight or more ABCP ( n = 40) was 85%. This supports the hypothesis that there is a relationship between patterns of functional brain organization and migraine prevalence.
Patient Preference in Clinical Trials for Headache Medication: The Patient's View
Authors: Leinisch-Dahlke E , Akova-Öztürk E , Bertheau U , Isberner I , Evers S , May A
Published: April 2004

From a clinical point of view, the subjective preference of the patient regarding headache medication is imperative. Consequently, a new trial design for headache medication, the so-called patient preference trial, has been vividly discussed. However, some critical questions have been raised concerning preference trials, such as whether placebos should be used, the necessity of blinding, and how to assess the data if a patient does not prefer medication A over B. As patient preference is the topic, we passed these questions on to headache patients using a questionnaire, which was handed out to 1112 headache patients. Out of 612, 486 returned questionnaires were correctly completed and analysed. Complete pain relief was the most important factor for 61% of patients to qualify a therapy effective. This is in contrast to the literature, where rapid speed of onset of the drug is discussed as the most important factor for migraineurs. Regarding the study design, 80% of the patients want to decide the time-point of taking acute medication themselves. About 60% of the patients would participate in placebo-controlled clinical trials and agree that studies should be blinded. If patients had to decide between two equally effective drugs, most would vote for the drug which is available in different application forms. Furthermore, we used the same questionnaire to ask headache specialists with expertise in performing headache studies the same questions. This was mailed to and completed by 22 experts in Germany. In this article, we discuss the patient preference compared with the expert preference regarding clinic trials and drug therapy.
Motion Processing Deficits in Migraine
Authors: McKendrick AM , Badcock DR
Published: April 2004

This study was designed to determine whether cortical motion processing abnormalities are present in individuals with migraine. Performance was measured using a visual motion coherence task (motion coherence perimetry, MCP) thought to depend on the operation of cortical area V5. Motion coherence thresholds were measured using stimuli composed of moving dots at 17 locations in the central ± 20° of visual field. Pre-cortical visual function was also measured using frequency doubling perimetry (FDP) at the same 17 locations. Several migraine subjects demonstrated significant pre-cortical visual functional abnormalities, however, most subjects had normal visual fields measured with FDP. Abnormal MCP performance was measured in 15 of 19 migraine-with-aura subjects, and 11 of 17 migraine-without-aura subjects. A decreased ability to detect coherent motion may possibly be explained by an increase in baseline neuronal noise, such as would be consistent with the concept of cortical hyperexcitability in migraine.
An Analysis of the Factors Associated with Visual Field Deficits Measured with Flickering Stimuli in-between Migraine
Authors: McKendrick AM , Badcock DR
Published: April 2004

We have previously demonstrated that perimetric performance measured with flickering stimuli is not normal in some individuals who experience migraine with aura in the period between their attacks. In this study, flicker perimetric performance is measured in a broad group of migraineurs to determine whether the existence of such visual field deficits is dependent on the presence of visual aura, is correlated with the duration of migraine history, or frequency of attacks. Twenty-eight migraine with aura, 25 migraine without aura, and 24 non-headache control subjects participated. The performance of the migraine groups was not significantly different from each other. The migraine groups showed significantly lower general sensitivity across the visual field and higher incidence of localized visual field deficits relative to controls. Both length of migraine history and frequency of migraine occurrence over the past 12 months were significantly correlated with lower general sensitivity to flickering visual stimuli.
Effects of Chronic Sumatriptan and Zolmitriptan Treatment on 5-HT1 Receptor Expression and Function in Rats
Authors: Reuter U , Salomone S , Ickenstein GW , Waeber C
Published: April 2004

Triptans are commonly used anti-migraine drugs and show agonist action mainly at serotonin 5-HT1B/1D/1F receptors. It is not known whether frequent or long-term treatment with these drugs would alter 5-HT receptor function. We investigated the effects of protracted (14-18 days) sumatriptan and zolmitriptan treatment in rats on 5-HT1 receptor mRNA expression and function in tissues related to migraine pathophysiology. RT-PCR analysis revealed that 5-HT1B/1D/1F receptor mRNA was reduced in the trigeminal ganglion after treatment with either triptan (reduction by: sumatriptan 39% and zolmitriptan 61% for 5-HT1B; 60% vs 41% for 5-HT1D; 32% vs 68% for 5-HT1F). Sumatriptan attenuated 5-HT1D receptor mRNA by 49% in the basilar artery, whereas zolmitriptan reduced 5-HT1B mRNA in this tissue by 70%. No change in 5-HT1 receptor mRNA expression was observed in coronary artery and dura mater. Chronic triptan treatment had no effect in two functional assays [sumatriptan mediated inhibition (50 mg/kg, i.p.) of electrically induced plasma protein extravasation in dura mater and 5-nonyloxytryptaminestimulated [35S]guanosine-5′-O-(3-thio)triphosphate binding in substantia nigra]. Furthermore, vasoconstriction to 5-HT in isolated basilar artery was not affected by chronic triptan treatment, while it was slightly reduced in coronary artery. We conclude that, although our treatment protocol altered mRNA receptor expression in several tissues relevant to migraine pathophysiology, it did not attenuate 5-HT1 receptor-dependent functions in rats.
Headache Related to a Specific Screen Flickering Frequency Band
Authors: Kowacs PA , Piovesan EJ , Werneck LC , Fameli H , Pereira da Silva H
Published: April 2004

The case of a 25-year-old white male, who had migrainous headaches each time he sat in front of his personal computer screen, is described. Changing the screen frequency from 60 to 75 Hz through a Windows command could abolish the headaches. In several surveys, computer screens have been reported to be a migraine trigger. We hypothesize that this environmental trigger may be related to the abnormal flicker fusion thresholds that have been described in migraineurs. It may be that modifying the frequencies of light sources, such as computer screens, could become a non-pharmacological approach to prevent migraine attacks.
A Comparison of a Collaborative and Top‐Down Approach to the Use of Science in Policy: Establishing Marine Protected Areas in California
Authors: Weible Christopher , Sabatier Paul A. , Lubell Mark
Published: April 2004

The National Research Council has proposed two distinct approaches over the past 20 years for guiding decision making about risk. These two approaches are widely applicable to environmental decision‐making and are exemplified by two attempts to establish Marine Protected Areas (MPAs) in California with the implementation of the 1999 Marine Life Protection Act. The first attempt, which parallels the NRC's 1983 linear scientific approach, was a top‐down process that involved a Master Plan Team of scientists who created a proposal before gathering public input. The second attempt, which parallels the NRC's 1996 analytic and deliberative approach, involved a diverse set of stakeholders, including scientists, who worked in a collaborative process to provide a range of recommendations. We apply a three‐tiered model of elite belief systems drawn from the Advocacy Coalition Framework to show that stakeholder preferences for either of these approaches is a function of their deep core beliefs. Stakeholders with strong preferences for scientific management support empirical claims for the benefits of MPAs and are more optimistic about the linear scientific approach compared to the analytic and deliberative approach for protecting major habitats, avoiding adverse fishing effects, and avoiding unfair agency domination. In contrast, stakeholders with pro‐collaborative beliefs respect local knowledge and are more optimistic about the analytic and deliberative approach compared to the linear scientific approach for avoiding adverse fishing effects and unfair agency domination.
Teachers’ Attitudes and the Success of School Choice
Authors: Ferraiolo Kathleen , Hess Frederick , Maranto Robert , Milliman Scott
Published: April 2004

The 1990s witnessed growing attention to the adoption of choice‐based school reforms, particularly charter schooling and school vouchers. Although researchers have approached the school choice debate from theoretical, normative, and empirical directions, little attention has been paid to examining how teachers view school choice or what factors shape their attitudes. This oversight is significant because teachers can impact the success of school choice experiments in many ways, such as through their willingness to launch and staff schools of choice, adopt new practices developed in schools of choice, and support choice‐based reform efforts in their unions and communities. Using a survey of Arizona and Nevada teachers, we find that White, experienced, unionized, Democratic educators and those working in a “positive” school environment are less supportive of school choice. Arizona teachers, who live in close approximation of a free market for education, are particularly hostile to choice, but teachers who have had personal contact with a charter school are more supportive. The results indicate that the success of school choice will likely be influenced by the characteristics of the teacher workforce and teachers’ familiarity with competition.
Get Your Tongue out of My Mouth ‘Cause I’m Kissin’ You Goodbye: The Politics of Ideas
Authors: Meier Kenneth J.
Published: April 2004

The seminal work of Derthick and Quirk (1985) argues that public policy changes when the intellectual debate of ideas establishes that policy options are legitimate and current policies are ineffective.1 Overlooked in their otherwise exceptional analysis is the role that country music plays in the politics of ideas.2 The thesis of this article is that country music is a crucial part of the politics of ideas, and, in fact, many policy debates are resolved in country music well before the intellectual community of policy analysts reaches a consensus. This article will recap some of the key policy debates in which country music set the agenda,3 established the key policy alternatives, or resolved the policy debate and permitted the adoption of public policy (Anderson, 1994).4