Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status?

AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

The Digestive Diverticula in the Carnivorous Nudibranch, Melibe leonina, Do Not Contain Photosynthetic Symbionts.

A number of nudibranchs, including Melibe engeli and Melibe pilosa, harbor symbiotic photosynthetic zooxanthellae. Melibe leonina spends most of its adult life on seagrass or kelp, capturing planktonic organisms in the water column with a large, tentacle-lined oral hood that brings food to its mouth. M. leonina also has an extensive network of digestive diverticula, located just beneath its translucent integument, that are typically filled with pigmented material likely derived from ingested food. Therefore, the focus of this project was to test the hypothesis that M. leonina accumulates symbiotic photosynthetic dinoflagellates in these diverticula. First, we conducted experiments to determine if M. leonina exhibits a preference for light, which would allow chloroplasts that it might be harboring to carry out photosynthesis. We found that most M. leonina preferred shaded areas and spent less time in direct sunlight. Second, we examined the small green circular structures in cells lining the digestive diverticula. Like chlorophyll, they exhibited autofluorescence when illuminated at 480 nm, and they were also about the same size as chloroplasts and symbiotic zooxanthellae. However, subsequent electron microscopy found no evidence of chloroplasts in the digestive diverticula of M. leonina; the structures exhibiting autofluorescence at 480 nm were most likely heterolysosomes, consistent with normal molluscan digestion. Third, we did not find evidence of altered oxygen consumption or production in M. leonina housed in different light conditions, suggesting the lack of any significant photosynthetic activity in sunlight. Fourth, we examined the contents of the diverticula, using HPLC, thin layer chromatography, and spectroscopy. The results of these studies indicate that the diverticula did not contain any chlorophyll, but rather harbored other pigments, such as astaxanthin, which likely came from crustaceans in their diet. Together, all of these data suggest that M. leonina does sequester pigments from its diet, but not for the purpose of symbiosis with photosynthetic zooxanthellae. Considering the translucent skin of M. leonina, the pigmented diverticula may instead provide camouflage.

Varios nudibranquios, incluidos Melibe engeli y Melibe pilosa, albergan zooxantelas fotosintéticas simbióticas. Melibe leonina pasa la mayoría de su vida adulta en pastos marinos o quelpo, donde captura organismos planctónicos en la columna de agua con una gran capucha oral forrada por tentáculos que llevan comida a su boca. Melibe leonina también tiene una extensa red de divertículos digestivos, ubicados justo debajo de su tegumento translúcido, que generalmente están llenos de material pigmentado probablemente derivado de alimentos ingeridos. Por lo tanto, el objetivo de este proyecto fue evaluar la hipótesis de que M. leonina acumula dinoflagelados fotosintéticos simbióticos en estos divertículos. Primero, realizamos experimentos para determinar si M. leonina se orienta hacia la luz, lo cual permitiría a los cloroplastos que podría albergar el realizar la fotosíntesis. Descubrimos que la mayoría de M. leonina prefería las áreas sombreadas y pasaba menos tiempo bajo la luz solar directa. En segundo lugar, examinamos las pequeñas estructuras circulares verdes en las células que recubren los divertículos digestivos. Al igual que la clorofila, exhibieron autofluorescencia cuando se iluminaban a 480 nm, y también tenían aproximadamente el mismo tamaño que los cloroplastos y las zooxantelas simbióticas. No obstante, la microscopía electrónica no produjo evidencia de cloroplastos en los divertículos digestivos de M. leonina. Es probable que las estructuras que exhibieron autofluorescencia en 480 nm fuesen heterolisosomas, lo cual es consistente con la digestión normal de moluscos. En tercer lugar, no encontramos evidencia de un consumo o producción de oxígeno alterado en M. leonina alojadas varias condiciones lumínicas, lo cual sugiere la ausencia de actividad fotosintética significativa en la presencia de luz solar. En cuarto lugar, examinamos el contenido de los divertículos mediante HPLC, cromatografía en capa fina, y espectroscopia. Los resultados de estos estudios indican que los divertículos no contenían clorofila, pero si otros pigmentos como la astaxantina que probablemente provenía de crustáceos en su dieta. Nuestros datos sugieren que M. leonina secuestra pigmentos de su dieta, pero no con el propósito de la simbiosis con zooxantelas fotosintéticas. Teniendo en cuenta la piel translúcida de M. leonina, los divertículos pigmentados podrían quizás proporcionar camuflaje.

Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence.

Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short-term, their use is often limited by concerns over long-term toxicity, including end-organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long-term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.

C57BL/6J mice exhibit reduced dopamine D3 receptor-mediated locomotor-inhibitory function relative to DBA/2J mice.

Previous reports have identified greater sensitivity to the locomotor-stimulating, sensitizing, and reinforcing effects of amphetamine in inbred C57BL/6J mice relative to inbred DBA/2J mice. The dopamine D3 receptor (D3R) plays an inhibitory role in the regulation of rodent locomotor activity, and exerts inhibitory opposition to D1 receptor (D1R)-mediated signaling. Based on these observations, we investigated D3R expression and D3R-mediated locomotor-inhibitory function, as well as D1R binding and D1R-mediated locomotor-stimulating function, in C57BL/6J and DBA/2J mice. C57BL/6J mice exhibited lower D3R binding density (-32%) in the ventral striatum (nucleus accumbens/islands of Calleja), lower D3R mRNA expression (-26%) in the substantia nigra/ventral tegmentum, and greater D3R mRNA expression (+40%) in the hippocampus, relative to DBA/2J mice. There were no strain differences in DR3 mRNA expression in the ventral striatum or prefrontal cortex, nor were there differences in D1R binding in the ventral striatum. Behaviorally, C57BL/6J mice were less sensitive to the locomotor-inhibitory effect of the D3R agonist PD128907 (10 microg/kg), and more sensitive to the locomotor-stimulating effects of novelty, amphetamine (1 mg/kg), and the D1R-like agonist +/- -1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8,-diol hydrochloride (SKF38393) (5-20 mg/kg) than DBA/2J mice. While the selective D3R antagonist N-(4-[4-{2,3-dichlorphenyl}-1 piperazinyl]butyl)-2-fluorenylcarboxamide (NGB 2904) (0.01-1.0 mg/kg) augmented novelty-, amphetamine-, and SKF38393-induced locomotor activity in DBA/2J mice, it reduced novelty-induced locomotor activity in C57BL/6J mice. Collectively, these results demonstrate that C57BL/6J mice exhibit less D3R-mediated inhibitory function relative to DBA/2J mice, and suggest that reduced D3R-mediated inhibitory function may contribute to heightened sensitivity to the locomotor-stimulating effects of amphetamine in the C57BL/6J mouse strain. Furthermore, these data demonstrate that comparisons between C57BL/6J and DBA/2J mouse strains provide a model for elucidating the molecular determinants of genetic influence on D3R function.

Effect of nitrous acid on lung function in asthmatics: a chamber study.

Nitrous acid, a component of photochemical smog and a common indoor air pollutant, may reach levels of 100 ppb where gas stoves and unvented portable kerosene heaters are used. Nitrous acid is a primary product of combustion and may also be a secondary product by reaction of nitrogen dioxide with water. Because the usual assays for nitrogen dioxide measure several oxides of nitrogen (including nitrous acid) together, previous studies of indoor nitrogen dioxide may have included exposure to and health effects of nitrous acid. To assess the respiratory effects of nitrous acid exposure alone, we carried out a double-blinded crossover chamber exposure study with 11 mildly asthmatic adult subjects. Each underwent 3-hr exposures to 650 ppb nitrous acid and to filtered room air with three 20-min periods of moderate cycle exercise. Symptoms, respiratory parameters during exercise, and spirometry after exercise were measured. A statistically significant decrease in forced vital capacity was seen on days when subjects were exposed to nitrous acid. This effect was most marked at 25 min and 85 min after exposure began. Aggregate respiratory and mucous membrane symptoms were also significantly higher with nitrous acid. We conclude that this concentration and duration of exposure to nitrous acid alters lung mechanics slightly, does not induce significant airflow obstruction, and produces mild irritant symptoms in asthmatics.

Phase I clinical trial of drug-monoclonal antibody conjugates in patients with advanced colorectal carcinoma: a preliminary report.

Melphalan (MEL), an alkylating agent, has been modified to a derivative, N-acetylmelphalan (N-AcMEL), which can be conjugated to anticolon cancer monoclonal antibodies (MoAbs 30.6, I-1, and JGT) and used for immunochemotherapy. The final immunoconjugates possess potent cytotoxicity and specificity in preclinical studies. In a phase I clinical study, N-AcMEL-MoAb conjugates were administered via the hepatic artery to 10 patients, nine of whom had disseminated colorectal cancer (including the liver) and one of whom had Dukes' C colon cancer that had been resected. The selection of MoAb was based on the immunoperoxidase staining of the primary colon cancer tissue. Thus far doses of 1000 mg/m2 MoAb conjugated to 20 mg/m2 of N-AcMEL have been administered with no significant side effects, whereas MEL unconjugated to monoclonal antibodies would have caused myelosuppression in a proportion of patients at the same dosage. Serum antimouse antibody responses were noted in all of the patients; febrile reactions were noted with higher doses but were easily controlled with antipyretics, antihistamines and, if necessary, steroids. Serum sickness developed in one patient who was given a second course of treatment in the presence of human antimouse antibody, but the episode was self-limiting. Eight of the 10 patients had evaluable disease. Subjective improvement was noted in almost all of the patients examined, and 33%, or 3 of 9, of the treatments (nine courses of treatment in eight patients with evaluable disease; one of the patients had two courses of treatment) led to antitumor responses (minor response) by objective assessment with computed tomography of the liver. It is important to note that treatment with N-AcMEL-MoAb conjugates was safe at a dose of 20 mg/m2 of N-AcMEL, whereas the efficacy of such a form of treatment remains to be determined.

A dual mesh scheme for finite element based reconstruction algorithms.

The finite element (FE) method has found several applications in emerging imaging modalities, especially microwave imaging which has been shown to be potentially useful in a number of areas including thermal estimation. In monitoring temperature distributions, the biological phenomena of temperature variations of tissue dielectric properties is exploited. By imaging these properties and their changes during such therapies as hyperthermia, temperature distributions can be deduced using difference imaging techniques. The authors focus on a microwave imaging problem where the hybrid element (HE) method is used in conjunction with a dual mesh scheme in an effort to image complex wavenumbers, k(2). The dual mesh scheme is introduced to improve the reconstructed images of tissue properties and is ideally suited for systems using FE methods as their computational base. Since the electric fields typically vary rapidly over a given body when irradiated by high-frequency electromagnetic sources, a dense mesh is needed for these fields to be accurately represented. Conversely, k(2) may be fairly constant over subregions of the body which would allow for a less dense sampling of this parameter in those regions. In the dual mesh system employed, the first mesh, which is uniformly dense, is used for calculating the electric fields over the body whereas the second mesh, which is nonuniform and less dense, is used for representing the k(2) distribution within the region of interest. The authors examine the 2-D TM polarization case for a pair of dielectric distributions on both a large and small problem to demonstrate the flexibility of the dual mesh method along with some of the difficulties associated with larger imaging problems. Results demonstrate the capabilities of the dual mesh concept in comparison to a single mesh approach for a variety of test cases, suggesting that the dual mesh method is critical for FE based image reconstruction where rapidly varying physical quantities are used to recover smoother property profiles, as can occur in microwave imaging of biological bodies.

Adult non-endemic Burkitt's lymphoma. An Australian case report.

This report describes the occurence in Australia of non-endemic Burkitt's lymphoma in a 43-yr-old European migrant. The patient presented with cervical lymphadenopathy and massive bone marrow involvement, and died 6 mth later with intracranial spread of the tumour. The pathological features, course and treatment of the disease are described.

Obstetric outcomes and infant birthweights for Vietnamese-born and Australian-born women in southwestern Sydney.

The southwestern Sydney area has the highest population of Vietnamese immigrants in New South Wales. The purpose of this study was to identify differences in obstetric outcomes and birthweights of infants of Vietnamese-born women and Australian-born women in southwestern Sydney during 1991. There was a higher incidence of gestational diabetes and a lower incidence of pre-eclampsia in Vietnamese-born women. The rate of induction of labour for Australian-born women (23.7 per cent) was almost double the rate for Vietnamese-born women (12.9 per cent). Birthweights of infants of vietnamese-born women were significantly lower at the 10th, 50th and 90th percentile. The use of racially appropriate growth charts will reduce overdiagnosis of growth-restricted infants and therefore unnecessary treatment. These findings highlight the need to take ethnic differences into account when planning health care.

Turgecaecum longifauces gen. et sp. n. (Digenea: Cryptogonimidae) from Suwanee bass, Micropterus notius Bailey and Hubbs, and emendation of the subfamily Caecincolinae Yamaguti 1958.

A new trematode of the family Cryptogonimidae is described from Suwanee bass (Micropterus notius Bailey and Hubbs) from Florida. Turgecaecum longifauces gen. et sp. n. is characterized by having a long esophagus, precrural acetabula, short expanded ceca and vitellaria in the shoulder region. It is placed in the subfamily Caecincolinae and is compared with Caecincola Marshall and Gilbert 1905, the only other genus in the subfamily. Emendments to the subfamily are made.

Integrating the creative arts into a midwifery curriculum: a teaching innovation report.

The practice of midwifery has long been recognized as both art and science. However, educational programmes for midwifery are most often undertaken within an academic health sciences environment, and tend to be based on knowledge derived from the sciences (e.g. life sciences, biomedical sciences, behavioural sciences and social sciences). These scientific perspectives, while essential to the preparatory and on-going education of midwives, do not necessarily fully prepare midwives to fulfil their practice roles. This paper reports a teaching innovation aimed at facilitating student exploration of fundamental, complex and ethereal concepts which are essential to the effective and skillful practice of midwifery. Through the exploration of the arts and humanities, students were encouraged to engage with concepts such as 'caring', 'empathy', 'suffering', 'motherhood', 'pain', 'love', 'attachment', 'health' and 'illness'. Students were also encouraged to explore cultural and social symbols pertaining to parenthood and family life. Evaluation revealed that students valued the course, and that they gained insights which assisted them to develop understanding of key concepts. Implications for practice and education are drawn from this paper.

The current approach to cancer treatment.

The therapeutic armamentarium in the treatment of cancer is now expanded to include surgery, radiotherapy, chemotherapy and immunotherapy. The aim is to achieve cure where possible. For some cancers the concept of cure can be questioned, and for many patients, cancer must be regarded as a chronic disease. A vigorous approach to palliation, particularly in regard to special problems such as hypercalcaemia, yields good dividends. Human values remain of paramount importance, and active antitumour treatment with attendant side effects must not be continued where there is no expectation of worthwhile response.

Development of father-infant attachment in fathers of preterm infants.

PURPOSE: To investigate the development of feelings of attachment between fathers and their preterm infants and to identify factors that help or hinder this process. DESIGN: A longitudinal descriptive design was used to obtain fathers' perceptions of their infants, feelings for their infants, and other related factors. SAMPLE: A convenience sample of 27 fathers of preterm infants was recruited. MAIN OUTCOME VARIABLE: The main outcome variable was the time at which fathers first held their infants. RESULTS: The earlier fathers held their babies, the sooner they reported feelings of warmth and love for them.

Lamotrigine-induced toxic epidermal necrolysis treated with intravenous cyclosporin: a discussion of pathogenesis and immunosuppressive management.

There is growing evidence that the final common pathway of toxic epidermal necrolysis (TEN) is mediated by the cellular immune system which targets drug altered epithelial antigens. This provides a rationale for immunosuppressive therapy. The ideal regimen for quickly turning off epidermal damage in TEN has not yet been determined and the use or benefit of routine immunosuppression remains highly controversial. This article reviews recent advances in the pathogenesis of TEN along with the theoretical benefits of early immunosuppressive treatment in severe cases, specifically utilizing cyclosporin. We describe a 29-year-old woman with TEN due to the anticonvulsant lamotrigine whose successful management included intravenous cyclosporin. The extension of her lesions ceased within 24 hours of initiating cyclosporin (day 7 of her admission). Complications included: scarring alopecia; Enterococcus faecalis septicaemia due to an infected central line; and ulceration and squamous metaplasia of conjunctivae. The potential role of lamotrigine as a cause of TEN is discussed.

Leukemic cell differentiation in vivo and in vitro: arrest of proliferation parallels the differentiation induced by the antileukemic drug Harringtonine.

A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.

Acquired scalp alopecia. Part I: A review.

In this two-part series we review the acquired scalp alopecias. A broad spectrum of diseases result in alopecia. In this first part we provide a framework for the assessment and diagnosis of scalp hair loss, and begin covering the individual conditions. The non-scarring alopecias covered include effluvium, androgenetic alopecia, alopecia areata, trichotillomania, and loose anagen syndrome. The scarring alopecias cause permanent pilosebaceous follicle loss; the lymphocyte-associated scarring alopecia described encompasses lichen planopilaris, discoid lupus erythematosus, pseudopelade, and follicular mucinosis. Part II will cover the neutrophil-associated and infiltrative processes causing scarring alopecia followed by the medical management of alopecia. There is particular reference to newly described conditions and progress in the understanding of older conditions. More recently characterized conditions include the loose anagen syndrome, chronic telogen effluvium, and the frontal fibrosing variant of lichen planopilaris.