How should we assess the effects of exposure to dietary polyphenols in vitro?

Human intervention studies have provided clear evidence that dietary polyphenols (eg, flavonoids--eg, flavonols--and isoflavones) are at least partly absorbed and that they have the potential to exert biological effects. Biological activity of polyphenols is often assessed by using cultured cells as tissue models; in almost all such studies, cells are treated with aglycones or polyphenol-rich extracts (derived from plants and foods), and data are reported at concentrations that elicited a response. There are 2 inherent flaws in such an approach. First, plasma and tissues are not exposed in vivo to polyphenols in these forms. Several human studies have identified the nature of polyphenol conjugates in vivo and have shown that dietary polyphenols undergo extensive modification during first-pass metabolism so that the forms reaching the blood and tissues are, in general, neither aglycones (except for green tea catechins) nor the same as the dietary source. Polyphenols are present as conjugates of glucuronate or sulfate, with or without methylation of the catechol functional group. As a consequence, the polyphenol conjugates are likely to possess different biological properties and distribution patterns within tissues and cells than do polyphenol aglycones. Although deconjugation can potentially occur in vivo to produce aglycone, it occurs only at certain sites. Second, the polyphenol concentrations tested should be of the same order as the maximum plasma concentrations attained after a polyphenol-rich meal, which are in the range of 0.1-10 micromol/L. For correct interpretation of results, future efforts to define biological activities of polyphenols must make use of the available data concerning bioavailability and metabolism in humans.     

Rationale for superficial injection techniques in lymphatic mapping in breast cancer patients

One of the most avidly debated issues in lymphatic mapping is where the tracers are best deposited in patients with breast cancer. The four superficial approaches are easy to perform and have several other distinct advantages. They are based on the hypothesis that the entire breast parenchyma and the overlying skin drain to a common node in the axilla because of their common embryological origin. Evidence is presented that casts doubt upon the correctness of this assumption. Tracer administration close to the tumor site appears to be the safest approach for the time being. Excellent results can be obtained with this latter approach, despite the fact that it is technically more demanding.     

Technology assessment of saline contrast hysterosonography

OBJECTIVE: The purpose of our study was to evaluate to which extent saline contrast hysterosonography (SCHS) is able to replace diagnostic hysteroscopy in uterine cavity evaluation in women suspected of intrauterine abnormalities. STUDY DESIGN: In this prospective observational study we performed SCHS instead of diagnostic hysteroscopy. Diagnostic hysteroscopy was performed in case of failed or inconclusive SCHS. Univariate and multivariate analyses were used to assess subgroups for their risk of failure and inconclusiveness. RESULTS: Two hundred fourteen women were included consecutively. SCHS was conclusive in 180 cases (84.1%), failed in 12 (5.6%), and inconclusive in 22 (10.3%). Uterine size above 600 cm(3) was the best predictor of failure and/or inconclusiveness (positive predictive value 0.42). CONCLUSION: SCHS was able to replace 84% of the outpatient diagnostic hysteroscopies in uterine cavity evaluation in women suspected of intrauterine abnormalities. Our study showed that diagnostic hysteroscopy can be restricted to inconclusive or failed SCHS.     

A femoral component with proximal HA coating. An analysis of survival and fixation at up to ten years

We describe the survival at ten years of 100 femoral components of the Freeman hip prosthesis. It is proximally hydroxyapatite (HA)-coated and was fixed without cement. Radiological assessment identified radiolucent lines (RLLs) and lytic lesions and was used to measure migration. The criterion of failure was revision or impending revision for aseptic femoral loosening. No femoral components were revised or are awaiting revision for aseptic loosening, giving 100% survival at ten years (95% confidence interval, 95.7 to 100), although 59 were at risk at ten years. Two components were revised for fracture of a ceramic head with damage to the trunnion. Although well fixed in each, for survival analysis we evaluated the hip as if the patient had died. Twelve acetabular components were revised and at each operation the femoral component was found to be well fixed, was not disturbed and remained in the survival analysis. Three patients were lost to follow-up, and 12 died with well-functioning prostheses. Radiologically, all except one of the components appeared to be well fixed with no RLLs and no lytic lesions at the latest follow-up. The mean vertical migration was 0.4 mm at one year, 0.8 mm at two years and 1.4 mm at ten years. One component had migrated 7.6 mm at ten years (2.1 mm in year 1) and developed RLLs in Gruen zones I and II. The symptoms, however, were only minor and revision was not indicated. Our study has shown that proximal HA coating gives effective fixation for a femoral component.     

Dynamic contrast-enhanced MR imaging in monitoring response to isolated limb perfusion in high-grade soft tissue sarcoma: initial results

The objective of this study was to evaluate whether dynamic contrast-enhanced MR imaging can determine tumor response and localize residual viable tumor after isolated limb perfusion (ILP) chemotherapy in soft tissue tumors. Twelve consecutive patients, with histologically proven high-grade soft tissue sarcoma, prospectively underwent non-enhanced MR and dynamic contrast-enhanced MR imaging before and after ILP. Tumor volume was measured on non-enhanced MR images. The temporal change of signal intensity in a region of interest on dynamic contrast-enhanced MR images was plotted against time. Start, pattern, and progression of enhancement were recorded. Histopathologic response was defined as complete response if no residual viable tumor was present, partial remission if <50% viable tumor was present, and no change if ≥50% viable tumor was present in the resection specimen. Resected specimens for correlation with histopathology were available for 10 patients; 5 patients had partial remission and 5 had no change. Volume measurements correctly predicted tumor response in 6 of 10 patients. Dynamic contrast-enhanced MR correctly predicted tumor response in 8 of 10 patients. Early rapidly progressive enhancement correlated histologically with residual viable tumor. Late and gradual, or absence of enhancement, was associated with necrosis, predominantly centrally located, or granulation tissue. These preliminary results show that dynamic contrast-enhanced MR imaging offers potential for non-invasive monitoring of response to isolated limb perfusion in soft tissue sarcomas due to identification of residual areas of viable tumor and subsequently may provide clinically useful information with regards to timing and planning of additional surgery. Further prospective studies in a larger patient population is warranted.     

Long-term results of a double perfusion schedule using high dose hyperthermia and melphalan sequentially in extensive melanoma of the lower limb

The aim of this study was to assess the results of an isolated limb perfusion (ILP) schedule with high dose hyperthermia (42-43 degrees C) and melphalan, applied sequentially in patients with advanced melanoma of the limbs. Seventeen patients with extensive recurrent or bulky melanoma of a limb were treated with hyperthermic femoral ILP (42-43 degrees C) without drugs followed by normothermic (37-38 degrees C) ILP with melphalan. Eleven patients (65%) had a complete response. Three patients (27%) had limb recurrences after 5, 6 and 18 months, respectively. The 5 year limb recurrence-free interval for patients with a complete response was 63%. Limb toxicity was mild; pressure-related blistering and transient sensory disturbances occurred after the hyperthermic ILP, and 88% of the patients had a grade II reaction (mild erythema and oedema) after the second ILP. This sequential ILP schedule resulted in a high complete response rate and a low limb-recurrence rate in patients with extensive, recurrent melanoma of the limbs at the cost of only mild toxicity. This regimen could be an alternative to ILP with tumour necrosis factor-alpha and melphalan.     

Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population: first results of the Hippocates study

BACKGROUND: Several studies have assessed the relationship between the angiotensin-converting enzyme (ACE) I/D or angiotensin II type 1 receptor (AT(1)R)-A C polymorphisms and blood pressure (BP). Since most data have been obtained in selected populations, the present study was performed in a healthy normotensive primary care population. OBJECTIVE: To investigate the individual effects of the aforementioned polymorphisms and their interaction on BP. METHODS: This cross-sectional study included 198 healthy subjects. Office BP was measured and polymorphisms were genotyped (polymerase chain reaction). Polymorphism interaction was tested using the following model: systolic blood pressure (SBP) (or diastolic blood pressure, DBP) = b(0)+ b(1)X + b(2)Y + b(3)XY, in which X and Y represent the polymorphisms' risk alleles. RESULTS: The ACE I/D polymorphism was associated with SBP (P = 0.002) and DBP (P = 0.004); highest pressures tracked with the DD genotype. Furthermore, in multiple linear regression analysis the ACE D allele was associated with SBP (P = 0.005) and DBP (P = 0.001), when adjusted for body mass index (BMI) and age. With respect to the AT(1)R-A C polymorphism, SBP was highest in the CC genotype (P = 0.025). In linear regression analysis the C allele was not associated with SBP. No synergistic effect of ACE D and AT(1)R C alleles on BP was found. Nevertheless, highest DBP tracked with the DDCC combination in comparison with other homozygous allele combinations (P = 0.030). CONCLUSIONS: This study confirmed an association of ACE I/D and AT(1)R-A C polymorphisms with BP in a healthy normotensive primary care population. Although synergistic effect of both polymorphisms on BP does not seem to be present, an additive effect on DBP is likely.     

Management of hypertension

Presently, many drugs are available for the treatment of patients with high blood pressure. Although there are several theoretical arguments favouring one particular type of drug over the other, prospective clinical trials have failed to show major differences between drug classes in terms of overall prognosis. A possible exception in this regard may be the development of diabetes mellitus which seems to occur less frequently with ACE inhibitors, AT1 receptor blockers and calcium entry blockers than with diuretics. The choice of the antihypertensive drug regimen should take certain patient characteristics into account, notably comorbid conditions. However, despite theoretical considerations concerning initial therapy many patients will end up using two or more medications.