bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of intranasally administered low dose melatonin
Authors: Helfrich E. , Neef C. , Merkus F. W. H. M. 
Published: March 2003

Melatonin is an endogenous hormone secreted by the pineal gland and plays a role in the regulation of the circadian rhythms, sleep and mood. Several studies evaluated the use of oral melatonin in sleep disorders, jet lag and shift work. No side‐effects have been reported in these trials [1]. However, it is known that oral melatonin shows poor bioavailability, either due to poor absorption, large first‐pass metabolism or both [2]. Other routes of administration, in particular nasal, have been described [3].Eight healthy male volunteers (mean age 25 years) received, in an open randomized cross‐over fashion, placebo and intranasal melatonin 200 and 400 µg. Blood was sampled 15 times during 8 h. The study was approved by the Ethics Committee. Melatonin was determined by r.i.a. Plasma melatonin concentrations were adjusted for the mean endogenous concentration after placebo. We calculated the pharmacokinetic parameters of intranasal melatonin by using the MW\Pharm programme [4] according to the ITSB method. The AUC(0, 8 h) was obtained by the trapezoidal rule. The model was validated by Monte Carlo simulation.Melatonin intranasal kinetics could best be described by a 2‐compartment model (Table 1). Melatonin 200 and 400 µg provided high blood plasma concentrations after fast absorption. The elimination half‐life of melatonin was 44±7 min and 60±20 min after dosing respectively 200 and 400 µg (P>0.05). Absorption was too rapid to be fitted. Monte Carlo analysis showed that data differed significantly (P<0.05) from the fitted population parameters.

Pharmacokinetic parameters after intranasal administration of 200 and 400 µg melatonin.

Parameters
200 µg (n=7)
95% CI

Median±d.f.
Median±s.d.

AUC(0, 8 h)&!emsp;(µg l−1 h)

2.99±1.16
2.06, 3.92

V
d/F(l kg−1 LBMc)
1.41±0.28

1.11, 1.67

k
el (h−1)
1.04±0.14

0.91, 1.16

k
12 (h−1)
0.10±0.12

−0.01, 0.22

k
21 (h−1)
0.05±0.04

0.01, 0.09

400 µg (n=8)

Parameters
Median±d.f.
Median±s.d.
95% CI

AUC(0, 8 h)(µg l−1 h)

5.98±2.23
4.12, 7.84

V
d/F (l kg−1 LBMc)
1.61±0.69

1.04, 2.18

k
el (h−1)
0.75±0.22

0.57, 0.93

k
12 (h−1)
0.19±0.08

0.13, 0.25

k
21 (h−1)
0.02±0.01

0.01, 0.03

AUC: area under the curve, F: absolute bioavailability, Vd/F: volume of distribution, kel: elimination rate constant, k12, k21: rate constants between compartments.

The pharmacokinetic parameters could not be validated by a Monte Carlo simulation probably due to large interindividual variability. Because the dose adjusted AUC(0, 8 h) for the 400 µg nasal dose was equal to the AUC(0, 8 h) for the 200 µg nasal dose (P<0.05), there appears to be linear absorption in the 200 to 400 µg dose range.
Lichen sclerosus premenarche: autoimmunity and immunogenetics
Authors: Powell J. , Wojnarowska F. , Winsey S. , Marren P. , Welsh K. 
Published: March 2003

Abstract
Lichen sclerosus is among the most frequently seen paediatric vulval disorders. In adults a strong association between lichen sclerosus and autoimmune diseases, and also with HLA class II locus DQ7, has been well demonstrated in women and a weaker association in men. These associations have not previously been studied in children, although in other autoimmune diseases, the HLA associations have been strongest in children. We performed HLA tissue typing and looked for autoimmune associations in a group of 30 children with vulval lichen sclerosus. HLA DQ7 was present in 66% of female children with lichen sclerosus compared with 31% in controls. Previous studies reported DQ7 in 51% of adult female patients and 45% of male patients. Sixteen per cent of the children were homozygous for DQ7 as opposed to 5% of controls. In the childhood group, only 4% had another autoimmune disease, but 56% of their parents or grandparents did. Age differences make comparison difficult, but the family history of autoimmunity appears to be strong in the early-onset group, in addition to the stronger association with DQ7.
Surveillance of occupational skin disease: EPIDERM and OPRA
Authors: Cherry N. , Meyer J.D. , Adisesh A. , Brooke R. , Owen-Smith V. , Swales C. , Beck M.H. 
Published: March 2003

Abstract
Consultant dermatologists in the U.K. have been reporting to EPIDERM, a voluntary surveillance scheme for occupational skin disease, since February 1993; reporting by occupational physicians to the scheme began in May 1994 and was superseded in January 1996 by OPRA (Occupational Physicians Reporting Activity). Currently 244 dermatologists and 790 occupational physicians report incident cases to these schemes. During the 6 years to January 1999 a total of 12,574 new cases of occupational skin disease was estimated from reports by consultant dermatologists and 10,136 cases estimated from occupational physicians (since May 1994). The annual incidence of occupational contact dermatitis using data from both schemes was 12·9 per 100,000 workers. The incidence of contact dermatitis per 100,000 workers increased with age in men from 4·9 (age 16–29 years) to 6·6 (age 45–60 years); in women a higher rate (9·5) was apparent in the younger age group, with lower rates in older female workers. High rates in young workers were associated with wet work and in older workers with exposure to oils. For men, high rates of contact dermatitis were seen in reports from both schemes for chemical operatives, machine tool setters and operatives, coach and spray painters and metal workers. For women, high rates were found for hairdressers, biological scientists and laboratory workers, nurses and those working in catering. The most frequent agents for contact dermatitis were rubber chemicals and materials (14·1% of cases reported by dermatologists), soaps and cleaners (12·7%), nickel (11·9%), wet work (11·1%), personal protective equipment (6·2%), petroleum products (6·3%), cutting oils and coolants (5·6%), and epoxy and other resins (6·1%). In the 1608 estimated cases of skin cancer all but 4% were attributed to ultraviolet radiation. Cases of contact urticaria attributed to latex peaked in 1996, with a decline in cases since that time.
Prevalence of solar damage and actinic keratosis in a Merseyside population
Authors: Memon A.A. , Tomenson J.A. , Bothwell J. , Friedmann P.S. 
Published: March 2003

Abstract
This study examines the prevalence of sun-related damage to the skin in a caucasian population in north-west England. The importance of constitutional factors (complexion, skin type and age) as well as environmental and occupational exposures for the development of actinic keratosis (AK) and skin cancers was assessed in people over 40 years of age attending outpatient clinics (non-dermatology) at four centres in north-west England (Mersey region). Nine hundred and sixty-eight volunteers (531 men and 437 women) were recruited. The overall prevalence of AK was 15·4% in men and 5·9% in women. The prevalence was strongly related to age in both sexes, being 34·1% and 18·2%, respectively, in men and women aged 70 years and above, and was most strongly related to two objective signs of sun exposure, namely degree of solar elastosis and presence of solar lentigines. The prevalence of AK was higher in subjects with red hair and freckles, particularly women. There was no evidence of an increased prevalence of AK in relation to any occupation. There was a high prevalence of seborrhoeic keratosis and viral warts in both sexes, which was age-related in the case of seborrhoeic keratosis. Ten cases of basal cell carcinoma, eight cases of Bowen’s disease and one case of malignant melanoma were identified. This study shows that the sun exposure received in ‘normal’ life in England is sufficient to cause potentially malignant skin damage in a significant proportion of the population.
Nailfold video capillaroscopy in psoriasis
Authors: Bhushan M. , Moore T. , Herrick A.L. , Griffiths C.E.M. 
Published: March 2003

AbstractChanges in the microvasculature are considered to play an important part in the pathogenesis of psoriasis and its associated arthritis. The novel method of nailfold video capillaroscopy is an extension of the technique of widefield nailfold microscopy which has been of diagnostic and predictive use in the in vivo study of the microcirculation in systemic sclerosis and other connective tissue disorders. However, similar studies in patients with psoriasis and psoriatic arthritis and/or nail changes have produced conflicting results. We tested the hypothesis that any abnormalities in nailfold capillaries of either a quantitative or qualitative nature might be observed more readily in subjects with pathology adjacent to the nailfold, i.e. distal interphalangeal (DIP) joint changes and/or nail dystrophy, when using this technique. Forty-four patients with psoriasis were recruited (21 males, 23 females). Twelve patients had psoriasis alone, 13 had psoriasis and nail changes, six had DIP joint involvement with changes of psoriasis elsewhere, and 13 had psoriasis, DIP arthritis and nail changes. Capillary density and standard capillary dimensions were studied and compared with those of 44 age- and sex-matched control subjects. There was a significant (P &lt; 0·05) decrease in capillary loop density in patients with either psoriasis plus nail disease (14·5 ± 5·7 capillaries per 3 mm field) or psoriasis plus nail and DIP joint disease (14·3 ± 5·0) when compared with controls (19·2 ± 3·8). In patients with psoriatic arthritis affecting the DIP joints, there was a statistically significant (P &lt; 0·05) decrease in arterial and venous capillary limb diameters, and this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis and/or nail changes when compared with normal controls. Morphological abnormalities previously described in the literature were not noted in any of our four patient groups. Our findings of diminution in both nailfold capillary bed density and dimensions of the arterial and venous capillary limbs suggest that vascular injury, previously noted in ultrastructural studies, may play a part in the pathogenesis of psoriatic arthritis. However, in contrast to previous studies, we found no specific pattern of a morphological nature of nailfold capillaries in patients with psoriasis with or without nail changes, when compared with normal controls.
Depigmented hypertrichosis following Blaschko’s lines associated with cerebral and ocular malformations: a new neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes?
Authors: Schauder S. , Hanefeld F. , Noske U.M. , Zoll B. 
Published: March 2003

AbstractThe lines of Blaschko represent one of the cutaneous patterns of mosaicism followed by various skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are occasionally associated. We describe a 30-year-old man with depigmented, bilateral hypertrichosis and dilated follicular orifices following Blaschko’s lines associated with cerebral and ocular malformations. The findings suggest a previously unreported neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes.
Red facial pseudochromhidrosis
Authors: Thami G.P. , Kanwar A.J. ,   MAMTA
Published: March 2003

Abstract
We describe a 9-year-old girl with pseudochromhidrosis simulating apocrine chromhidrosis. Treatment with topical and systemic erythromycin resulted in complete clearance of the reddish discoloration of the face. No relapse or recurrence was observed over a 3-month period.
Photosensitive mycosis fungoides or actinic reticuloid?
Authors: De Silva B.D. , Mclaren K. , Kavanagh G.M. 
Published: March 2003

Abstract
We report two patients who satisfied the diagnostic criteria for actinic reticuloid (AR) on initial presentation, in whom genotypic analysis of early skin biopsies failed to show T-cell gene receptor rearrangements. Both patients progressed to widespread skin involvement associated with histopathological and genotypic features of mycosis fungoides (MF). Arguably, these patients may have had photosensitive MF from the outset, but their clinical features, phototesting, and subsequent demonstration of a T-cell gene receptor rearrangement in the skin could also suggest progression of AR to MF.
Longitudinal study on activated factors XII and VII levels during normal pregnancy
Authors: De Moerloose  , Amiral  , Vissac  , Reber  
Published: March 2003

Levels of activated factor XII (FXIIa) and VII (FVIIa) were determined in 100 women with uneventful pregnancies. Samples were divided into five study intervals: three during pregnancy, one at delivery and one 3 d postpartum.The median (range) for FXIIa levels were 3.4 ng/ml (1.2–9.1) from 11 to 20 weeks, 4.6 ng/ml (1.4–15.2) from 21 to 30 weeks, 5.4 ng/ml (1.9–14.3) from 31st week to delivery, 5.2 (1.3–11.4) at delivery and 4.3 (1.8–8.5) ng/ml in the postpartum sample. For FVIIa the median and range levels for the five periods were 4.9 (1.7–77.3), 7.2 (2.5–80.4), 11.1 (2.9–90.6), 12.0 (3.1–64.1) and 8.2 (4.0–23.5) ng/ml. Although the increase of FVIIa was higher than that of FXIIa during pregnancy, the overall changes of FXIIa and FVIIa were highly correlated (P < 0.0001). At each time period the changes of FVIIa correlated with FVII:C which was not the case with FVII:Ag. These data indicate that during pregnancy both the contact phase and extrinsic pathway are activated.
Chimaeric anti‐interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose‐escalating study
Authors: Van Zaanen  , Lokhorst  , Aarden  , Rensink  , Warnaar  , Van Der Lelie  , Van Oers  
Published: March 2003

Interleukin 6 plays a key role in the pathogenesis of multiple myeloma (MM). Therefore we conducted a phase I dose‐escalating study with chimaeric monoclonal anti‐IL6 antibodies (cMab) in MM patients resistant to second‐line chemotherapy. The cMab (CLB IL6/8; Kd 6.25 × 10−12 M) was given in two cycles of 14 daily infusions, starting on day 1 and day 28, repectively, with a daily dose of 5 mg in patients 1–3, 10 mg in patients 4–6, 20 mg in patients 7–9 and 40 mg in patients 10–12 (total dose 140 mg, 280 mg, 560 mg and 1120 mg of anti‐IL6, respectively). 11/12 patients had elevated pretreatment IL6 levels.Except for transient thrombocytopenia in two patients there was no toxicity. There were no changes in haemoglobin levels, granulocyte count, liver enzymes or renal function. No human anti‐chimaeric antibodies were induced. This was also reflected in a long half‐life time of the cMab (median 17.8 d), resulting in accumulation of the anti‐IL6 cMab and high levels of circulating IL6. However, this was in the form of biologically inactive IL6/cMab complexes and did not result in acceleration of the disease. Although C‐reactive protein (CRP) levels were decreased to below detection level in 11/12 patients, indicating effective IL6 blocking, none of the patients achieved a response according to the standard criteria. We conclude that this chimaeric anti‐IL6 Mab has a low toxicity, low immunogenicity and a long T1/2. A dose of 40 mg/d for 14 d can safely be used in future phase II studies.
Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease
Authors: Bonfante  , Viviani  , Santoro  , Devizzi  , Di Russo  , Zanini  , Soncini  , Soto Parra  , Valagussa  , Bonadonna  
Published: March 2003

Twenty‐six patients with relapsed or refractory Hodgkin's disease (HD) were treated with an intensive salvage regimen combining ifosfamide (3000 mg/m2/d, days 1–4 through continuous intravenous infusion) and vinorelbine (25 mg/m2, i.v. days 1 and 5) with mesna uroprotection and G‐CSF support. Courses were given at 3‐week intervals.Ten patients achieved a complete and 10 patients a partial response, yielding an overall response rate of 77%. The main toxic effect was neutropenia and the combination was well tolerated.
No treatment for low‐risk thrombocythaemia:results from a prospective study
Authors: Ruggeri  , Finazzi  , Tosetto  , Riva  , Rodeghiero  , Barbui  
Published: March 2003

Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder characterized by the occurrence of thromboembolic episodes, particularly in patients aged > 60 years or with a previous history of thrombosis, and/or by haemorrhages in patients with an exceedingly high platelet count. In these subgroups of patients the use of cytoreductive therapy is beneficial in terms of risk/benefit ratio. Only limited anecdotal data are available on the thrombotic or haemorrhagic risk and survival in young asymptomatic ET patients with a platelet count < 1500 × 109/l. Therefore the optimal management of these patients is unknown.To assess the incidence of thrombosis and haemorrhages in this group of patients we carried out a prospective observational study in a cohort of 65 patients with ET, aged < 60 years, with no history of thrombosis or haemorrhage and platelet count < 1500 × 109/l, and in 65 age‐ and sex‐matched controls. Patients were not treated with cytoreductive therapy until the occurrence of thrombosis or haemorrhage. Arterial or venous thrombotic events were objectively documented both in cases and in controls.The median follow‐up was 4.1 years, with an incidence of thrombosis in patients and controls of 1.91 and 1.50 cases/100 patient‐years, respectively. The age‐ and sex‐adjusted risk rate ratio was 1.43 (95% CI 0.37–5.4). Only three minor haemorrhagic episodes occurred in patients, with an incidence of 1.12 cases/100 patient‐years.Pregnancy and surgery were not associated with thrombosis in these patients.We conclude that the thrombotic risk in young ET patients, with no thrombotic history and a platelet count < 1500 × 109/l, is not increased compared to the normal population and that a conservative therapeutic approach should therefore be considered in these patients.
Chromosomal abnormalities in systemic amyloidosis
Authors: Fonseca Rafael , Ahmann Gregory J. , Jalal Syed M. , Dewald Gordon W. , Larson Dirk R. , Therneau Terry M. , Gertz Morie A. , Kyle Robert A. , Greipp Philip R. 
Published: March 2003

Primary systemic amyloidosis (AL) is a plasma cell disorder characterized by deposition of monoclonal light chains in different organ systems. Although multiple and complex numerical chromosomal abnormalities have been described in patients with multiple myeloma, it is currently unknown whether such changes occur in systemic amyloidosis.Bone marrow samples from 21 patients with AL were studied by standard cytogenetics and interphase fluorescencein situhybridization (FISH) for the presence of numerical chromosomal abnormalities. We tested for six chromosomes (7, 11, 9, 15, 18 and X) using centromere‐specific probes. The monoclonal plasma cells were identified by simultaneous fluorescent staining of the monotypic cytoplasmic immunoglobulin. We compared these results with those obtained from 19 patients with monoclonal gammopathy of undetermined significance (MGUS) and normal controls.Multiple numerical chromosomal abnormalities were detected in AL by interphase FISH, including trisomy of chromosomes 7 (42%), 9 (52%), 11 (47%), 15 (39%), 18 (33%) and X (13% in women and 54% in men). Monosomy of chromosome 18 was seen in 72% of cases. Previous exposure to alkylator therapy did not appear to correlate with these abnormalities. No significant difference was observed in the prevalence of these abnormalities between AL and MGUS.Multiple chromosomal numerical abnormalities were detected by interphase FISH analysis in patients with AL, especially monosomy of chromosome 18. Aneuploidy in the monotypic plasma supports a neoplastic nature for the disorder.
Levels of soluble FasL and FasL gene expression during the development of graft‐versus‐host disease in DLT‐treated patients
Authors: Das Hiranmoy , Imoto Shion , Murayama Tohru , Kajimoto Kazuyoshi , Sugimoto Takeshi , Isobe Takashi , Nakagawa Toshitaro , Nishimura Ryuichiro , Koizumi Tamio 
Published: March 2003

Three patients with different clinical symptoms of graft‐versus‐host disease (GVHD) who had received donor lymphocyte transfusion (DLT) for the treatment of relapsed leukaemia after an allogeneic bone marrow transplantation (BMT) from HLA‐matched sibling donors were analysed for the presence of soluble FasL (sFasL) in the sera and for the expression of the Fas ligand (FasL) gene in the peripheral blood mononuclear cells (PBMNC). Two patients who demonstrated liver damage with increased levels of serum bilirubin showed significantly increased levels of serum sFasL. The increase in the sFasL level was observed prior to the increase in the bilirubin during the clinical courses of both patients. The high dose of methyl predonisolone administered to one of these patients greatly reduced the levels of sFasL in the serum. The bilirubin levels were also reduced thereafter. The third patient (without liver damage) did not show any increase in the serum sFasL level.The expression of the FasL gene in the PBMNC of these three patients was examined. All three patients showed increased levels of the FasL gene expression during their clinical courses. However, only one patient showed a parallel alteration of FasL gene expression with sFasL in the serum. These cases provide evidence that the Fas/FasL system is closely associated with human GVHD, especially in the development of liver GVHD.
Engagement of the CrkL adaptor in interferon α signalling in BCR–ABL‐expressing cells
Authors: Grumbach Isabella M. , Mayer Ingrid A. , Uddin Shahab , Lekmine Fatima , Majchrzak Beata , Yamauchi Hayato , Fujita Shigeru , Druker Brian J. , Fish Eleanor N. , Platanias Leonidas C. 
Published: March 2003

Interferon α (IFNα) has significant clinical activity in the treatment of patients with chronic myelogenous leukaemia (CML), but the mechanisms of its selective efficacy in the treatment of the disease are unknown. The CrkL adaptor protein interacts directly with the BCR–ABL fusion protein that causes the malignant transformation and is constitutively phosphorylated in BCR–ABL‐expressing cells. In the present study, we provide evidence that CrkL was engaged in IFNα‐signalling in the CML‐derived KT‐1 cell line, which expresses BCR–ABL and is sensitive to the growth inhibitory effects of IFNα. CrkL is constitutively associated with BCR–ABL in these cells and treatment with IFNα had no effect on the BCR–ABL/CrkL interaction. After IFNα stimulation, CrkL associated with Stat5, which also underwent phosphorylation in an IFNα‐dependent manner. The interaction of CrkL with Stat5 was facilitated by the function of both the SH2 and the N‐terminus SH3 domains of CrkL. The resulting CrkL–Stat5 complex translocated to the nucleus and could be detected in gel shift assays using elements derived from either the β‐casein promoter or the promoter of the PML gene, an IFNα‐inducible gene that mediates growth inhibitory responses. In addition to its interaction with Stat5, CrkL interacts with C3G in KT‐1 cells and such an interaction regulates the downstream activation of the small GTPase Rap1, which also mediates inhibition of cell proliferation. Thus, despite its engagement by BCR–ABL in CML‐derived cells, CrkL mediates activation of downstream signalling pathways in response to the activated type I IFN receptor and such signals may contribute to the generation of the anti‐proliferative effects of IFNα in CML.