Incidence of haemoglobinopathies in various populations — The impact of immigration

Objectives

The aim of this study was to update the incidence data of beta thalassaemia mutations in various populations and compare it to the spectrum of mutations in the United Kingdom (UK) population in order to determine the impact of immigration.

Design and methods

Published data for the β-thalassaemia mutation spectrum and allele frequencies for 60 other countries was updated and collated into regional tables. The β-thalassaemia mutations in the UK population have been characterised in 1712 unrelated carriers referred for antenatal screening. Similarly, the α-thalassaemia mutations in the UK population have been characterised in 2500 possible α-thalassaemia carriers.

Results

A total of 68 different β-thalassaemia mutations were identified in couples requiring screening for antenatal diagnosis in the UK population. Of these mutations, 59 were found in immigrants to the UK, from all major ethnic groups with a high incidence of haemoglobinopathies. A total of 40 different α-thalassaemia mutations were characterised in the UK population. Ten deletion mutations were identified, including all the Southeast Asian and Mediterranean α⁰-thalassaemia mutations. In addition, 30 non-deletion α⁺-thalassaemia mutations were discovered, accounting for 46% of the worldwide known non-deletion mutations.

Conclusions

The impact of immigration has resulted in the UK population having a higher number of β-thalassaemia mutations and α-thalassaemia mutations than any of the 60 other countries with a published spectrum of mutations, including both endemic countries and the non-endemic countries of Northern Europe. The racial heterogeneity of the immigrant population in a non-endemic country significantly increases the spectrum of haemoglobinopathy mutations and their combinations found in individuals, making the provision of a molecular diagnostic prenatal diagnosis service more challenging.     

Can galactography-guided stereotactic, 11-gauge, vacuum-assisted breast biopsy of intraductal lesions serve as an alternative to surgical biopsy?

The purpose of this study was to determine the value of galactography-guided, stereotactic, vacuum-assisted breast biopsy (VABB) for the assessment of intraductal breast lesions and its potential as a therapeutic tool that could eliminate the need for surgical excision. Eighteen patients (median age 64 years, range 37–80) with nipple discharge and galactography-verified intraductal lesions underwent galactography-guided, stereotactic, 11-gauge VABB followed by surgery. Histopathology findings from VABB and subsequent surgery were compared. Underestimation and false-negative rates were assessed. After VABB, histopathology revealed invasive ductal carcinoma (IDC) in three (17%), ductal carcinoma in situ (DCIS) in six (33%), high-risk lesions in six (33%) and benign lesions in three (17%) cases. After surgical biopsy, histopathology confirmed the previously established diagnosis in 11 lesions (61%). The underestimation rate for high-risk lesions and DCIS was 50% (6/12). The false-negative rate was 7% (1/14). Histopathology examination after surgery showed that not a single lesion had been completely removed at VABB. Galactography-guided VABB is a feasible diagnostic tool. However, its value as a therapeutic procedure is limited because of the high number of underestimated and missed lesions and because of the histopathological detection of lesions’ remnants in every case. Surgical excision should be the therapeutic gold standard in cases of pathological nipple discharge and galactography abnormalities.     

Celecoxib inhibits growth of tumors in a syngeneic rat liver metastases model for colorectal cancer

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer in cyclooxygenase-2 (COX-2) overexpressing colorectal cancers. The present study was designed to evaluate the inhibitory effects of the COX-2 inhibitor celecoxib on the growth of colorectal cancer liver metastases in a syngeneic rat model, CC531. MATERIALS AND METHODS: The effects of celecoxib on cell viability in vitro were evaluated by treatment of CC531 tumor cell cultures with celecoxib. In vivo, Wag/Rij rats were inoculated with CC531 tumor cells at two sites in the liver and treated with celecoxib starting one week before, or directly after tumor inoculation. Control rats were inoculated without treatment. Three weeks after tumor inoculation rats were sacrificed. Tumor size, immune cell infiltration, caspase-3 activity, PGE(2) and celecoxib levels were determined. RESULTS: CC531 tumors did not show COX-2 expression. Tumor growth was significantly inhibited by celecoxib treatment in a dose dependent manner. Immune cell infiltration was decreased after celecoxib treatment, indicating that the immune system was not involved in preventing tumor growth. Tumor caspase-3 levels were only significantly increased if treatment was started before tumor inoculation. Celecoxib serum concentration starting at 0.84 mug/ml significantly inhibited the outgrowth of CC531 liver tumors. In contrast, in vitro concentrations of celecoxib of at least 12 mug/ml were needed to affect tumor cell viability. CONCLUSION: These results suggest that the inhibitory effects of celecoxib on tumor growth are not by direct cytotoxicity, but by creating an unfavorable environment for tumor growth.     

Mast cell activation tests by flow cytometry: A new diagnostic asset?

Since the late nineties, evidence has accumulated that flow-assisted basophil activation test (BAT) might be an accessible and reliable method to explore the mechanisms governing basophil degranulation and diagnostic allowing correct prediction of the clinical outcome following exposure to the offending allergen(s) and cross-reactive structures for different IgE-dependent allergies and particular forms of autoimmune urticaria. Although the BAT offers many advantages over mediator release tests, it is left with some weaknesses that hinder a wider application. It is preferable to perform the BAT analysis within 4 h of collection, and the technique does not advance diagnosis in patients with non-responsive cells. Besides, the BAT is difficult to standardize mainly because of the difficulty to perform large batch analyses that might span over several days. This article reviews the status of flow cytometric mast cell activation test (MAT) using passively sensitized mast cells (MCs) with patients' sera or plasma (henceforth indicated as passive MAT; pMAT) using both MC lines and cultured MCs in the diagnosis of IgE-dependent allergies. In addition, this paper provides guidance for generating human MCs from peripheral blood CD34⁺ progenitor cells (PBCMCs) and correct interpretation of flow cytometric analyses of activated and/or degranulating cells. With the recent recognition of the mas-related G protein-coupled receptor X2 (MRGPRX2) occupation as a putative mechanism of immediate drug hypersensitivity reactions (IDHRs), we also speculate how direct activation of MCs (dMAT)—that is direct activation by MRGPRX2 agonists without prior passive sensitization—could advance paradigms for this novel endotype of IDHRs.     

Lack of evidence of increased lethality due to propoxyphene overdose in the presence of ethanol in male wistar rats

The primary purpose of the present investigation was to evaluate if the presence of ethanol increased lethality induced by propoxyphene. A secondary aim was to study the effect of naloxone on propoxyphene lethality alone, and on the concomitant administration of propoxyphene and ethanol. Male Wistar rats (210–330 g) were used as test animals. Propoxyphene (175 mg/kg) and ethanol (2 g/kg) were administered by gastric intubation, naloxone (2 mg/kg) by subcutaneous injection. Four groups, each consisting of 19 rats, received either of the following drug treatments: Propoxyphene, ethanol + propoxyphene, naloxone + propoxyphene, and naloxone + ethanol + propoxyphene respectively. The drugs were given in the sequence mentioned at the beginning of the experiment. Naloxone was also given 45 and 90 min later. Mortality was reduced to 42% in the group that received ethanol and propoxyphene compared to 73% in the group that received propoxyphene only. Naloxone protected against lethality in both groups. Some animals died despite naloxone administration, possibly due to a nonopioid cardiotoxic effect of propoxyphene or its metabolite. An increase in the propoxyphene/norpropoxyphene (P/N) ratio due to an increase in the absolute concentrations of propoxyphene and a decrease in the absolute levels of norpropoxyphene in blood, brain, and heart tissues was observed in the ethanol + propoxyphene group, compared to the propoxyphene group. In the animals which died, the highest P/N ratio was observed in brain tissue and the lowest in heart muscle. Despite the pharmacokinetic data obtained in this investigation indicating impaired propoxyphene metabolism in the presence of ethanol, ethanol did not enhance propoxyphene-induced lethality. This is also contrary to suggestions from previous studies. Our results demonstrate that at least in one species and at one dose ratio (ethanol/propoxyphene) ethanol might reduce the lethality caused by propoxyphene alone. This suggests some kind of antagonism between the two drugs, probably in the central nervous system. The work was supported by the Norwegian Research Council for Science and the Humanities     

History of Prepubertal Overweight in Adolescent Girls With Pronounced Body Dissatisfaction

In a group of 257 high school girls, aged 16-17, 10% showed a body mass index (BMI) above 26, and on the Body Attitude Test (BAT; M. Probst, W. Vandereycken, H. Van Coppenolle, & J. Vand-erlin, 1995) almost 25% scored within the pathological range (above the cutoff point of 36). An analysis of the medical records at the local school health center (examinations conducted every 2 years between the age of 8 and 14 years) revealed that adolescent girls with a pronounced body dissatisfaction had a higher BMI at the age of 8 years and that their BMI increased relatively more in the following 4 years. These findings show that a negative body image in adolescence might have its roots in childhood overweight.     

Secretory pattern and blood pressure in pheochromocytoma

The diagnostic accuracy of urinary and plasma catecholamines was studied in 16 patients with pheochromocytoma. Five of 16 patients had 1 or more plasma samples within the normal range, while all 16 patients had increased urinary samples. Urinary catecholamines, therefore, have a higher diagnostic specificity than plasma catecholamines. No diurnal rhythm of catecholamine secretion was found in 7 patients in whom plasma catecholamines and blood pressure were followed for 24 hours. No correlation was found between blood pressure and plasma catecholamines in patients at rest.

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Resumen La precisión diagnóstica del nivel de catecolaminas urinarias y plasmáticas fue estudiada en 16 pacientes con feocromocitoma. Cinco de 16 pacientes exhibieron una o más determinaciones plasmáticas dentro de limites normales, en tanto que todas las determinaciones en orina aparecieron elevadas. Por consiguiente, se puede afirmar que las catecolaminas urinarias poseen una más alta especificidad diagnóstica que las catecolaminas plasmáticas. No se encontró ritmo diurno de secreción de catecolaminas en 7 pacientes en quienes se determinaron las catecolaminas plasmáticas y la presión arterial durante períodos de 24 horas. No se encontró correlación entre la presión arterial y el nivel de catecolaminas plasmáticas en los pacientes en reposo.

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Résumé La précision du diagnostic apportée par le dosage des catécholamines dans le plasma et les urines a été étudiée chez 16 malades qui présentaient un phéochromocytome. Chez 5 d'entre eux les dosages dans un ou plusieurs échantillons de plasma étaient normaux alors que le taux des catécholamines était élevé dans les échantillons d'urine. Il apparaît ainsi que les dosages urinaires ont une spécificité diagnostique supérieure à celle des dosages plasmatiques. Aucun rythme diurne de la sécrétion des catécholamines ne fut découvert chez 7 sujets chez qui les catécholamines plasmatiques et la pression artérielle furent suivis au cours de 24 heures. Aucune corrélation ne fut constatée entre la pression artérielle et les catécholamines plasmatiques chez les subjets au repos.

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Presented at the International Association of Endocrine Surgeons in Paris, September 1985.

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Supported by the Swedish Medical Research Council (02330) and Karolinska Institute.     

Serotonin,reserpine, and motility inMesocestoides tetrathyridia

The relationship between serotonin (5-HT) and motility in tetrathyridia ofMesocestoides vogae (syn.M. corti) was studied with the aid of reserpine. Reserpine decreases the content of 5-HT as measured spectrofluorometrically and immunocytochemically and, furthermore, inhibits the motility, thus indicating a connection between the two. The results support the hypothesis about 5-HT being an excitatory neurotransmitter of motor activity inM. vogae. New neuroanatomical details were revealed by immunocytochemical staining.