bluuebunny/crossref_metadata_2025 huggingface dataset:
Metastatic nevoid melanoma in a 41/2‐year‐old child
Authors: Cassarino David S. , Fullen Douglas R. , Sondak Vernon K. , Duray Paul H.
Published: October 2003

Background:  Childhood melanoma is a rare and controversial diagnosis.

Methods:  We present the case of a 4½‐year‐old child found to have an expanding, elevated pigmented lesion on her back.

Results:  The biopsy showed a symmetrical, well circumscribed lesion. However, higher magnification revealed sheets of nevoid cells infiltrating deep into the dermis, lacking maturation, and exhibiting a high mitotic rate (average 5/10 high‐power field) with deep mitoses. The possibility of nevoid melanoma was raised, and re‐excision and sentinel lymph node (SLN) biopsy were recommended. Two SLNs were positive for melanoma, verified by immunohistochemical staining. In order to further characterize this melanoma, we performed immunohistochemistry for the tumor‐suppressor p53, proliferation marker MIB‐1, and oncogenes Bcl‐2, cyclin D‐1, and MDM‐2. Staining for p53 was diffusely positive in the primary and the metastasis; MIB‐1 showed moderate proliferative rate in the primary (approximately 10%); Bcl‐2 was weakly positive in the primary and showed focal staining in the metastasis; cyclin D‐1 was strongly positive in the primary and metastasis; and MDM‐2 staining showed scattered positive cells in both lesions.

Conclusions:  These findings are consistent with a metastatic nevoid melanoma arising in the absence of predisposing disease in a young child, a distinctly unusual occurrence.
Mucoepidermoid carcinoma arising within nevus sebaceus of Jadassohn
Authors: Diwan A. Hafeez , Smith Kathleen J. , Brown R. , Skelton Henry G.
Published: October 2003

Background:  Nevus sebaceus (NS) of Jadassohn is a common congenital lesion associated with numerous benign and malignant tumors. However, mucoepidermoid carcinoma (MEC) has not been described in association with NS.

Methods:  We describe an unusual case of MEC arising within NS.

Results:  A 72‐year‐old man presented with an enlarging plaque on his forehead, along the hairline. Physical examination revealed a mounded, erythematous lesion that was completely excised. Histological evaluation revealed a typical MEC with areas of squamous and adenomatous differentiation with foci of typical intermediate cells.

Conclusion:  The diagnosis of MEC is an important one, because it portends a poor prognosis, requiring long follow‐up. This is, to our knowledge, the first report of MEC arising within NS.
Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala‐azar dermal leishmaniasis
Authors: Beena K R , Ramesh V , Mukherjee Ashok
Published: October 2003

Background:  Post kala‐azar dermal leishmaniasis (PKDL) is an unusual dermatosis following kala‐azar (KA). Demonstration of the amastigotes in lesions plays an important role in the diagnosis of PKDL. It was aimed to evaluate the utility of an antibody G2D10 in detecting leishmania parasite antigen, to correlate the parasite number/percentage of parasites with the inflammation, and to assess the epidemiological significance associated with the location of the parasites.

Material and methods:  The study was conducted on 50 cases. Hematoxylin and eosin (H & E) stains and immunohistochemical (IHC) stains, using G2D10 antibody, was performed on the skin biopsies. The number of parasites and density of inflammation were semiquantitatively assessed.

Results:  Leishmania donovan bodies (LDBs) were identified in 50% of cases with the H & E compared to 80% positivity with the IHC. All 50 cases showed inflammation in the superficial dermis (SD). About 44% showed dense inflammation compared to 16% sparse and 40% moderate inflammation. Parasite percentage was maximum in the SD (100%) compared to 75 and 42% in the mid and deep dermis, respectively.

Conclusions:  The IHC showed a higher percentage of LDB localization (80 vs. 50%). Density of inflammation was maximum in the SD. The parasite percentage was correlated with the inflammation. Location of parasites could have an epidemiological significance.
Histologic features of melanocytic nevi seen in association with mycosis fungoides
Authors: McNiff Jennifer M. , Glusac Earl J.
Published: October 2003

Background:  Many different tumors have been reported to occur simultaneously as collision lesions. To date, no such events have been reported between mycosis fungoides (MFs) and melanocytic neoplasms.

Methods:  Two cases are presented in which patches of MF were superimposed on melanocytic nevi. In addition, 967 biopsies of MF from 411 patients were identified in an 8‐year retrospective database search. Patient pathology history summaries were reviewed to identify inflamed nevi, atypical nevi, and melanoma submitted for histologic evaluation from this population.

Results:  The occurrence of MF in a congenital nevus was associated with a halo phenomenon restricted to the affected region of the nevus in one patient. In the other patient, nests of two morphologies (lymphocytic and melanocytic) in the same biopsy presented a potentially confusing histologic picture. No other cases of MF superimposed on a nevus were identified in 967 biopsies from 411 patients with a histological diagnosis of MF seen over the past 8 years. In this population, 57 biopsies of melanocytic lesions were identified from 28 patients, including three atypical nevi and three melanomas.

Conclusions:  The presence of MF superimposed on a nevus is rare and may lead to confounding histologic features or the development of a halo nevus phenomenon.
Cutaneous metastasis of hepatocellular carcinoma diagnosed with hepatocyte paraffin (Hep Par 1) antibody immunohistochemistry
Authors: Kanitakis J. , Causeret A. S. , Claudy A. , Scoazec J. Y.
Published: October 2003

Cutaneous metastases from hepatocellular carcinomas are rare, and their diagnosis may be difficult on histological grounds. We report a case of metastatic hepatocellular carcinoma to the skin that was confirmed immunohistochemically by the expression of a hepatomitochondria‐specific antigen detectable on paraffin‐embedded sections (Hep Par 1).
Epidermotropic metastases from breast carcinoma showing different clinical and histopathological features on the trunk and on the scalp in a single patient
Authors: Brasanac Dimitrije , Boricic Ivan , Todorovic Vera
Published: October 2003

A 54‐year‐old female presented with the cutaneous metastases of the breast carcinoma that produced combination of pigmented zosteriform eruption on the trunk and eroded plaque on the scalp, 13 years after radical mastectomy. Histologically, zosteriform lesions displayed prominent infiltration of the epidermis in nesting or linear pattern by neoplastic cells with focal formation of intraepidermal and subepidermal vesicles due to discohesion of tumor cells and dermal edema. Examination of scalp plaque revealed ulcerations and infiltration of the epidermis with scattered basal and suprabasal malignant cells in pagetoid fashion. Immunohistochemically, tumor cells were cytokeratin 7‐ and estrogen receptor‐positive and cytokeratin 20 negative. HMB‐45 and Melan‐A‐stained numerous dendritic melanocytes intermingled with intraepidermal and superficial dermal tumor cells in the trunk lesion, whereas on the scalp, only occasional melanocytes surrounding intraepidermal carcinomatous cells were identified. Our case described, to our knowledge, so far unreported combination of individually rare, clinical and histological patterns of cutaneous metastases from breast carcinoma in a single patient.
Inhibitory effect of stiripentol on carbamazepine and saquinavir metabolism in human
Authors: Cazali N. , Tran A. , Treluyer J. M. , Rey E. , D’Athis P. , Vincent J. , Pons G.
Published: October 2003

Aims  To characterize the in vitro and in vivo inhibitory effect of stiripentol, a new anticonvulsant, on the metabolism of carbamazepine and saquinavir, which are substrates of CYP3A4.

Methods  Human liver microsomes and cDNA‐expressed CYP enzymes were used for the in vitro experiments. Pharmacokinetic data from epileptic children and healthy adults were used for the carbamazepine and saquinavir in vivo studies, respectively.

Results  Carbamazepine biotransformation to its 10,11‐epoxide by human liver microsomes (Vmax = 10.3 nmol min−1 nmol−1 P450, apparent Km = 362 µm), cDNA‐expressed CYP3A4 (Vmax = 1.17 nmol min−1 nmol−1 P450, apparent Km = 119 µm) and CYP2C8 (Vmax = 0.669 nmol min−1 nmol−1 P450, apparent Km = 757 µm) was inhibited by stiripentol (IC50 14, 5.1, 37 µM and apparent Ki 3.7, 2.5, 35 µm, respectively). Saquinavir biotransformation to its major metabolite M7 by human liver microsomes (Vmax = 5.7 nmol min−1 nmol−1 P450, apparent Km = 0.79 µm) was inhibited by stiripentol (IC50 163 µM, apparent Ki 86 µm). In epileptic children treated with carbamazepine and stiripentol, the plasma concentration ratio of carbamazepine epoxide/carbamazepine was decreased by 65%. The in vivo apparent Ki for stiripentol ranged from 10.5 to 41.4 µm. The pharmacokinetics of saquinavir was not modified by stiripentol in healthy adults. The 95% confidence intervals for the difference for Cmax and AUC of saquinavir between the placebo and stiripentol phase were (−39.8, 39.8) and (−33.2, 112), respectively.

Conclusions  These results showed that stiripentol was a weak inhibitor of saquinavir metabolism both in vitro and in vivo. In contrast, stiripentol is a potent inhibitor of carbamazepine 10,11‐epoxide formation in vitro and in vivo in epileptic patients.
Cost–utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy
Authors: McCrone Paul , Chisholm Daniel , Knapp Martin , Hughes Richard , Comi Giancarlo , Dalakas Marinos C. , Illa Isabel , Kilindireas Costas , Nobile‐Orazio Eduardo , Swan Anthony , Bergh Peter Van den , Willison Hugh J. ,   the INCAT Study Group
Published: October 2003

The aim of this study was to provide an incremental cost‐effectiveness analysis comparing intravenous immunoglobulin (IVIg) and prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy. Patients were recruited to a double‐blind randomized crossover trial from nine European centres and received either prednisolone or IVIg during the first 6‐week treatment period on which the economic evaluation was based. A societal perspective was adopted in measuring service use and costs, although the costs of lost employment were not included. The main outcome measure in the economic evaluation was the number of quality adjusted life years (QALYs) gained, with change in a 11‐point disability scale used to measure clinical outcomes. Service use and quality of life data were available for 25 patients. Baseline costs were controlled for using a bootstrapped multiple regression model. The cost difference between the two treatments was estimated to be €3754 over the 6‐week period. Health‐related quality of life, as measured by the EuroQol EQ‐5D instrument, increased more in the IVIg group but the difference was not statistically significant. Using a net‐benefit approach it was shown that the probability of IVIg being cost‐effective in comparison with prednisolone was 0.5 or above (i.e. was more likely to be cost‐effective than cost‐ineffective) only if one QALY was valued at over €250 000. The cost‐effectiveness of IVIg is greatly affected by the price of IVIg and the amount administered. The impact of later side‐effects of prednisolone on long‐term costs and quality of life are likely to reduce the cost per QALY of IVIg treatment.
Detection of malaria sporozoites by standard ELISA and VecTestTM dipstick assay in field‐collected anopheline mosquitoes from a malaria endemic site in Ghana
Authors: Appawu Maxwell A. , Bosompem Kwabena M. , Dadzie Samuel , McKakpo Uri S. , Anim‐Baidoo Isaac , Dykstra Elizabeth , Szumlas Daniel E. , Rogers William O. , Koram Kwadwo , Fryauff David J.
Published: October 2003

We compared the VecTestTM dipstick assay for detection of Plasmodium sporozoites in Anopheles vectors of malaria with standard circumsporozoite (CS) microplate ELISA for detection of Plasmodium falciparum circumsporozoite protein (PfCSP) in Anopheles mosquitoes. Mosquitoes were collected from a malaria endemic site (Kassena Nankana district) in northern Ghana. Of 2620 randomly sampled mosquitoes tested, the standard CS‐ELISA gave a sporozoite rate of 10.8% compared with 11.2% by VecTestTM, which was not statistically different (P = 0.66). Visual reading of the CS‐ELISA results gave a sporozoite rate of 13.4%, which was higher than the other tests (P > 0.05). To allow a more objective evaluation of the sensitivity of the dipstick, an additional 136 known CS‐ELISA‐positive specimens were analysed. The prevalence of the test (including the additional samples) was 14.6% and 14.7% for CS‐ELISA and dipstick, respectively (P > 0.05). The estimated prevalence by visual assessment of the CS‐ELISA results was 17.5%. The relative specificity and sensitivity of the VecTestTM dipstick and visually read ELISA were estimated based on the CS‐ELISA as a gold standard. The specificities of the dipstick and visual ELISA were high, 98.0% and 96.6%, respectively. However, the sensitivities of the two assays were 88.8% for VecTest and 100% for visual ELISA (P < 0.01). Concordance between VecTest and CS‐ELISA was good (κ = 0.86). Similarly, there was a good concordance between the dipstick and the visually read ELISA (κ =  0.88). Extrapolating from PfCSP controls (titrated quantities of P. falciparum sporozoites), mean sporozoite loads of CS‐ELISA‐positive An. gambiae (286 ± 28.05) and An. funestus (236 ± 19.32) were determined (P = 0.146). The visual dipstick grades showed high correlation with sporozoite load. The more intense the dipstick colour, the higher the mean sporozoite load (+ = 108, ++  = 207, +++ = 290, r = 0.99, r2 = 1). The VecTest dipstick offers practical advantages for field workers needing rapid and accurate means of detection of sporozoites in mosquitoes.
Polyparasitism with Schistosoma haematobium and soil‐transmitted helminth infections among school children in Loum, Cameroon
Authors: Tchuem Tchuenté L.‐A. , Behnke J. M. , Gilbert F. S. , Southgate V. R. , Vercruysse J.
Published: October 2003

Prevalence and abundance of Schistosoma haematobium and soil‐transmitted helminths (STH) were assessed among a total of 1600 pupils (urine, n = 1190; faecal samples, n = 1454) attending five schools in Loum, Littoral Province, Cameroon, with the specific aim of assessing the extent of polyparasitism and the extent to which infections were focused in particular subsets of the study group. Prevalence of S. haematobium was 62.8% with an abundance (arithmetic mean of egg counts) of 54 eggs/10 ml urine. For the STH these were 47.7% and 619 eggs per gram of faeces (EPG) for Trichuris trichiura, 65.5% and 3636 EPG for Ascaris lumbricoides, and 1.4% and <0.1 EPG for hookworms. Most children (90.3%) were infected with at least one of these four species, the largest proportion (34.3%) carrying two species; 27.4% carried three and 1.1% carried concurrently all four species of parasites. The average number of species harboured increased with age, as did the prevalences of S. haematobium and T. trichiura but not that of A. lumbricoides. All STH showed marked differences in prevalence between the five schools but only T. trichiura varied significantly between sexes. Mean abundance of infection varied significantly between age classes, among schools and between the sexes, with females showing heavier mean EPGs for A. lumbricoides and T. trichiura and males higher mean eggs/10 ml urine for S. haematobium infections. A highly significant association was detected between A. lumbricoides and T. trichiura, that was not context‐dependent. This was confirmed in quantitative analyses after controlling for differences in abundance between schools, sexes and age classes. A weaker context‐dependent association (prevalence data) was detected between S. haematobium and A. lumbricoides (sex‐ and age‐dependent) but quantitative associations between these two species, as well as between S. haematobium and T. trichiura, were not convincing.
Transmission of Helicobacter pylori infection in families of preschool‐aged children from Minas Gerais, Brazil
Authors: Rocha Gifone Aguiar , Rocha Andreia Maria Camargos , Silva Luciana Diniz , Santos Adriana , Bocewicz Ana Carolina Dias , Queiroz Renata de Magalhães , Bethony Jeffrey , Gazzinelli Andréa , Corrêa‐Oliveira Rodrigo , Queiroz Dulciene Maria Magalhães
Published: October 2003

We evaluated the role of the family in the transmission of Helicobacter pylori infection in preschool‐aged children from a rural district in the State of Minas Gerais, Brazil. Sixty‐six families (66 index children, 63 mothers, 60 fathers and 134 siblings), defined as at least one parent living in the same household with at least one offspring up to 8 years old, were studied. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression controlling for age, gender, number of children in household and H. pylori status of the father, mother and siblings. The prevalence of the infection was 69.7% (469 of 673) and it increased with age (P < 0.001). Positive mothers were a strong and independent risk factor for infection (OR 22.70; 95% CI 2.31–223.21). Positive siblings were also positively associated with infection (OR 1.81; 95% CI 1.01–3.30).
Breastfeeding status as a predictor of mortality among refugee children in an emergency situation in Guinea‐Bissau
Authors: Jakobsen Marianne , Sodemann Morten , Nylén Gunnar , Balé Carlitos , Nielsen Jens , Lisse Ida , Aaby Peter
Published: October 2003

Objective To identify the population risk factors in emergency situations, we studied breastfeeding status as a predictor for child mortality during a war in Guinea‐Bissau.

Methods Data on breastfeeding status are routinely collected by the surveillance system of the Bandim Health Project in Bissau. We used data collected during a 3‐month period prior to the war in Guinea‐Bissau in June 1998 to assess the impact of breastfeeding status on mortality in an emergency. We compared the war cohort with two cohorts of children who had had their breastfeeding status assessed in a similar way by the surveillance system in the 3 months prior to June 1996 and June 1997. As very few are weaned prior to 9 months of age and the median age of weaning is 22 months, we assessed the risk of dying over a 3‐month period for breastfed and weaned children aged 9–20 months.

Results Controlling for age, weaned children experienced a sixfold higher mortality [mortality rate (MR) = 5.73 (95% CI 2.40–13.71)] during the first 3 months of the war compared with children still breastfeeding. In the two control cohorts from 1996 and 1997, weaned children did not have higher mortality than the breastfed children over a similar 3‐month period. Mortality in weaned children was five times higher [MR = 4.96 (1.44–16.63)] during the first 3 months of the conflict than in a similar group of weaned children from early June 1996 and June 1997, whereas there was no significant difference in mortality between breastfed children during the conflict and the preceding years [MR = 1.46 (0.84–2.55)]. Control for other background factors, including living with mother, gender, ethnic group, mother's schooling and district, did not change these differences.

Conclusion The protective effect of breastfeeding against infections may be particularly important in emergencies. Continuing or recommencing breastfeeding should be emphasized in emergency situations.
Integrated community‐directed treatment for the control of onchocerciasis, schistosomiasis and intestinal helminths infections in Uganda: advantages and disadvantages
Authors: Ndyomugyenyi Richard , Kabatereine Narcis
Published: October 2003

Onchocerciasis is co‐endemic with schistosomiasis and intestinal helminths infections, which are all diseases of the rural and the poorest communities in Africa. Community‐directed treatment (ComDT) for the control of onchocerciasis is the only functional health approach in most of these communities and the strategy has proven to be effective for onchocerciasis control. This study was conducted to assess the feasibility of integrating ComDT with ivermectin for the control of onchocerciasis, and with praziquantel (PZQ) and mebendazole (MBD) for the control of schistosomiasis and intestinal helminths infections in children aged 5–14 years, and to assess advantages and disadvantages of the integrated ComDT over the routine ComDT and the school‐based treatment approach. Integrated ComDT achieved higher treatment coverage (85%) for PZQ and MBD than the school‐based treatment approach (79%) among children aged 5–14 years (P = 0.03). There were more reported adverse reactions after treatment with a combination of PZQ and MBD in the school‐based treatment approach (33%) than for the combination of ivermectin and MBD on day 1 and PZQ on day 2 in the integrated ComDT (18%). However, all adverse reactions were mild (headache, nausea/vomiting and abdominal pain). The integrated ComDT also achieved higher ivermectin treatment coverage for all ages (81.3%) than routine ComDT (77.2%) (P = 0.0003). To achieve even better coverage for PZQ and MBD among the targeted high risk groups, integrated ComDT should treat all age groups in areas where the prevalence of schistosomiasis and intestinal helminths infections is >50%. This would minimize the shortage of the drugs targeted to treat the high risk groups, as the non‐targeted groups, will inevitably demand and receive the treatment from the distributors. The results of this study show that PZQ and MBD treatment for the control of schistosomiasis and intestinal helminths, respectively, can be integrated with ivermectin treatment for the control of onchocerciasis without negatively affecting ivermectin treatment coverage.
Field efficacy of thermally expelled or live potted repellent plants against African malaria vectors in western Kenya
Authors: Seyoum Aklilu , Killeen Gerry F. , Kabiru Ephantus W. , Knols Bart G. J. , Hassanali Ahmed
Published: October 2003

Objective To estimate the effectiveness of live potted plants and thermal expulsion of plant materials in repelling African malaria vectors in traditional houses in western Kenya.

Methods Ocimum americanum, Lantana camara and Lippia ukambensis were tested in live, intact potted form whereas leaves of Corymbia citriodora, leaves and seeds of O. kilimandscharicum and O. suave were tested by thermal expulsion from modified traditional stoves. A latin square design was applied for randomly assigning the treatment and control plants to experimental houses over different nights.

Results All plant species showed significant repellency against Anopheles gambiae sensu lato Giles (Diptera: Culicidae) (81.5%An. arabiensis Patton and 18.5%An. gambiae sensu stricto Giles), the main vectors of malaria in Africa, with the highest repellency by C. citriodora (48.71%, P < 0.0001) followed by an equal level of repellency of O. kilimandscharicum and O. suave (44.54%, P = 0.001) during application of plant material by thermal expulsion. All three plant species also showed a residual effect against An. gambiae s.l. with 36–44% repellency post‐application period (22.30–06.30 hours) after a period of thermal expulsion. Similarly, intact potted plants of O. americanum and L. camara repelled An. gambiae s.l. significantly (37.91%, P = 0.004; and 27.22%, P = 0.05, respectively). Thermal expulsion of leaves and seeds of O. kilimandscharicum significantly repelled An. funestus Giles, although none of the potted plants repelled this species.

Conclusion Both methods of application may offer cost‐effective alternatives as additional means of household protection, and a useful complement to bed nets, particularly for the early part of the evening before bedtime.
CTLA‐4 positive T cells in contrast to procalcitonin plasma levels discriminate between severe and uncomplicated Plasmodium falciparum malaria in Ghanaian children
Authors: Braun Nele , Marfo Yeboah , Von Gärtner Christiane , Burchard Gerd D. , Zipfel P. F. , Browne N. Edmund N. , Fleischer Bernhard , Bröker Barbara M.
Published: October 2003

Procalcitonin (PCT) plasma levels and the fraction of CTLA‐4‐positive T cells are both elevated in acute Plasmodium falciparum malaria in human adults and the degree of elevation is positively correlated with other markers of disease severity, for example with parasitaemia. However, the clinical manifestations of malaria are strongly age‐dependent and children from endemic areas carry the main disease burden. Therefore, we measured PCT plasma levels and CTLA‐4 expression by T cells in four groups of children from the Ashanti Region in Ghana: asymptomatic children with or without parasitaemia, children with uncomplicated P. falciparum malaria and children with severe disease. PCT levels were highly elevated in both groups with acute malaria but they did not discriminate between uncomplicated and severe disease. In contrast, CTLA‐4‐expression by T cells was increased only in severe malaria. The fraction of CTLA‐4 positive T cells in the blood of children with severe disease differed significantly from that in uncomplicated malaria, which was not elevated in spite of the high parasite loads observed in these children. This was unexpected, as in adults uncomplicated malaria is associated with a dramatic sixfold increase of the fraction of CTLA‐4‐positive T cells. The data from this study support the hypothesis that strong T cell activation as measured here by CTLA‐4 expression is not just the by‐product of a high parasite burden, but that it contributes to the pathogenesis of P. falciparum malaria.
Use of glycerol as an alternative to freeze‐drying for long‐term preservation of antigen for the direct agglutination test
Authors: Harith Abdallah el , Mutasim Mohamed el , Mansour Durria , Fadil Mustafa El , Arvidson Harold
Published: October 2003

The potential of glycerol for long‐term preservation of the direct agglutination test (DAT) antigen was evaluated at a fluctuating laboratory temperature of 25–37 °C and at constant temperatures of 37 and 45 °C for a period of 222 days. DAT titres recorded for the three antigen aliquots preserved in 50% (v/v) glycerol and stored at 25–37, 37 or 45 °C at 11 time intervals were within the same range of the control antigen kept at 4 °C. Performance of the glycerol‐preserved antigen stored at 45 °C was compared with that of a freeze‐dried version on 24 visceral leishmaniasis (VL) and 54 non‐VL patients. For all non‐VL patients, a maximum DAT titre of 1/800 was recorded for either of the two antigens. For all VL patients, in comparison with the freeze‐dried, the glycerol‐preserved antigen always had equal or higher titre; in 16 of the 24 VL sera tested, the latter antigen scored three‐ to sixfold higher titres. As this glycerol preservation method is economical and easy to perform, it has better potential for wider‐scale application than freeze‐drying.
Treatment of amoebic liver abscess with metronidazole alone or in combination with ultrasound‐guided needle aspiration: a comparative, prospective and randomized study
Authors: Blessmann Joerg , Binh Ho Duy , Hung Duong Manh , Tannich Egbert , Burchard Gerd
Published: October 2003

Thirty‐nine patients with amoebic liver abscess (ALA), admitted to the Central Hospital of Hué (Vietnam), were evaluated in a comparative, prospective and randomized study for the treatment of ALA. Adult patients with an abscess located in the right liver lobe and an abscess diameter of 6 to 10 cm were included. Bacterial abscesses were excluded by microbiological examination of abscess fluid in all patients. Nineteen patients were treated with metronidazole for 10 days alone and 20 patients were punctured under ultrasound guidance with aspiration of abscess fluid in addition to drug administration. The clinical symptoms fever, pain in right upper abdomen and liver tenderness, and the laboratory parameters erythrocyte sedimentation rate, white blood cells, haemoglobin and C‐reactive protein and the abscess size were determined on the day of admission and followed during an observation period of 38 days. Improvement of liver tenderness was significantly faster in the aspiration group during the first 3 days (P < 0.001), whereas all the other parameters showed no differences between the two groups. This minor benefit is obviously not sufficient to justify routine needle aspiration and advocates drug treatment alone for uncomplicated amoebic liver abscesses with a diameter up to 10 cm located in the right liver lobe.
Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma
Authors: Lee Daniel K. C. , Jackson Catherine M. , Currie Graeme P. , Cockburn Wendy J. , Lipworth Brian J.
Published: October 2003

Aims  Inhalers combining long acting β2‐adrenoceptor agonists (LABA) and corticosteroids (ICS) are indicated at Step 3 of current asthma guidelines. We evaluated the relative effects of LABA + ICS combination vs ICS alone on pulmonary function, bronchoprotection, acute salbutamol recovery following methacholine bronchial challenge, and surrogate inflammatory markers in patients with moderate persistent asthma.

Methods  Twenty‐nine patients with mean FEV1 (± SEM) of 78 ± 3% predicted completed a randomized, double‐blind, double‐dummy, cross‐over study. Patients received either 4 weeks of budesonide 400 µg + formoterol 12 µg (BUD + FM) combination twice daily followed by 1 week of BUD 400 µg alone twice daily, or 4 weeks of fluticasone propionate 250 µg + salmeterol 50 µg (FP + SM) combination twice daily followed by 1 week of FP 250 µg alone twice daily. Measurements were made at baseline and following each randomized treatment.

Results  FEV1 increase from pretreatment baseline as mean (± SEM) % predicted was significantly higher (P < 0.05) for BUD + FM (8 ± 1%) vs BUD (2 ± 1%), and for FP + SM (8 ± 1%) vs FP (2 ± 1%). The fall in FEV1 following methacholine challenge as percentage change from prechallenge baseline FEV1 was not significantly different in all four groups; BUD + FM (22 ± 1%), BUD (24 ± 1%), FP + SM (23 ± 1%) and FP (23 ± 1%). Salbutamol recovery over 30 min following methacholine challenge as area under curve (AUC %.min) was significantly blunted (P < 0.05) with BUD + FM (486.7 ± 35.5) vs BUD (281.1 ± 52.8), and with FP + SM (553.1 ± 34.1) vs FP (368.3 ± 46.7). There were no significant differences between respective combination inhalers or between respective ICS alone. Decreases in exhaled nitric oxide (NO) and serum eosinophilic cationic protein (ECP) from baseline were not significantly different between treatments.

Conclusions  Combination inhalers improve pulmonary function without potentiating anti‐inflammatory effects on exhaled NO and serum ECP as compared with ICS alone, but delay acute salbutamol recovery after bronchoconstriction.
Ultramolecular homeopathy has no observable clinical effects. A randomized, double‐blind, placebo‐controlled proving trial of Belladonna 30C
Authors: Brien Sarah , Lewith George , Bryant Trevor
Published: October 2003

Aims  To investigate if ultramolecular homeopathy has any clinical effects. This was assessed using the proving of the homeopathic remedy Belladonna given at an ultramolecular dose (30C), as a model. A proving states that when a homeopathic remedy is given to a healthy person, they will experience symptomatic effects specific to that remedy. If ultramolecular doses are clinically active, the Belladonna 30C group should experience more true Belladonna proving symptoms than the placebo group.

Methods  Healthy subjects (n = 253), aged 18–30 years, took part in this double‐blind, randomized placebo‐controlled study. Total study duration was 4 weeks. Subjects were randomized before 1 week placebo run‐in. They received 2 weeks of treatment intervention (Belladonna 30C or placebo) and were followed up for 1 week. Subjects recorded any symptoms experienced during the total study period on a daily basis using a structured questionnaire. Symptom diaries were analysed blind to determine if each subject had proved or not (based on predefined criteria). The main outcome was the proportion of subjects who had proved in each treatment group.

Results  No significant group differences in proving rates were observed [Belladonna provers N = 14 (13.9%); placebo provers N = 15 (14.3%); mean difference − 0.4%, 95% confidence interval − 9.3, 10.1] based on intention to treat analysis. Primary outcome was not affected by seasonality or the individual's attitude to complementary medicine.

Conclusion  Ultramolecular homeopathy had no observable clinical effects.
Changes in antipsychotic drug prescribing by general practitioners in the United Kingdom from 1991 to 2000: a population‐based observational study
Authors: Kaye James A. , Bradbury Brian D. , Jick Hershel
Published: October 2003

Aim  To estimate changes in the frequency of use of various antipsychotic drugs in the UK from 1991 to 2000 and to relate these changes to patients’ characteristics.

Methods  We conducted a population‐based observational study using data from general practices that contribute information to the General Practice Research Database (GPRD). The study population comprised men and women 10–99 years old. We estimated annual use, first‐time use, duration of use and, in a sample of 200 patients, indications for use of various antipsychotic drugs, and we observed how these measures had changed over the past decade.

Results  The annual use of antipsychotic drugs increased from 10.5 per thousand in 1991 to 12.2 per thousand in 2000, an overall increase of 16%. The increase was greater in men (25.2%) than women (2.7%). At the same time, the rate of new use of antipsychotic drugs was stable in men and decreased by 21% in women. The difference between patterns of annual use and rates of new use is attributable to the increasing average annual duration of treatment in both men and women during the past decade. Thioridazine, which the UK Committee on the Safety of Medicines (CSM) recently recommended should be used only for second‐line treatment of schizophrenia in adults, was the most commonly prescribed antipsychotic throughout the study period. Its use increased as a proportion of all antipsychotic drug use from 1991 to 2000 in men and women aged 10–69 years, but decreased in older users. More than half of all first‐time use of antipsychotic drugs in the sample of patients we evaluated was for treatment of depression, anxiety states, and panic disorders, while less than 10% was for treatment of schizophrenia and other psychoses.

Conclusion  The use of antipsychotic drugs has increased in the UK during the past decade, primarily due to increased average annual duration of use rather than higher rates of new use. Most antipsychotic drug use appears to have been prescribed to treat nonpsychotic disorders. It will be of interest to see whether the use of thioridazine, which was the most widely prescribed antipsychotic during 1991–2000, decreases during the next decade in response to the recent CSM recommendation.
Neonatal intraventricular haemorrhage associated with maternal use of paroxetine
Authors: Duijvestijn Yvonne C. M. , Kalmeijer Mathijs D. , Passier Anneke L. M. , Dahlem Peter , Smiers Frans
Published: October 2003

Selective serotonin reuptake inhibitors (SSRIs) have been reported to inhibit serotonin uptake into platelets, resulting in decreased platelet function. We report a case of a large intraventricular haemorrhage in a 6‐h‐old boy, whose mother used paroxetine during pregnancy.
Free and bound propofol concentrations in human cerebrospinal fluid
Authors: Dawidowicz Andrzej L. , Kalitynski Rafal , Fijalkowska Anna
Published: October 2003

Aims  The aim of this study was to define the relationship between unbound propofol concentrations in plasma and total drug concentrations in human cerebrospinal fluid (CSF), and to determine whether propofol exists in the CSF in bound form.

Methods  Forty‐three patients (divided into three groups) scheduled for elective intracranial procedures and anaesthetized by propofol target control infusion (TCI) were studied. Blood and CSF samples (taken from the radial artery, and the intraventricular drainage, respectively) from group I (17 patients) were used to investigate the relationship between unbound propofol concentration in plasma and total concentration of the drug in CSF. CSF samples taken from group II (18 patients) were used to confirm the presence of the bound form of propofol in this fluid. The CSF and blood samples taken from group III (eight patients) were used to monitor the course of free and bound CSF propofol concentrations during anaesthesia.

Results  For group I patients the mean (and 95% confidence interval) total plasma propofol concentration was 6113 (4971, 7255) ng ml−1, the mean free propofol concentration in plasma was 63 (42, 84) ng ml−1, and the mean total propofol concentration in CSF was 96 (76, 116) ng ml−1 (P < 0.05 for the difference between the last two values). For group II patients the fraction of free propofol in CSF was 31 (26, 37)%. For group III patients the fraction of free propofol in CSF during TCI was almost constant (about 36%).

Conclusions  The unbound propofol concentration in plasma was not equal to its total concentration in CSF and cannot be directly related to the drug concentration in the brain. Binding of propofol to components of the CSF may be an additional mechanism regulating the transport of the drug from blood into CSF.
Quinine intoxications reported to the Scottish Poisons Information Bureau 1997–2002: a continuing problem
Authors: Langford N. J. , Good A. M. , Laing W. J. , Bateman D. N.
Published: October 2003

Quinine is widely prescribed in the UK for night cramps. Its potential toxicity in overdose is well known. We have reviewed the Scottish experience of enquiries regarding quinine overdose to the poisons information service responsible for Scotland over a 6‐year period. Between 1997 and 2002 there were 96 reports of suspected quinine toxicity from Scotland (population 5.2 million), 19 of which were in children. The largest quantities of drug ingested were in patients between the ages of 11 and 30. In comparison with older studies the pattern of quinine poisoning does not appear to have changed in the UK over 20 years, despite recognition that it is a toxic agent in overdose, and particularly in children.
An in vitro interethnic comparison of monoamine oxidase activities between Japanese and Caucasian livers using rizatriptan, a serotonin receptor 1B/1D agonist, as a model drug
Authors: Iwasa T. , Sano H. , Sugiura A. , Uchiyama N. , Hara K. , Okochi H. , Nakagawa K. , Yasumori T. , Ishizaki T.
Published: October 2003

Aims  Monoamine oxidase (MAO) is located in human liver, and catalyses the oxidative deamination step of many xenobiotics. However, whether there exists an interethnic difference in MAO activities has, to our knowledge, not been clarified. We aimed to assess the MAO type A (MAO‐A) involvement in the metabolic pathway of rizatriptan (RIZ), an antimigraine 5‐hydroxytryptamine (5‐HT)1B/1D agonist, and the interethnic difference in MAO activities between Caucasians and Japanese using RIZ as a model drug in in vitro experiments.

Methods  Oxidative deaminase activities were determined with the subcellular fractions of Japanese livers and the microsomal fraction of Caucasian livers using RIZ, 5‐HT (MAO‐A substrate) and 2‐phenylethylamine (PEA) (MAO‐B substrate) as substrates.

Results  The oxidative deaminase activities of RIZ vs. 5‐HT were highly (r = 0.87 and 0.96, P < 0.001) correlated with each other in both the microsomal and mitochondrial fractions of Japanese livers. Subsequent results were obtained from in vitro experiments using liver microsomes based upon these findings. The oxidative deaminase activities of RIZ were inhibited completely by the nanomolar‐order concentration of clorgyline and Ro 41‐1049 (MAO‐A selective inhibitors), but not by that of Ro 16‐6491 (MAO‐B selective inhibitor). The majority of the mean Michaelis–Menten values for three substrates toward MAO obtained from six Japanese and six Caucasian liver microsomes reached no significant differences between the two ethnic groups. The mean microsomal oxidative deaminase activities assessed in 18 Japanese and 20 Caucasian livers using the three substrates also showed no significant differences between the two ethnic groups.

Conclusions  RIZ is mainly metabolized by MAO‐A and the in vitro oxidative deaminase activities mediated via MAO‐A and ‐B do not appear to differ between Japanese and Caucasians.
Evaluation of two carrier protein–angiotensin I conjugate vaccines to assess their future potential to control high blood pressure (hypertension) in man
Authors: Downham M. R. , Auton T. R. , Rosul A. , Sharp H. L. , Sjöström L. , Rushton A. , Richards J. P. , Mant T. G. K. , Gardiner S. M. , Bennett T. , Glover J. F.
Published: October 2003

Aims  We aim to modulate the renin–angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man.

Methods  Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue (AI). Cardiovascular responses were assessed in immunized rats and human subjects (two‐dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII).

Results  The AI–TT and AI–KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single‐dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two‐dose clinical trial of AI–KLH conjugate vaccine resulted in a significant immune response to AI. A shift in diastolic blood pressure (DBP) dose–response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti‐AI IgG induction.

Conclusion  KLH was shown to be a suitable alternative to TT as a carrier protein for AI, thus supporting continued evaluation of our AI–KLH conjugate vaccine for treatment of hypertension in man.
Steady‐state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients
Authors: Belldina Eric B. , Huang Mei Y. , Schneider Jerry A. , Brundage Richard C. , Tracy Timothy S.
Published: October 2003

Aims  Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis.

Methods  Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single‐dose, open‐label, steady‐state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic–pharmacodynamic model.

Results  Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min−1 kg−1, range = 17.3–52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7–32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post‐dosing was significantly decreased compared with pre‐ and post‐dose values (average decrement approximately 47%). A counter‐clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22–0.92) between drug concentration and effect.

Conclusions  The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.
Human subcutaneous tissue distribution of fluconazole: comparison of microdialysis and suction blister techniques
Authors: Sasongko Lucy , Williams Kenneth M. , Day Richard O. , McLachlan Andrew J.
Published: October 2003

Aims  To investigate uptake of fluconazole into the interstitial fluid of human subcutaneous tissue using the microdialysis and suction blister techniques.

Methods  A sterile microdialysis probe (CMA/60) was inserted subcutaneously into the upper arm of five healthy volunteers following an overnight fast. Blisters were induced on the lower arm using gentle suction prior to ingestion of a single oral dose of fluconazole (200 mg). Microdialysate, blister fluid and blood were sampled over 8 h. Fluconazole concentrations were determined in each sample using a validated HPLC assay. In vivo recovery of fluconazole from the microdialysis probe was determined in each subject by perfusing the probe with fluconazole solution at the end of the 8 h sampling period. Individual in vivo recovery was used to calculate fluconazole concentrations in subcutaneous interstitial fluid. A physiologically based pharmacokinetic (PBPK) model was used to predict fluconazole concentrations in human subcutaneous interstitial fluid.

Results  There was a lag‐time (approximately 0.5 h) between detection of fluconazole in microdialysate compared with plasma in each subject. The in vivo recovery of fluconazole from the microdialysis probe ranged from 57.0 to 67.2%. The subcutaneous interstitial fluid concentrations obtained by microdialysis were very similar to the unbound concentrations of fluconazole in plasma with maximum concentration of 4.29 ± 1.19 µg ml−1 in subcutaneous interstitial fluid and 3.58 ± 0.14 µg ml−1 in plasma. Subcutaneous interstitial fluid‐to‐plasma partition coefficient (Kp) of fluconazole was 1.16 ± 0.22 (95% CI 0.96, 1.35). By contrast, fluconazole concentrations in blister fluid were significantly lower (P < 0.05, paired t‐test) than unbound plasma concentrations over the first 3 h and maximum concentrations in blister fluid had not been achieved at the end of the sampling period. There was good agreement between fluconazole concentrations derived from microdialysis sampling and those estimated using a blood flow‐limited PBPK model.

Conclusions  Microdialysis and suction blister techniques did not yield comparable results. It appears that microdialysis is a more appropriate technique for studying the rate of uptake of fluconazole into subcutaneous tissue. PBPK model simulation suggested that the distribution of fluconazole into subcutaneous interstitial fluid is dependent on tissue blood flow.