Medical treatment of hepatic amebic abscess: rare need for percutaneous drainage

Although amebic liver abscess can virtually always be successfully treated medically, percutaneous drainage has been advocated recently. In 96 recently treated patients, therapeutic aspiration and percutaneous drainage were rarely needed. Most cases were correctly diagnosed by means of clinical, laboratory, and sonographic findings. Abscesses in only 13 (13.5%) patients were diagnostically aspirated. An abscess in one patient was therapeutically aspirated because the patient was responding slowly to medical therapy. No patient required catheter drainage. The key to successful amebic abscess management is medical therapy. Therapeutic drainage is rarely needed. Successfully treated patients occasionally respond slowly to medical therapy, and successfully treated amebic abscesses may enlarge or become bizarre-appearing on sonograms. This should not prompt therapeutic drainage. Diagnostic aspiration is appropriate when amebic and pyogenic abscesses are indistinguishable using clinical and imaging findings. Rare indications for therapeutic aspiration or drainage include pyogenic superinfection and large, juxtacardiac abscesses (potential intrapericardial rupture).     

Posttransplantation cyclosporine-induced lymphoproliferative disorders: clinical and radiologic manifestations

Fifteen allograft transplant recipients acquired lymphoproliferative disorders after immunosuppressive therapy with cyclosporine and steroids. Many of these lymphoproliferative disorders regressed or disappeared completely after reduction of cyclosporine dose. This disease has several aspects that distinguish it from usual posttransplantation lymphomas that occur with regimens that do not contain cyclosporine. The time course from transplantation to onset of lymphoma is relatively short, with an average of approximately 8 months. Organs show a wide spectrum of abnormalities typical of other immunosuppression-associated lymphomas, but there is unique sparing of the central nervous system. The tumor is also unique in that it responds to a decrease in the cyclosporine dose.     

Preclinical Assessment of Anti-cancer Therapeutic Strategies using in vivo Videomicroscopy

Preclinical in vivo studies of agents targeted against metastasis have to date been based primarily on end-point assays. Such assays can determine whether a treatment affects the number or size of metastases in an organ at a given time, but are poorly suited to determining how and at what stage in the process the treatment affected the end point. High resolution in vivo videomicroscopy permits direct observation of the process of metastasis as it occurs in living animals over time. Studies based on this technique and a cell accounting procedure we have devised, have shown that early steps in the metastatic process (survival in the circulation, extravasation) contribute relatively little to cell loss and metastatic inefficiency. Steps that occur after extravasation appear to be primarily responsible for the significant losses that result in metastatic inefficiency, and these steps may represent good targets for the design of new antimetastatic therapies. Matrix metalloproteinases have been implicated functionally in metastasis, and are viewed as an appropriate target in the development of inhibitors of metastasis. Using both endogenous and synthetic exogenous metalloproteinase inhibitors, we have shown that the inhibition of metastasis which these agents produce is not due to inhibition of cell extravasation from the circulation into the tissue, but to reduction of angiogenesis within metastases. A similar conclusion was reached concerning the mechanism of action, on metastasis, of carboxyamidotriazole, an inhibitor of calcium-mediated signal transduction which is currently in Phase II single agent clinical trials. In vivo videomicroscopy of sequential steps in metastasis, coupled with methods that allow precise quantification of cell loss at specific steps in the metastatic process, as well as standard histological assessment at stages identified as crucial, allow characterization of the details of metastasis as an ongoing process. This provides a powerful complement to end-point assays, for it allows mechanistic information to be obtained from in vivo experiments, an approach which provides better understanding of how and when a drug may function in vivo to inhibit metastasis. This revised version was published online in July 2006 with corrections to the Cover Date.     

The potency of immunomodulatory herbs may be primarily dependent upon macrophage activation

Standardized extracts of Echinacea, cat's claw, and saw palmetto were each evaluated for ability to activate macrophage and natural killer cells, in vitro, using two independent measures of activation for each immune cell population. A standard series of exposure concentrations were tested for each herbal extract in a panel of four assays that evaluated macrophage phagocytosis, macrophage synthesis of interleukin-12, natural killer (NK) cell cytocidal activity (synthesis of granzyme B), and NK cell synthesis of interferon-gamma. Macrophage phagocytosis was stimulated by all three herbs tested: saw palmetto (up to 2.3-fold, P < .05), Echinacea (up to 3.6-fold, P < .01), and cat's claw (up to 4.7-fold, P < .01). Additionally, NK cell synthesis of interferon-gamma was stimulated by saw palmetto (up to 6.3-fold, P < .01) and Echinacea (up to 8.1 fold, P < .01) but not by exposure to cat's claw. None of the three herbs stimulated macrophage synthesis of interleukin-12 or NK cell synthesis of granzyme B. Comparison of the in vitro data with our earlier observations that cat's claw and Echinacea (but not saw palmetto) were each effective in reducing B16/F10 lung tumor colony formation in C57BL/6J mice suggests macrophage activation is the primary means by which these herbs modulate the immune system. Thus, macrophage activation (phagocytosis) may provide a potentially higher throughput method to identify herbal extracts with in vivo stimulatory effects.     

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sj?gren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.     

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.     

亚太地区炎症性肠病处理共识意见(一)

虽然目前亚太地区尚无炎症性肠病（IBD）的大规模流行病学资料，但一系列研究显示其发病率和患病率呈上升趋势。与西方国家相比仍呈滞后现象。溃疡性结肠炎（UC）的发病率仍较克罗恩病（CD）高。除地域差异外。在一些多民族国家中，IBD尚可见种族差异。亚太地区IBD的遗传背景有异于西方国家。如据报道该地区CD患者未检出NOD2／CARDI5变异。一般而言，该地区IBD患者的临床过程似不如西方国家严重。 亚太地区IBD的诊断存在一些特殊问题。如缺乏IBD诊断金标准。存在多种小肠结肠炎，与IBD临床表现相似，使鉴别诊断特别困难。迄今为止，亚太地区IBD的诊断标准多采用西方国家的诊断标准。诊断必须逐步排除非IBD的小肠结肠炎。确诊应有典型的组织学表现。某些患者需借助随访和诊断性治疗才能确诊。进一步研究IBD发病机制将有助于开发更好的诊断标记物。 亚太地区IBD的治疗亦存在特殊问题。由于诊断困难。IBD患者常未能及时接受适当的药物治疗，但该地区仍广泛采用药物治疗方案。结合西方指南和本地经验可制定类似的处理原则。以利诱导缓解和维持缓解。提倡逐级使用基于病变范围、活动性和严重度的阶梯式治疗方案。对不同病例采用综合性、个体化的方法。随着对IBD发病机制和亚太地区IBD独特性的深入理解。合理、实用的药物治疗指南和应用生物制剂治疗将改善该地区IBD的治疗前景。     

Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation

Culture-based preemptive therapy with ganciclovir was shown to reduce the incidence of cytomegalovirus (CMV) disease after bone marrow transplantation (BMT). Culture techniques did not detect CMV in 12% to 13% of patients before the onset of CMV disease. In a prospective study, 71 patients either received preemptive therapy based on polymerase chain reaction (PCR) technique (37 patients) or on culture assays (34 patients). In both groups, therapy was continued until clinical signs disappeared and PCR negativity was documented. Twenty- two patients in the PCR group and 15 patients in the culture group received antiviral therapy. PCR allowed detection of the virus (median day, +32 v day +49; P = .006) and introduction of antiviral therapy (median day, +44 v day +54; P = .02) earlier than did culture assays. The incidences of CMV disease (2 of 37 v 8 of 34 in PCR group v culture group, respectively; P = .02) and CMV-associated mortality (0 of 37 v 5 of 34 in PCR group v culture group, respectively; P = .02) were decreased, and the duration of ganciclovir therapy (P < .001) was shorter in the PCR-monitored group. Incidence and median duration of severe neutropenia (less than 500/microL) were lower in the PCR group (two v eight episodes, P = .02; median duration, 1.5 v 5 days, P = .04), as was the incidence of nonviral infections during/after antiviral therapy (2 of 37 v 9 of 34; P = .012). Thus, preemptive therapy based on more sensitive detection methods such as the PCR assay reduces the incidence of CMV disease and CMV-related mortality. Additionally, stopping and withholding antiviral therapy in a PCR- negative patient is safe and allows reduction of the duration and side effects of antiviral therapy.     

In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.