Pharmacotherapy of congestive heart failure in elderly patients

With longer life expectancy, as well as better survival rates after myocardial infarction, the population of elderly patients with congestive heart failure steadily increases. Large, randomized, placebo-controlled studies have shown significant beneficial effects for several classes of drugs (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists) in patients with congestive heart failure. In most of these studies, however, elderly patients were either excluded or represented only a minority of the study population. Therefore, the treatment benefit for the large population of patients aged 65 and older is still not very well documented. In this paper, we critically review the current literature with regard to outcome of heart failure therapy in this particular subpopulation.     

Coronary anatomy and left ventricular ejection fraction in patients with type 2 diabetes admitted for elective coronary angiography

Patients with diabetes mellitus (DM) have more severe coronary artery disease and a two‐ to fourfold higher risk for myocardial infarction and death as compared to patients without DM. In this study, we analyzed coronary anatomy, left ventricular ejection fraction, and cardiac risk factors in patients with DM referred for coronary angiography and compared them with findings in nondiabetic patients. Coronary anatomy was assessed in a total of 6,234 patients and left ventricular ejection fraction in a subset of 4,767 (76.5%) patients. Diabetic patients (n = 641) were older (60.8 ± 9.6 vs. 58.5 ± 10.5 years; P < 0.0001) and had higher rates of hypertension (65% vs. 47%; P < 0.0001). Three‐vessel disease (DM 44.7% vs. no DM 25.4%; P < 0.0001) and reduced left ventricular ejection fraction (DM 58.4% ± 15.2 vs. no DM 63.9% ± 13.2; P < 0.0001) were significantly associated with DM. After adjustment for age and other vascular risk factors, the presence of DM was associated with a higher atherosclerotic burden. We conclude that advanced coronary heart disease and left ventricular dysfunction are highly prevalent in diabetic patients, independent of age and other cardiovascular risk factors. Thus, cardiac assessment in diabetic patients should, in addition to optimal diabetic control, involve screening for left ventricular dysfunction. Cathet Cardiovasc Intervent 2004;62:432–468. © 2004 Wiley‐Liss, Inc.     

Targeted stent use in clinical practice based on evidence from the Basel Stent Cost Effectiveness Trial (BASKET): reply

We thank Agostini Pierfranco and colleagues for their interestin our analysis of the     

E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

The salivary glands are important effector sites for IgA-mediated humoral immunity to protect oral surfaces. Within murine submandibular glands (SMG), we identified a memory CD8 T-cell population that exhibited a unique cell-surface phenotype distinct from memory CD8 T cells in spleen but similar to memory T cells resident in the intraepithelial lymphocyte compartment of the intestinal mucosa. In mice immune to lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus(VSV), virus-specific memory CD8 T cells with this unusual phenotype were present in SMG at remarkably high frequencies. LCMV-specific memory CD8 T cells in SMG showed potent functional activities in vivo, including cytokine-induced bystander proliferation, antigen-triggered IFNγ production, and viral clearance. Adoptive transfer experiments further revealed that the capacity to accumulate in SMG decreased during CD8 T-cell differentiation and that SMG CD8 T cells were poorly replenished from the circulation, indicating that they were tissue-resident. Moreover, they preferentially relocalized within their tissue of origin after adoptive transfer and antigen rechallenge, thus revealing an imprinted differentiation status. Accumulation of memory CD8 T cells within SMG did not require local antigen presentation but was promoted by the epithelial differentiation molecule E-cadherin intrinsically expressed by these CD8 T cells. This finding extends the epithelial-restricted function of E-cadherin to an impact on lymphocyte accumulation within epithelial tissues.     

Modified amino acid copolymers suppress myelin basic protein 85-99-induced encephalomyelitis in humanized mice through different effects on T cells

A humanized mouse bearing the HLA-DR2 (DRA/DRB1*1501) protein associated with multiple sclerosis (MS) and the myelin basic protein (MBP) 85-99-specific HLA-DR2-restricted T cell receptor from an MS patient has been used to examine the effectiveness of modified amino acid copolymers poly(F,Y,A,K)n and poly-(V,W,A,K)n in therapy of MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in comparison to Copolymer 1 [Copaxone, poly(Y,E,A,K)n]. The copolymers were designed to optimize binding to HLA-DR2. Vaccination, prevention, and treatment of MBP-induced EAE in the humanized mice with copolymers FYAK and VWAK ameliorated EAE more effectively than Copolymer 1, reduced the number of pathological lesions, and prevented the up-regulation of human HLA-DR on CNS microglia. Moreover, VWAK inhibited MBP 85-99-specific T cell proliferation more efficiently than either FYAK or Copolymer 1 and induced anergy of HLA-DR2-restricted transgenic T cells as its principle mechanism. In contrast, FYAK induced proliferation and a pronounced production of the antiinflammatory T helper 2 cytokines IL-4 and IL-10 from nontransgenic T cells as its principle mechanism of immunosuppression. Thus, copolymers generated by using different amino acids inhibited disease using different mechanisms to regulate T cell responses.     

Craniopharyngioma surgery

Ideal surgical treatment of craniopharyngiomas remains a major challenge for neurosurgeons. Craniopharyngiomas grow in the deep-seated hypothalamic area that is paramount for vegetative, emotional and endocrine function, and for maintaining worthwhile life. The benign histological nature of craniopharyngiomas belies their biological behavior and the propensity to recur is a major threat. Surgical treatment has to weigh the risk of hypothalamic damage against the risk of tumor recurrence or progression. Both aggressive surgery and conservative minor surgery followed by radiotherapy has been proclaimed by the proponents of different schools. During the past decade, the pendulum has swung back to surgery with the attempt at radical removal. Refined neurosurgical techniques and innovative approaches yielded improved surgical results. The contemporary neurosurgical strategy of treating craniopharyngiomas with early and late outcome data is presented. Neurosurgical therapy is only beneficial in the context of an interdisciplinary treatment concept as discussed here.     

Unbinding forces of single antibody-antigen complexes correlate with their thermal dissociation rates

Point mutants of three unrelated antifluorescein antibodies were constructed to obtain nine different single-chain Fv fragments, whose on-rates, off-rates, and equilibrium binding affinities were determined in solution. Additionally, activation energies for unbinding were estimated from the temperature dependence of the off-rate in solution. Loading rate-dependent unbinding forces were determined for single molecules by atomic force microscopy, which extrapolated at zero force to a value close to the off-rate measured in solution, without any indication for multiple transition states. The measured unbinding forces of all nine mutants correlated well with the off-rate in solution, but not with the temperature dependence of the reaction, indicating that the same transition state must be crossed in spontaneous and forced unbinding and that the unbinding path under load cannot be too different from the one at zero force. The distance of the transition state from the ground state along the unbinding pathway is directly proportional to the barrier height, regardless of the details of the binding site, which most likely reflects the elasticity of the protein in the unbinding process. Atomic force microscopy thus can be a valuable tool for the characterization of solution properties of protein-ligand systems at the single molecule level, predicting relative off-rates, potentially of great value for combinatorial chemistry and biology.     

Close association between HER-2 amplification and overexpression in human tumors of non-breast origin.

The relationship between HER-2 overexpression and gene amplification is well evaluated in breast cancers but remains unclear or controversial in many other tumor entities. Therefore, we tested the HER-2 status in more than 120 different tumor entities. 5751 tumor samples were analyzed on TMAs by immunohistochemistry (Hercept-Test, DAKO) and fluorescence in situ hybridization (PathVysion, Abbott-Vysis) under highly standardized conditions. HER-2 overexpression (score 2/3+) and amplification occurred most often in breast cancers but was also seen in 18 other tumor entities including cancers of the urinary bladder (amplification in 14.3%, overexpression in 6.7%), stomach (8.3/4.9%), endometrium (6.6/6.8%), lung (2.8/3.1%) and ovary (2.3/1.2%). Remarkably, a strong association between overexpression and amplification was seen in all examined cancer entities. Trastuzumab therapy is highly efficient in HER-2 amplified breast cancer both in metastatic disease and as an adjuvant therapy. A variety of other tumor entities including frequent neoplasms and cancers with often limited therapeutic options have similar patterns of HER-2 alterations as observed in breast cancer (ie high overexpression due to high level gene amplification). Such tumor entities should be carefully evaluated for a possible utility of trastuzumab treatment.