Evidence for environmental influence on CYP2D6-catalysed debrisoquine hydroxylation as demonstrated by phenotyping and genotyping of Ethiopians living in Ethiopia or in Sweden

Black Africans show lower rates of CYP2D6- and CYP2C19-dependent drug metabolism compared to Caucasians of the same apparent genotype. To determine if environmental factors are responsible for this difference, the genotypes and phenotypes of CYP2D6 and CYP2C19 among Ethiopians living in Sweden (n = 70) were assessed and compared to our previously published data from Ethiopians living in Ethiopia (n = 114) and Swedish Caucasians (n = 134). There was no significant difference in CYP2C19 genotype or phenotype as assessed by mephenytoin between Ethiopians in Sweden or in Ethiopia. However, Swedes were significantly more rapid for CYP2C19 activity than both Ethiopian groups (P < 0.01). A comparison of the debrisoquine MR among individuals of the same CYP2D6 genotype revealed that Swedes exhibited the highest rate of debrisoquine metabolism, followed by Ethiopians in Sweden and Ethiopians in Ethiopia. The difference between the Ethiopian groups was significant (P < 0.02 using a univariate test ANOVA) and amounted to approximately 50% of the magnitude of the MR difference between Swedes and Ethiopians in Ethiopia. It is tempting to speculate that inhibitory dietary factors may explain the differences seen between the two Ethiopian groups and that these components in the past might have contributed to dietary stress-mediated selection of duplicated and multiduplicated active CYP2D6 genes, as frequently seen in Ethiopians. In conclusion, the results indicate a significant influence of environmental factors as an explanation for the difference in capacity for CYP2D6, but not CYP2C19 metabolism between Caucasians and Black Africans. Additional factors remain to be elucidated to fully explain the interethnic differences in CYP2D6 activity.     

Assessment of a new immunocytochemical technique in HbF-cell counting by a novel objective evaluation method

A recently developed immunocytochemical technique in HbF-cell counting was assessed by an objective evaluation method. The basic principle of this method is the preparation of aliquots with predetermined HbF-cell (target) values. These aliquots serve as control samples to standardize the HbF-cell measurements by the new immunocytochemical technique, which uses the StreptABComplex/AP staining procedure (SAP) and visualization under white light. Immunofluorescence optical counts (IF) were performed in parallel with the new technique. A trend of inaccuracy was observed in low target values for both methods. As the level of target values increased, deviations became insignificant (relative accuracy < 8%) with SAP having slightly better results. Linear regression data of the estimated %HbF-cell rates by the two methods versus the target values were very satisfactory for both methods with SAP being slightly better. SAP seems to provide an accurate and reliable alternative for HbF-cell estimation comparable with the classical IF optical count.     

Safety and efficacy of molgramostim as an adjunctive therapy in critically ill patients with severe sepsis

The aim of this uncontrolled, prospective, clinical study was to investigate the efficacy and safety of molgramostim administration in patients with severe sepsis. The subjects were 20 critically ill, mechanically ventilated patients with severe sepsis in a university intensive care unit (ICU). Molgramostim 300 microg s.c. was given every 12 h for 3 d. Treatment for severe sepsis was also administered as medically indicated. No adverse events (clinical or serum chemistry) were considered as drug related. Temperature (p = 0.334) and PaO2/FiO2 index (arterial oxygen tension/inspiratory oxygen fraction) (p = 0.178) were not significantly changed. Total leukocyte and neutrophil count increased significantly (p < 0.001) during drug administration. Simplified Acute Physiology Score II (SAPS II) was not significantly increased (p = 0.955), but there was a statistically significant decrease (p = 0.006) in Sepsis-related Organ Failure Assessment (SOFA) score. Death probability was not statistically different compared with mortality rate on day 28 and overall mortality (p = 0.238 and 0.700, respectively). There were statistically significant decreases (p < 0.01) in serum tumor necrosis factor-alpha (TNF-alpha), TNF-RII and interleukin-2 (IL-2), and an increase in TNF-RI levels between study entry and day 3. Mean ICU stay was 40.2 +/- 7.7 d. In conclusion, molgramostim administration may not affect serum chemistry and PaO2/FiO2 index, may decrease SOFA score but does not produce significant clinical benefit in terms of patients' outcome compared with death probability. It may also influence TNF-alpha, TNF-RI and TNF-RII serum complex levels. These changes may be attributed to the natural clinical course of sepsis or therapy applied.     

“Isn’t he wonderful?” Exploring the contribution and conceptualization of older husbands as carers

This paper explores the relationship between the dimensions of a debate cited at the intersection of ageing, gender, and family care. It draws together evidence from the General Household Survey for Britain 2000 and social research to explore the contribution and conceptualization of caring by older husbands. UK research on caring reveals that among older spouses, equal numbers of husbands and wives provide intensive care. It has been argued that within late-life marriage an over-riding desire to retain independence erodes gender-determined task allocation, suggesting not only similarity but equality between wives and husbands as carers. More recent qualitative research challenges this assumption and suggests two key findings: that older husbands are motivated to care by a combination of marital duty and reciprocal love, and that they manage the tasks of caring within an instrumental framework. Further, it is clear that pre-existing gender relations continue to be powerful determinants of the experience of caring, and that marital power is retained by men in late-life marriage. Overall, the caring contribution of older husbands is imbued with positive meaning, is highly valued, and offers a distinctive role and identity; this contrasts sharply with the caring experiences of older wives. Her key research interests are older people with mental health problems, older carers, preventive services, and social inequalities and later life. Her current research interests are service provision for older people and quality of life, the service user movement in welfare, citizenship rights, and user empowerment. Material from the National Statistics is Crown Copyright; it has been made available by the Office of National Statistics through the Data Archive and has been used with their permission. Neither the ONS nor the Data Archive bears any responsibility for the analysis or interpretation of the data reported in this paper.     

Screening for left ventricular dysfunction using a hand-carried cardiac ultrasound device

BACKGROUND: The hand-carried cardiac ultrasound (HCU) device is a recently introduced imaging device, which may be potentially useful in the primary care setting. AIM: To test the screening potential of a HCU for the detection of left ventricular (LV) dysfunction by evaluating LV ejection fraction (LVEF) and inferior vena cava (IVC) collapse. Standard echocardiographic system (SE) and plasma brain natriuretic peptide (BNP) measurements were used as a reference. METHODS: Eighty-eight consecutive patients (56 male, aged 59+/-12 years) with suspected LV dysfunction were enrolled in the study. The HCU-LVEF was visually estimated and the SE-LVEF was derived by the Simpson's biplane method. A LVEF <40% represented LV dysfunction. An IVC collapse of <50% and BNP levels > or =15 pmol/l were considered abnormal. The correlation of HCU-LVEF, HCU-IVC and BNP to the SE-LVEF and SE-IVC was analysed independently using 2x2 tables. RESULTS: Six patients were excluded because of poor echo images. 19/82 patients had LV dysfunction. The HCU and BNP could identify 17 and 18 out of these 19 patients, respectively. The agreement for LVEF and IVC collapse between SE and HCU was 96% for both parameters. The sensitivity of IVC collapse, HCU-LVEF and BNP in identifying patients with LV dysfunction was 26, 89 and 94%, respectively. CONCLUSION: A HCU device can reliably be used as a screening tool for LV dysfunction.     

Endoscopic and laparoscopic treatment of ureteropelvic junction obstruction

PURPOSE: Although open pyeloplasty remains the gold standard for treating ureteropelvic junction obstruction, endourology and laparoscopy have revolutionized the management of upper tract stenosis. We present our diagnostic and minimally invasive therapeutic algorithm for the treatment of ureteropelvic junction obstruction. MATERIALS AND METHODS: A total of 13 females and 9 males with a mean age of 34.2 years suffering from ureteropelvic junction obstruction were treated with percutaneous endopyelotomy or laparoscopic dismembered pyeloplasty and followed for 47 to 61 months (mean 53.8) and 47 to 62 months (mean 52.5), respectively. Diagnosis was based on findings of ultrasound, excretory urography, furosemide washout renogram and retrograde ureteropyelography. In cases of ureteral kinking color duplex sonography and spiral computerized tomography were performed. In 14 patients with intrinsic stenosis percutaneous endopyelotomy was performed, while the remaining 8 patients (5 with crossing vessels, 2 with an extremely distended pelvis and 1 with a 2.5 cm. stricture) were treated with a laparoscopic dismembered Anderson-Hynes pyeloplasty. RESULTS: In the endopyelotomy group (success rate 92.8%), mean operation time was 1.2 hours, estimated blood loss was 152 ml., unit doses of analgesics were 5.4 tablets, days of hospitalization were 4.2 and time to return to normal activities was 15.7 days. In the laparoscopic group (success rate of 100%) the aforementioned variables were 3.5 hours (p <0.05), 150 ml., 6.3 tablets, 5 and 17.8 days, respectively. Long-term followup excretory urography and/or diuretic renal scan demonstrated improvement in all patients. CONCLUSIONS: Percutaneous endopyelotomy should be the treatment of choice for intrinsic ureteropelvic junction obstruction. Laparoscopic dismembered pyeloplasty, although technically challenging, provides excellent results for extrinsic or complicated ureteropelvic junction stenosis.     

Long-term findings on brain magnetic resonance imaging in acute encephalopathy with bilateral striatal necrosis associated with measles

The long-term findings on brain magnetic resonance imaging (MRI) in a 7 10/12-year-old boy with a history of acute encephalopathy with bilateral striatal necrosis following measles at the age of 22 months are described. At the early stage of illness, brain MRI studies revealed bilateral, symmetric basal ganglia lesions, predominant on the globi pallidi, appearing as hyperintense signals on T1- and T2-weighted images. Six years later, follow-up brain MRI studies showed that the bilateral, symmetric lesions on the globi pallidi persisted with low signal on T1- and high signal on T2 weighted images. At present, the patient has some persistent neurologic signs. These findings suggest that both clinical and neuroradiologic findings may persist in children with acute encephalopathy with bilateral striatal necrosis following measles.     

Are the effects of tamoxifen on the serum lipid profile modified by apolipoprotein E phenotypes?

BACKGROUND: Tamoxifen has favorable effects on the serum lipid profile. It has been suggested that the apolipoprotein (Apo) E phenotype can influence serum lipid parameters; the ApoE allele 4 (ApoE4) is associated with higher total and low-density lipoprotein (LDL) cholesterol levels. The ApoE phenotype also affects lipid responses to diets or treatment with statins. However, the effect of tamoxifen on the lipid profile in different ApoE phenotypes is unknown. PATIENTS AND METHODS: In the present study, we evaluated the effects of tamoxifen on the serum lipid profile in 11 ApoE4-positive postmenopausal women with breast cancer (phenotypes 3/4 and 4/4) compared with 33 ApoE4-negative women (phenotypes 3/2 and 3/3). Serum lipid parameters [high-density (HDL), LDL and total cholesterol, triglycerides, ApoAI, ApoB and lipoprotein (a)] were measured after an overnight fast before treatment and after 3 and 12 months. ApoE isoforms were determined by isoelectric focusing of delipidated very-low-density lipoproteins (VLDL). RESULTS: During the follow-up period, serum levels of total and LDL cholesterol and ApoB decreased significantly in both groups, but no significant differences were found. Concentrations of serum HDL cholesterol were not significantly different between both groups. However, serum ApoAI levels increased significantly in ApoE4-negative subjects (p = 0.00005), but no significant changes in ApoE4-positive women were observed. Serum triglyceride levels increased by 23.2% (p < 0.05) in ApoE4-positive patients, but they did not change significantly in ApoE4-negative patients. The LDL/HDL cholesterol ratio decreased similarly in the two groups, but the ApoAI/ApoB ratio, which may be a better predictor of cardiovascular events, significantly changed in the ApoE4-negative subjects. Finally, the median level of Lp(a) decreased by 43.4% in the ApoE4-negative patients, whereas it did not change significantly in the ApoE4-positive group. CONCLUSION: In postmenopausal Greek women with breast cancer, the levels of Lp(a) and triglycerides and the ApoAI/ApoB ratio respond more favorably to tamoxifen treatment in ApoE4-negative than in ApoE4-positive patients.