Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6

Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6-/- pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.     

Triggering sleep slow waves by transcranial magnetic stimulation

During much of sleep, cortical neurons undergo near-synchronous slow oscillation cycles in membrane potential, which give rise to the largest spontaneous waves observed in the normal electroencephalogram (EEG). Slow oscillations underlie characteristic features of the sleep EEG, such as slow waves and spindles. Here we show that, in sleeping subjects, slow waves and spindles can be triggered noninvasively and reliably by transcranial magnetic stimulation (TMS). With appropriate stimulation parameters, each TMS pulse at <1 Hz evokes an individual, high-amplitude slow wave that originates under the coil and spreads over the cortex. TMS triggering of slow waves reveals intrinsic bistability in thalamocortical networks during non-rapid eye movement sleep. Moreover, evoked slow waves lead to a deepening of sleep and to an increase in EEG slow-wave activity (0.5-4.5 Hz), which is thought to play a role in brain restoration and memory consolidation.     

Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.     

Pathologic Determinants of Survival After Resection of T3N0 (Stage IIA) Colorectal Cancer: Proposal for a New Prognostic Model

Purpose There is an increasing need for accurate prognostic stratification of patients with Stage II colorectal cancer to identify a subgroup of high-risk patients who may benefit from adjuvant therapies. This study was designed to evaluate the prognostic impact of a wide spectrum of pathologic parameters in a consecutive series of homogenously treated and well-characterized patients with Stage IIA (T3N0M0) colorectal cancer. Methods The study included 238 patients operated on by a single surgeon for Stage IIA colorectal tumors. The median postoperative follow-up was 110 (range, 96–120) months. At least 12 lymph nodes were harvested and examined in all the resection specimens. The prognostic value of 13 pathologic parameters, including lymph node occult disease (micrometastases) detected by immunohistochemistry, was investigated. Results Multivariate analysis identified tumor growth pattern (expanding or infiltrating; P = 0.01) and extent of tumor spread beyond muscularis propria (≤5 mm or >5 mm; P = 0.04) as the only factors having independent prognostic value. The combination of these two easily determined parameters allowed us to identify two groups of patients at low risk or high risk of tumor recurrence. The eight-year survival rates were 83.3 and 53.4 percent for the two groups, respectively. The high-risk group comprised those patients with infiltrating tumors and extramural tumor spread > 5 mm. Conclusions We propose a new and simple prognostic model to identify patients with high-risk Stage IIA colorectal cancer for whom adjuvant therapies may be justified and effective. Supported by grants from the Italian Ministry of University, Scientific and Technological Research, the Ente Cassa di Risparmio di Firenze, and the Associazione Italiana Ricerca sul Cancro.     

The attrition of young physician-scientists: problems and potential solutions

Physician-scientists have played a prominent role as thought leaders in American medicine over the past century. This group has produced many basic scientific advances and pioneered the translation of these advances into clinical practice. Now that we are in the post-genomic era, there is a greater need than ever for the continued participation of this group because of their unique ability to bridge the "bench to bedside." However, the number of physicians pursuing this career is static and their average age is rising. Recent data indicate that the many benefits of this career path are seen as being outweighed by so many negative factors, as to prompt the question, "Is this a career that a reasonable person should undertake in 2007 and beyond?" The following analysis suggests that the current answer is "no." We have identified the lack of professional security as a major factor that prompts young physicians to abandon the physician-scientist track. Because this problem has not been sufficiently emphasized, we believe current efforts are unlikely to reverse this disturbing trend. We propose strategies that seek to address this problem and help sustain young physician-scientists at career transition points at which they are most vulnerable to give up.     

Cardiac troponin I concentrations during on-pump coronary artery surgery

Perioperative myocardial infarction remains a frequent complication after coronary artery bypass grafting, and is associated with a poor prognosis. This retrospective study compared cardiac troponin I concentrations after on-pump bypass grafting in 2 groups of patients: 100 operated on using a single-clamp technique to perform anastomoses, and 80 operated on using a double-clamp technique. Postoperative cardiac troponin I levels were not significantly different between groups. It was concluded that the double-clamp technique did not reduce the incidence of myocardial infarction after elective on-pump coronary artery bypass grafting, and use of a single clamp is safe with no adverse effect on postoperative outcome.     

Estimate of white-coat effect and arterial stiffness

OBJECTIVES: Blood pressure (BP) measured in the office is usually higher than the average ambulatory BP, a difference generally taken as an estimate of the white-coat effect. This study was designed to assess whether such a difference is associated with impairment of the conduit arterial system. METHODS: We calculated the difference between office and average daytime peak systolic blood pressure (DeltaSBP) in 2778 hypertensive participants (1240 women) of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale cohort. Arterial stiffness was evaluated using an adjusted office pulse pressure to stroke volume ratio (PP/SV), measured at rest, which has previously been shown to predict cardiovascular outcome independent of echocardiographic left ventricular hypertrophy. Effective arterial elastance was also estimated. RESULTS: Across quintiles of PP/SV, significant linear, positive trends were found with age, the proportion of women, plasma glucose and triglyceride levels (0.05 > P < 0.0001). Heart rate measured in the office increased mildly with quintiles of PP/SV (P < 0.05). After adjusting for age, sex, body weight and office heart rate, DeltaSBP progressively increased with increasing quintiles of PP/SV (P for trend < 0.0001), whereas stroke volume decreased, paralleling the increase in left ventricular relative wall thickness (both P < 0.0001) and left ventricular mass index (P < 0.05). The significant increase in effective arterial elastance with quintiles of PP/SV was also independent of peak systolic BP, in addition to age, sex, heart rate and body weight. CONCLUSIONS: The difference between office BP and ambulatory BP, an estimate of the white-coat effect, is strongly associated with increased arterial stiffness, evaluated by a two-element fluid system accumulator.