Trade Herbal Products and Induction of CYP2C19 and CYP2E1 in Cultured Human Hepatocytes

Abstract: The aim of this study was to evaluate in vitro the dose‐dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S‐mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP‐modulating herb, showing a dose‐dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log‐linear dose‐dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non‐inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug‐herb interactions with selected CYP2C19 substrates.     

Detection of serum antibodies to bovine norovirus in veterinarians and the general population in the Netherlands

The close genetic relationship of human and animal strains of norovirus has raised the possibility of transmission of noroviruses from animals to humans and may explain the emergence of certain norovirus strains. To assess if exposure to bovine noroviruses (NoV) might result in infection in humans, an enzyme immunoassay (EIA) was designed and validated in order to detect antibodies against bovine norovirus. This and two other EIAs were used to test sera from 210 veterinarians and 630 matched population controls for IgG and IgA antibodies to recombinant capsid protein of bovine NoV (rBoV), Norwalk virus (rNV), and Lordsdale virus (rLDV). Of 840 participants, IgG reactivity to rBoV was found in 185 (22%), to rNV in 638 (76%) and to rLDV in 760 (90%). IgG reactivity to rBoV was more common in veterinarians (58/210: 28%) than in controls (127/630: 20% [P = 0.03]). IgA reactivity to rBoV was similar in both veterinarians and controls. Cross-reactivity of IgA and IgG antibodies to rBoV and rNV was seen, but 26% of all specimens positive rBoV antibodies showed high IgG reactivity to rBoV but low reactivity to rNV, suggesting a specific response to bovine antigen. No evidence of overall cross-reactivity of antibodies to rBoV and rLDV was seen. Among veterinarians, youth spent on farm (Odds Ratio [OR] = 1.8) and membership of the bovine practitioners' society (OR = 2.7) were significantly associated with IgG seroreactivity to rBoV. These data indicate that bovine strains of NoV may infect humans though less frequently than human strains.     

The distribution of clinical findings in Bechterew's syndrome (ankylosing spondylitis) suggests distinct genetic subgroups

One hundred and twenty-two consecutive patients hospitalized for ankylosing spondylitis (AS) were reexamined. The frequency of clinical signs and results of tests for associations are presented. Psoriasis was associated with a distal pattern of peripheral arthropathy. Spinal rigidity was predominantly seen in males. Males with phalangeal arthropathy exhibited preserved spinal mobility. This was the case also when HLA B27 positives and patients who did not have psoriasis were considered separately. HLA B27 positive patients in this group had frequently experienced acute anterior uveitis. It seems possible that the disease in such males is the result of combined predisposition to ankylosing spondylitis and psoriatic arthropathy. Hip arthropathy was frequently present in males with spinal rigidity. The associations observed confirm that AS is a heterogenous group of diseases. The term "syndrome" may be suitable for such a heterogenous group, and we prefer the term "Bechterew's syndrome" as the name of this group. When these new findings are added to the previous observations that acute anterior uveitis probably is a clinical, sex-influenced characteristic of HLA B27 positive Bechterew's syndrome, that HLA B27 negative patients with Bechterew's syndrome frequently had psoriasis and were HLA B13 and B17 negative, and that psoriasis was frequent in HLA B27 positive patients as well, we tentatively conclude that different and interacting genetic mechanisms may be involved in the etiology of Bechterew's syndrome.     

HLA antigens, psoriasis and acute anterior uveitis in Bechterew's syndrome (ankylosing spondylitis)

One hundred and twenty-two consecutively hospitalized patients with ankylosing spondylitis (AS) were reexamined. Ninety-two per cent were HLA B27 positive. Of the HLA B27 negative patients, 60% were found to have psoriasis, as opposed to 11 % of the HLA B27 positive patients. Acute anterior uveitis (AAU) was found only in HLA B27 positive patients, and more frequently in males than in females. The genetic and clinical heterogeneity of AS, together with the overlapping clinical criteria for AS and psoriatic spondylitis, may make the term "Bechterew's syndrome" preferable. Based on these findings and previous reports, we conclude that (i) AAU is a manifestation of Bechterew's syndrome in HLA B27 positive patients, (ii) HLA B27 negative patients without any obvious accompanying manifestations may suffer from psoriatic spondylitis, and (iii) genetic predisposition to psoriasis in persons who are HLA B13, B17 and B37 negative, may interact with the genetic predisposition to Bechterew's syndrome in HLA B27 positive persons and produce Bechterew's syndrome with psoriasis or psoriasis-like skin eruptions.     

Quantitative determination of cell surface β-adrenoceptors in different rat skeletal muscles

In the present study, the density of cell surface beta-adrenergic receptors was determined in different skeletal muscles using the hydrophilic ligand [3H]CGP 12177. The density of beta-adrenergic receptors was highest in the slow-twitch soleus muscle (32.8+/-0.9 fmol mg dw(-1)) and lowest in the fast-twitch glycolytic white gastrocnemius (10.4+/-0.5 fmol mg dw(-1)) beta-Adrenoceptor density correlated closely with the percentage of type-I fibres (r=0.979; P<0.0001) and inversely with the percentage of type-IIB fibres (r=696; P<0.03). Incubation with isoprenaline (10 microM) for 30 min decreased the density of beta-adrenergic receptors in the cell surface from 32.9+/-0.8 to 19.3+/-0.7 fmol mg dw(-1) in the soleus and from 16.8+/-1.0 to 12.0+/-0.7 fmol mg dw(-1) in the epitrochlearis. Internalisation appeared rapid (half-time less than 5 min). To study externalisation of beta-adrenergic receptors, soleus strips were incubated 30 min with 10 microM isoprenaline and then transferred to buffer without agonist. The first incubation reduced the density to approximately 50%, the subsequent incubation without agonist increased cell surface receptor density to approximately 80% of the initial density after 1 h. No further increase was observed over the next 2 h, suggesting that some of the receptors had been degraded. Insulin or contractile activity did not influence rate of externalisation.     

Marfan syndrome: Evolving organ manifestations—A 10‐year follow‐up study

The age‐dependent penetrance of organ manifestations in Marfan syndrome (MFS) is not known. The aims of this follow‐up study were to explore how clinical features change over a 10‐year period in the same Norwegian MFS cohort. In 2003–2004, we investigated 105 adults for all manifestations in the 1996 Ghent nosology. Ten years later, we performed follow‐up investigations of the survivors (n = 48) who consented. Forty‐six fulfilled the revised Ghent criteria. Median age: females 51 years, range 32–80 years; males 45 years, range 30–67 years. New aortic root dilatation was detected in patients up to 70 years. Ascending aortic pathology was diagnosed in 93 versus 72% at baseline. Sixty‐five percent had undergone aortic surgery compared to 39% at baseline. Pulmonary trunk mean diameter had increased significantly compared to baseline. From inclusion to follow‐up, two patients (three eyes) developed ectopia lentis, four developed dural ectasia, four developed scoliosis, three developed incisional or recurrent herniae, and 14 developed hindfoot deformity. No changes were found regarding protrusio acetabuli, spontaneous pneumothorax, or striae atrophicae. The study confirms that knowledge of incidence and progression of organ manifestations throughout life is important for diagnosis, treatment, and follow‐up of patients with verified or suspected MFS.     

Fine-needle biopsy of the pancreas: Results of 204 routinely performed biopsies in 190 patients

Two-hundred and four fine-needle aspiration biopsies of the pancreas have been performed in 190 patients during a 12-year period. Sixty-one of these were performed percutaneously guided by endoscopic retrograde cholangio-pancreatography, percutaneous transhepatic cholangiography, angiography, or ultrasonography; and 143 were taken intraoperatively. In 77 (67%) out of 115 patients with pancreatic cancer, a correct cytological diagnosis was obtained. Two biopsies were reported as malignant in 1 patient who ultimately was found to have chronic pancreatitis (false positives). The frequency of not representative biopsies varied from 20.8% in patients with suspected cancer biopsied intraoperatively to 48.4% in patients biopsied preoperatively. A correct cytological diagnosis of malignancy was obtained preoperatively in 54.6% of patients with cancer, in 60.0% of patients evaluated without later operation, and in 71.1% of patients biopsied during laparotomy for suspected pancreatic cancer. The overall false-negative rate was 9.8%. The predictive value of a positive test was almost 100%, whereas the predictive value of a negative test was only 69.6% (total material). Analyses may indicate that a more aggressive approach with multiple punctures may lower the not representative biopsy rate and increase the diagnostic accuracy in patients with pancreatic cancer.

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Resumen Doscientas y cuatro biopsias pancreáticas por aspiración con aguja fina han sido realizadas en 190 pacientes en un período de 12 años. Sesenta y una de éstas fueron realizadas por vía percutánea guiada por colangiopancreatografía endoscópica retrógrada, colangiografía percutánea transhepática, angiografía, o ultrasonografía, y 143 fueron intraoperatorias. En 77 (67%) de 115 pacientes con cáncer del páncreas se obtuvo un diagnóstico citológico correcto. Dos biopsias fueron informadas como malignas en un paciente en quien finalmente se demostró pancreatitis crónica (falsas positivas). La frecuencia de biopsias no representativas varió entre 20.8% en pacientes con sospecha de cáncer y biopsia realizada intraoperatoriamente, a 48.4% en pacientes con biopsias realizadas en la fase preoperatoria. El diagnóstico citológico correcto de malignidad fue logrado preoperatoriamente en 54.6% de los pacientes con cáncer, en el 60.0% de los pacientes evaluados y sin operación posterior y en el 71.1% de los pacientes en quienes se realizó biopsia durante la laparotomía por sospecha de cáncer pancreático. La tasa global de resultados falsos negativos fue de 9.8%. El valor de predicción de una prueba positiva fue de casi 100%, mientras el valor de predicción de una prueba negativa fue de sólo 69.6% (material total). La implicación práctica de esto es que cuando se obtenga un resultado negativo se debe proceder con la toma de nuevas biopsias. En conclusión, creemos que la biopsia del páncreas con aguja fina es un procedimiento seguro que puede ser recomendado en todas las fases del proceso diagnóstico o terapéutico de lesiones pancreáticas, y que es valioso en la planeación de la terapia en pacientes con cáncer. Sinembargo, las biopsias negativas en casos de sospecha clínica de cáncer no siempre excluyen su presencia. Mayor análisis puede indicar que una actitud más agresiva, con punciones mÚltiples, puede disminuir la tasa de biopsias no representativas y aumentar la precisión diagnóstica en pacientes con cáncer pancreático.

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Résumé Deux cent quatre biopsies-aspirations à l'aiguille fine du pancréas ont été pratiquées chez 190 sujets au cours d'une période de 12 ans. Soixante et une d'entre elles ont été pratiquées par voie souscutanée en étant guidées par cathétérisme rétrograde, cholangiographie transpariétale, angiographie ou ultrasonographie et 143 ont été effectuées au cours de l'intervention. Chez 77 (67%) sujets appartenant à une série de 115 malades atteints de cancer du pancréas le diagnostic cytologique exact a été porté. Deux biopsies en faveur du diagnostic de cancer répondaient en réalité à des lésions de pancréatite chronique (faux positifs). La fréquence des biopsies ininterprétables chez les sujets suspects de cancer a varié de 20.8% lorsque l'examen a été pratiqué au cours de l'intervention à 48.4% lorsque ce mÊme examen a été effectué avant l'opération. Le taux de diagnostic cytologique exact de cancer a été respectivement de 54.6%, de 60.0% et 71.1% selon que la biopsie cytologique a l'aiguille a été pratiquée avant l'intervention, après un certain délai et au cours de l'opération. Au total, le taux des faux positifs s'est élevé à 9.8%. La fiabilité de la biopsie à l'aiguille a été proche de 100% en cas de biopsie positive mais seulement de 69.6% en cas de biopsie négative. L'analyse de l'ensemble de ces faits incite à adopter une attitude plus agressive c'est-à-dire à pratiquer des biopsies multiples au lieu d'une ponction unique pour réduire le taux des prélèvements ininterprétables et accroÎtre celui des résultats exacts.

     

Preventing Macrovascular Disease in Patients with Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (DM) is associated with an increased risk for both micro-and macrovascular complications, and cardiovascular diseases (CVD) are the most common causes of death in these patients, accounting for almost 70% of the deaths. Given the high prevalence of the condition and the expected global increase in the prevalence of type 2 DM, a case is made for prevention of these serious complications in order to reduce the individual morbidity and the economic burden on society. In this review we present the knowledge of how macrovascular disease in patients with type 2 DM may be prevented, and suggest possible strategies for doing so. A thorough search of the published literature was conducted and we first present relevant epidemiological studies demonstrating the impact of important risk factors for CVD in DM, such as dyslipidemia, hyperglycemia, hypertension, smoking, familial premature coronary heart disease and some non-classical risk factors such as hyperinsulinemia, insulin resistance, endothelial dysfunction and inflammation. Secondly, we review the results from published randomized controlled clinical trials and meta-analysis of these, evaluate the findings and suggest strategies for preventing CVD in patients with type 2 DM using non-pharmacological and pharmacological approaches. Present knowledge indicates that most patients with type 2 DM either have manifest CVD or have a high risk for future cardiovascular events, men with DM have a 2- to 4-fold; and women with DM a 3- to 5-fold increased risk for cardiovascular death compared with non-diabetic individuals. Care of patients with type 2 DM should include yearly risk assessment by the use of published risk equations or risk charts. On the background of this assessment, an individual risk reducing strategy should be tailored to each patient’s need, including the treatment of hyperglycemia, hypertension and dyslipidemia together with the use of aspirin (acetylsalicylic acid) and ACE inhibitors. Such measures can reduce the risk of cardiovascular events in patients with type 2 DM.     

Fibrosarcoma in Children: A Rare Tumour with Long-Term Survival even with Advanced Disease A Report of 3 Cases

Fibrosarcoma is a rare tumour in children. The potential of malignancy has been questioned. We present three cases of fibrosarcoma in children. The follow-up periods range from 10 to 37 years. The first patient had pulmonary metastases at the time of diagnosis in 1958. The primary tumour in fossa ischio-rectalis was resected in 1960. Lung metastases were resected in 1960 and 1989. Radiotherapy was given in 1992. He is still alive with metastases 37 years after the first manifestation of disease. The second patient had a primary tumour and several local recurrences in the mandible. He is alive without evidence of disease 4 years after resection of pulmonary metastases and 21 years after resection of the primary tumour. The third patient has no signs of recurrence or metastasic spread 10 years after a wide excision of subcutanous tumours of the left upper arm. The cases demonstrate a special tumour-entity of low-grade malignancy, which show a good prognosis and a wide spectrum of biological behaviour.