Optimal timing of the Ross procedure in the management of chronic aortic incompetence in the young

The appropriate timing of intervention in patients with chronic aortic incompetence allows recovery of ventricular function. We sought to determine the optimal timing of the Ross procedure for chronic aortic incompetence in young patients. We retrospectively analysed case notes, and measured pre- and postoperative echocardiographic indexes of left ventricular function, in patients who had undergone the Ross procedure for chronic aortic incompetence. METHODS AND RESULTS: We found 21 patients with preoperative and postoperative data suitable for analysis. Their age at operation ranged from 5.6 to 26 years, with a median of 13.8 years, and the duration of follow-up was from 0.5 to 6.8 years, with a median of 2.4 years. The preoperative left ventricular end-diastolic dimension was converted to a z-score, and this was used as a threshold to divide the population. Using the threshold of a preoperative left ventricular z-score of more than 3 to divide the population did not show any difference in postoperative parameters of left ventricular function. Significant differences were found postoperatively, however, in both the left ventricular z-score and the ratio of left ventricular end-diastolic radius to posterior wall thickness in diastole, with a cutoff preoperative threshold z-score greater than 4. CONCLUSION: The increase in the ratio of left ventricular end-diastolic radius to the thickness of the posterior wall in diastole would suggest that there is disruption of left ventricular short axis architecture and myocardial contractile function when intervention is postponed. The significantly larger left ventricular dimension at end-diastole, despite the reduction in volume loading post surgery, may also demonstrate irreversible structural changes. Our data would suggest that recovery of left ventricular function is less likely when the left ventricular z-score has reached the value of 4, and that, ideally, intervention should be performed when the z-score approaches or exceeds 3.     

Evaluation of a simple operational approach for monitoring resistance to antimalarial drugs in Peru

Since 1994, the Peruvian Malaria Control Program has used a simplified operational approach for monitoring antimalarial drug efficacy, in which blood smears are taken 7 and 14 days after treatment from all patients diagnosed with malaria at Ministry of Health facilities. The proportion of patients with parasitaemia on one of their return visits provides an indication of the efficacy of the drug being administered. We compared this approach for antimalarial drug resistance monitoring to the more labour-intensive and expensive World Health Organization (WHO) 14-day in vivo efficacy trial at six sites in the Amazon Basin and the north coast of Peru. Although the proportion of treatment failures at 7 and 14 days identified by the operational monitoring system was considerably lower than the results of the WHO in vivo efficacy test, the operational approach did accurately reflect the overall efficacy or lack of efficacy of the drugs being evaluated. Differences in the results of the two methods were greatest in the Peruvian Amazon region, where fully supervised treatment and patient follow-up is very difficult due to the widely dispersed population. While the operational approach cannot be considered an alternative to WHO in vivo testing for evaluating the efficacy of antimalarial drugs or for recommending changes in malaria treatment policy, if treatment is supervised and follow-up blood smears taken as scheduled, this method could serve as a simple, inexpensive and sustainable early warning system for reduced drug efficacy.     

Hypoxia,angiotensin-II,and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK,Fas-L and cyclin D1

BACKGROUND: Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fas-L, or through decreased expression of cyclin D(1). AIMS: We tested the hypothesis that hypoxia (HX), angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK, and thus initiating stimulus specific changes in Fas-L and cyclin D(1) expression in failing cardiomyocytes. METHODS AND RESULTS: Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D(1) detection were performed. HX-induced apoptosis was associated with increased Fas-L expression, A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D(1) expression, and NEPI-induced apoptosis was associated with decreased cyclin D(1) expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D(1) expression. CONCLUSIONS: HX, A-II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas-L and cyclin D(1) expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D(1).     

Suppressed clinical experimental autoimmune myasthenia gravis in bm12 mice is linked to reduced intracellular calcium mobilization and IL-10 and IFN-gamma release by acetylcholine receptor-specific T cells

Class II MHC mutant bm12 mice have an increased resistance to experimental autoimmune myasthenia gravis (EAMG) compared to C57BL/6 mice. In vitro, this relative resistance was mainly associated with a reduced cytokine response to acetylcholine receptor (AChR) and its dominant pathogenic peptide alpha 146-162, whereas the response to the epitope alpha 111-126 remained intact. Calcium mobilization after stimulation of AChR-immune T cells with AChR or alpha 146-162 peptide, but not alpha 111-126 peptide, was decreased in bm12 compared to C57BL/6. Thus, the reduced incidence of clinical EAMG in bm12 is linked to lower IFN-gamma and IL-10 release, and intracellular calcium mobilization by alpha 146-162-specific T cells.     

T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice

BACKGROUND: Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development. METHODS: Three anti-human CD3-directed immunotoxins, DT389-scFv(UCHT1), scFv(UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tg(epsilon)600+/-, that have T cells expressing both human and murine CD3epsilon antigens. RESULTS: These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted >99% of tg(epsilon)600+/- lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tg(epsilon)600+/- recipients to 25 days from 10 days in untreated animals. T-cells recovered to approximately 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited >100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection. CONCLUSION: These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.     

Regulatory functions of alloreactive Th2 clones in human renal transplant recipients

BACKGROUND: Chronic allograft rejection is the major clinical problem in organ transplantation. There is evidence that indirect T cell recognition of donor-specific HLA peptides may play an important role in the immunopathogenesis of chronic allograft rejection. We have recently shown that HLA allopeptide-specific T cell clones generated from renal transplant recipients with chronic allograft nephropathy are of the Th1 phenotype, while those from stable patients are Th2. There is evidence in experimental animal models of autoimmunity and transplantation that Th2 cells may function to regulate immune responses, but the biological relevance of these observations in humans has not been reported. METHODS: The purpose of this study was to investigate the putative regulatory functions of alloreactive human Th2 clones. HLA-DR allopeptide-specific Th1 and Th2 cell clones were generated from peripheral blood lymphocytes of human renal allograft recipients with chronic allograft nephropathy (CAN) or with stable renal function (SRF), respectively. RESULTS: An in vitro co-culture system showed that the proliferative responses of Th1 clones from patients with CAN were significantly inhibited by the Th2 clones in response to the donor-derived HLA allopeptides. In addition, co-culture of the Th2 clones inhibited cytokine production (IFN-gamma) by the Th1 clones in response to the donor-specific peptides. The regulatory functions of Th2 clones were antigen-specific since they only occurred when both the Th1 and Th2 clones were reactive to the same HLA-DR allopeptide, and were mediated by IL-4 and IL-10. CONCLUSIONS: This is the first demonstration, to our knowledge, indicating that Th2 cells may function to regulate indirect Th1 alloimmune responses that are critical for the progression of CAN in humans.     

The effects of general anesthetics on norepinephrine release from isolated rat cortical nerve terminals

Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release from sympathetic neurons and other neurosecretory cells. However, the actions of general anesthetics on NE release from central nervous system (CNS) neurons are unclear. We investigated the effects of representative IV and volatile anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were preloaded with [(3)H]NE and superfused with buffer containing pargyline (a monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the superfusate in the absence or presence of various anesthetics. Depolarization with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM) evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30 microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at larger concentrations, reduced stimulus-evoked release. The volatile anesthetic halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect stimulus-evoked release. These findings demonstrate drug-specific stimulation of basal NE release. Noradrenergic transmission may represent a presynaptic target for selected general anesthetics in the CNS. Given the contrasting effects of general anesthetics on the release of other CNS transmitters, the presynaptic actions of general anesthetics are both drug- and transmitter-specific. IMPLICATIONS: General anesthetics affect synaptic transmission both by altering neurotransmitter release and by modulating postsynaptic responses to transmitter. Anesthetics exert both drug-specific and transmitter-specific effects on transmitter release: therapeutic concentrations of some anesthetics stimulate basal, but not evoked, norepinephrine release, in contrast to evoked glutamate release, which is inhibited.     

Endovascular repair of abdominal aortic aneurysms: risk stratified outcomes

OBJECTIVE: The impact of co-morbid conditions on early and late clinical outcomes after endovascular treatment of abdominal aortic aneurysm (AAA) was assessed in concurrent cohorts of patients stratified with respect to risk for intervention. SUMMARY BACKGROUND DATA: As a minimally invasive strategy for the treatment of AAA, endovascular repair has been embraced with enthusiasm for all prospective patients who are suitable anatomical candidates because of the promise of achieving a durable result with a reduced risk of perioperative morbidity and mortality. METHODS: From April 1994 to March 2001, endovascular AAA repair was performed in 236 patients using commercially available systems. A subset of patients considered at increased risk for intervention (n = 123) were categorized, as such, based on a preexisting history of ischemic coronary artery disease, with documentation of myocardial infarction (60%) or congestive heart failure (35%), or due to the presence of chronic obstructive disease (21%), liver disease, or malignancy. RESULTS: Perioperative mortality (30-day) was 6.5% in the increased-risk patients as compared to 1.8% among those classified as low risk (P = NS). There was no difference between groups in age (74 +/- 9 years vs. 72 +/- 6 years; mean +/- SD), surgical time (235 +/- 95 minutes vs. 219 +/- 84 minutes), blood loss (457 +/- 432 mL vs. 351 +/- 273 mL), postoperative hospital stay (4.8 +/- 3.4 days vs. 4.0 +/- 3.9 days), or days in the ICU (1.3 +/- 1.8 days vs. 0.5 +/- 1.6 days). Patients at increased risk of intervention had larger aneurysms than low-risk patients (59 +/- 13 mm vs. 51 +/- 14 mm; P <.05). Stent grafts were successfully implanted in 116 (95%) increased-risk versus 107 (95%) low-risk patients (P = NS). Conversion rates to open operative repair were similar in increased-risk and low-risk groups at 3% and 5%, respectively. The initial endoleak rate was 22% versus 20%, based on the first CT performed (either at discharge or 1 month; P = NS). To date, increased-risk patients have been followed for 17.4 +/- 15 months and low-risk patients for 16.3 +/- 14 months. Kaplan-Meier analysis for cumulative patient survival demonstrated a reduced probability of survival among those patients initially classified as at increased risk for intervention (P <.05, Mantel-Cox test). Both cohorts had similar two-year primary and secondary clinical success rates of approximately 75% and 80%, respectively. CONCLUSIONS: Early and late clinical outcomes are comparable after endovascular repair of AAA, regardless of risk-stratification. Notably, 2 years after endovascular repair, at least one in five patients was classified as a clinical failure. Given the need for close life-long surveillance and the continued uncertainty associated with clinical outcome, caution is dictated in advocating endovascular treatment for the patient who is otherwise considered an ideal candidate for standard open surgical repair.     

Surgical repair of supposedly multiple defects within the apical part of the muscular ventricular septum

BACKGROUND: A distinct defect has been described within the apical part of the muscular ventricular septum, which has multiple orifices when seen from its right ventricular aspect. Closure has been suggested using umbrella devices introduced on a catheter. Such an intervention, however, can be technically difficult in small infants. METHODS: We have recently seen two examples of this type of complex communication between the apexes of both left and right ventricles. Neither could be closed by catheterization. A surgical approach was used through a modified apical right ventriculotomy. We have also studied two autopsied specimens, which clarify the morphologic arrangement. RESULTS: Both patients were closed successfully, with trivial residual shunt and good biventricular functions. The patients were clinically well at 2-year follow-up. CONCLUSIONS: Surgical division of right ventricular trabeculations makes it feasible to identify and repair the septal deficiency, which is a solitary hole. On the basis of our morphologic study, we offer an explanation for the anatomic arrangement that differs from the one proposed by recent previous investigators. If the ventricular incision is appropriately placed, our anatomic studies suggest that it is possible to visualize the solitary opening from its right ventricular aspect, and achieve surgical closure with a single patch.