Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension.

Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists (CAs) and blockers of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (ARBs)] are widely used today to initiate antihypertensive treatment but, when given as monotherapy, do not suffice in most patients to normalise blood pressure (BP). Combining a CA and either an ACE-inhibitor or an ARB considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. Several fixed-dose combinations are available (CA + ACE-inhibitors: amlodipine + benazepril, felodipine + ramipril, verapamil + trandolapril; CA + ARB: amlodipine + valsartan). They are expected not only to improve BP control, but also to facilitate long-term adherence with antihypertensive therapy, thereby providing maximal protection against the cardiovascular and renal damage caused by high BP.     

The acidic tumor microenvironment promotes the reconversion of nitrite into nitric oxide: towards a new and safe radiosensitizing strategy.

PURPOSE: The biological status of nitrite recently evolved from an inactive end product of nitric oxide catabolism to the largest intravascular and tissue storage of nitric oxide (NO). Although low partial O(2) pressure favors enzymatic reconversion of nitrite into NO, low pH supports a nonenzymatic pathway. Because hypoxia and acidity are characteristics of the tumor microenvironment, we examined whether nitrite injection could preferentially lead to NO production in tumors and influence response to treatments. EXPERIMENTAL DESIGN: The effects of nitrite were evaluated on arteriole vasorelaxation, tumor cell respiration and tumor blood flow, oxygenation, and response to radiotherapy. RESULTS: We first showed that a small drop in pH (-0.6 pH unit) favored the production of bioactive NO from nitrite by documenting a higher cyclic guanosine 3',5'-monophosphate-dependent arteriole vasorelaxation. We then documented that an i.v. bolus injection of nitrite to tumor-bearing mice led to a transient increase in partial O(2) pressure in tumor but not in healthy tissues. Blood flow measurements failed to reveal an effect of nitrite on tumor perfusion, but we found that O(2) consumption by nitrite-exposed tumor cells was decreased at acidic pH. Finally, we showed that low dose of nitrite could sensitize tumors to radiotherapy, leading to a significant growth delay and an increase in mouse survival (versus irradiation alone). CONCLUSIONS: This study identified low pH condition (encountered in many tumors) as an exquisite environment that favors tumor-selective production of NO in response to nitrite systemic injection. This work opens new perspectives for the use of nitrite as a safe and clinically applicable radiosensitizing modality.     

Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells.

PURPOSE: T-cell infiltration is associated with good tumor prognosis in many cancers. To assess the capacity of neoadjuvant chemotherapy to affect T-cell infiltration in breast cancer, we evaluated CD3 and CD8 infiltrates, and the Foxp3 immunosuppressive T cells. EXPERIMENTAL DESIGN: CD3+, CD8+, and Foxp3+ cell infiltrates were detected by immunohistochemistry in a series of 56 breast cancer patients before and after the end of neoadjuvant chemotherapy. RESULTS: Poor prognostic factors (negative hormonal receptors, high tumor grade, and nodal involvement) were associated with a significantly higher number of CD3, CD8, and Foxp3 infiltrates before the beginning of chemotherapy. Chemotherapy resulted in a decrease in Foxp3 infiltrates, whereas the level of CD8 and CD3 infiltrates remained unchanged. Pathologic complete responses (pCR) had a drastic decrease of Foxp3+ cells, whereas these cells remained elevated in nonresponders. A cutoff criterion that combined high CD8 infiltration and no Foxp3 cell infiltration on surgical specimens is associated with pCR with a sensitivity of 75% and a specificity of 93%. The infiltrate of cytotoxic TiA1 and granzyme B-positive cells was dramatically enhanced after chemotherapy only in patients with pCR. By multivariate analysis, association of a high CD8 infiltration and no Foxp3 infiltration on final histologic specimens were independently associated with pCR. CONCLUSION: These findings indicate that pCR to neoadjuvant chemotherapy is associated with an immunologic profile combining the absence of immunosuppressive Foxp3 cells and the presence of a high number of CD8 T cells and cytotoxic cells. These results argue for the induction of an antitumor immune response by chemotherapy.     

Les cancers du rectum T2 N0 M0, vers la conservation du rectum: une nouvelle voie de recherche clinique

Surgery remains the milestone of rectal cancer treatment. In elderly patients, the postoperative mortality within the 6 months following surgery can be above 14% and anal continence following anterioresection may be poor. Radiotherapy, especially contact X-ray therapy (CXRT), is proposed as an alternative to radical surgery in elderly patients with severe comorbidity and high surgical risk. For T2 N0 lesion less than 4 cm of diameter, external beam radiotherapy (± CXRT, ± chemotherapy) can achieve local control in about 80% of the cases. Transanal local excision is an attractive field of research in case clinical response to neoadjuvant treatment is fully or quite fully achieved. Some prospective clinical trials are ongoing (ACOSOG, GRECCAR 2, CONTEM) aiming a high rate of local control with rectal preservation to achieve good anorectal function, especially in elderly patients.     

Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity

Members of the newly discovered glycoprotein-associated amino acid transporter family (gpaAT-family) share a similar primary structure with >40% identity, a predicted 12-transmembrane segment topology and the requirement for association with a glycoprotein (heavy chain) for functional surface expression. Five of the six identified gpaATs (light chains) associate with the surface antigen 4F2 heavy chain (4F2hc = CD98), a ubiquitous plasma membrane protein induced in cell proliferation, and which is also highly expressed at the basolateral surface of amino acid transporting epithelia. The differing tissue localizations of the 4F2hc-associated gpaATs appear to complement each other. As yet, a single gpaAT (b(0,+)AT) has been shown to associate with rBAT, a 4F2hc-related glycoprotein mainly localized in intestine and kidney luminal brush-border membranes. The transport characteristics of gpaATs have been shown, by expression in heterologous systems, to correspond to the previously described transport systems L, y+L, xc- and b(o,+). These (obligatory) exchangers of broad substrate specificity (with the exception of xCT) are expected to equilibrate the concentrations of their substrate amino acids across membranes. Thus, the driving force provided by a transmembrane gradient of one substrate amino acid, such as that generated by a parallel functioning unidirectional transporter, can be used by a gpaAT to fuel the secondary active vectorial transport of other exchangeable species. Vectorial transport of specific amino acids is also promoted by the intrinsic asymmetry of these exchangers. The fact that genetic defects of the epithelial gpaATs b(0,+)AT and y+LAT1 cause non-type I cystinuria and lysinuric protein intolerance, respectively, demonstrates that these gpaATs perform vectorial secondary and/or tertiary active transport of specific amino acids in vivo.     

Factors associated with delay in diagnosis of childhood amblyopia

The prevention of permanent visual impairment from amblyopia is an important goal of pediatric vision screening. Unfortunately, many cases of amblyopia are not diagnosed until the child is too old to benefit maximally from treatment. A review of patient records from the practice of a private pediatric ophthalmologist confirmed that late detection is a frequent occurrence among children with amblyopia who have had good access to health care. A case-control study was then used to identify factors associated with delayed diagnosis, in which children with an adverse outcome (diagnosed at or after 5 years of age) were compared with those with an optimal outcome (diagnosed before 5 years of age). The chart review identified 161 children with amblyopia who participated in this study; 75 had late diagnoses (case patients) and 86 served as control patients. Children with early diagnoses more often had the following characteristics: a positive family history of strabismus, greater degrees of strabismus (when strabismus was present), higher maternal educational level, greater parental suspicion that an eye problem existed, and an increased chance that the parents requested the eye examination that led to the diagnosis. The parents of children with late diagnoses expressed less concern over the seriousness of amblyopia but were more likely to report that their children had suffered adverse consequences of amblyopia. When diagnosed early, amblyopia was more often detected by the child's primary health care provider. Physicians of the children with early diagnoses more often reported compliance with both the American Academy of Pediatrics guidelines for vision screening in infancy and referral for vision problems.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of soluble bacterial antigens detected by electrosyneresis in infectious diseases in children

The diagnostic interest of the search for soluble bacterial antigens, using counter-current immunoelectrophoresis (CIE) has been evaluated in 109 children hospitalized with acute infection. In meningitis, CIE was well correlated with cerebrospinal fluid (CSF) culture and allowed a rapid diagnostic orientation in 82% of meningitis which were confirmed by classical bacteriology (CIE has to be performed using CSF and concentrated urine). False positive results were observed with type B meningococcus, especially on urine samples. In respiratory infections, the search for soluble antigens was of no interest except for focal pneumonitis; in that case, CIE was more frequently positive (35%) than blood culture (28%) and led to a 31% increase of correct diagnosis (CIE must be performed using concentrated urine). Serum and pleural fluid investigations were less sensitive. CIE was not useful in case of upper respiratory or nonfocal broncho-pulmonary infection, due to its very low efficiency.