Retained common bile duct stone as a consequence of a fundus-first laparoscopic cholecystectomy.

The fundus-first technique for laparoscopic cholecystectomy provides an alternative to the conventional dissection technique in patients at high risk for conversion to open cholecystectomy or at risk for bile duct injury. We report the complication of a retained common bile duct (CBD) stone after utilizing this technique. Intraoperative cholangiography (IOC) was not performed due to the concern for causing CBD injury in a patient with significant periductal inflammation and no risk factors for CBD stones. Following discharge, the patient developed scleral icterus 3 days later and returned for evaluation. He required endoscopic retrograde cholangiopancreatography for removal of a CBD stone. None of the four series reporting on this technique have described this complication. It should now be recognized that there is a risk of displacing a gallstone into the CBD in utilizing this technique. This report highlights the importance of intraoperative imaging of the CBD when using this technique, even in patients considered to be at low risk for having CBD stones. If IOC is considered hazardous, then intraoperative ultrasound should be the modality of choice.

Suramin inhibits the growth of malignant mesothelioma in vitro, and in vivo, in murine flank and intraperitoneal models.

Surgical debulking of malignant mesothelioma (MM) ultimately fails due to local recurrence. Suramin, an inhibitor of extracellular growth factors (ECGFs), has demonstrated efficacy in the treatment of malignant mesothelioma in a small case series. Our goal was to study survival benefits and disease progression in several MM animal models treated with suramin as a potential agent for adjuvant therapy. In vitro growth of human (REN, I-45), rat (II-45) and murine (AB12) mesothelioma cell lines were measured with or without suramin exposure. Human and murine MM tumors were implanted subcutaneously into murine flanks or injected intraperitoneally (i.p.) into murine abdominal cavities. Dose and treatment schedules were optimized to reduce the rate of tumor progression and to improve survival curves. Suramin inhibited the in vitro growth of all cell lines, reaching statistical significance (P<0.01) three doubling cycles after suramin administration, with a maximum inhibition of 10-25% of control growth. A significant time- and dose-dependent effect was observed. In vivo, suramin inhibited the growth of MM in the xenogeneic model (55% of control growth, P<0.01), and in the syngeneic model at both the low and high loading doses (46 and 36% of control growth, respectively, P<0.01). Suramin treatment inhibited in vivo growth in the REN intraperitoneal model shown grossly by necropsy of same day deaths comparing treatment and control animals. Tumor inhibition with the higher dose was also reflected by the lower mean tumor burden scores (control: 4.0 and high dose: 3.4). Suramin inhibits the growth of human, murine, and rat MM in vitro, in a time- and dose-dependent manner. Suramin also inhibits the growth of human MM flank and intraperitoneal xenografts in vivo in an immunodeficient host, as well as the growth of syngeneic murine flank tumors in an immunocompetent host. These studies demonstrate that suramin may have the potential to provide effective therapy for MM, and that further studies are necessary to elucidate the survival advantage of suramin mediated MM growth inhibition.

Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplants.

Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear. In the present study, we determined the kinetics of RCMV-accelerated TVS in a rat heart transplant model. Acute RCMV infection enhances the development of TVS in rat heart allografts, and this process is initiated between 21 and 24 days posttransplantation. The virus is consistently detected in the heart grafts from day 7 until day 35 posttransplantation but is rarely found at the time of graft rejection (day 45 posttransplantation). Grafts from RCMV-infected recipients had upregulation of chemokine expression compared to uninfected controls, and the timing of this increased expression paralleled that of RCMV-accelerated neointimal formation. In addition, graft vessels from RCMV-infected grafts demonstrate the increased infiltration of T cells and macrophages during periods of highest chemokine expression. These results suggest that CMV-induced acceleration of TVS involves the increased graft vascular infiltration of inflammatory cells through enhanced chemokine expression.

Homocysteine and arterial disease. Experimental mechanisms.

Hyperhomocysteinemia (hH(e)) in the general population is associated with incidence and progression of arterial occlusive disease, although the underlying mechanisms are not well defined. Current research supports a role for homocysteine (H(e))-mediated endothelial damage and endothelial dysfunction. This mechanism appears to be a key factor in subsequent impaired endothelial-dependent vasoreactivity and decreased endothelium thromboresistance. These consequences may predispose hyperhomocysteinemic vessels to the development of increased atherogenesis. Additional mechanisms of H(e)-mediated vascular pathology, including protein homocysteinylation and vascular smooth muscle cell proliferation may also play a role. Continued investigation into the mechanisms contributing to H(e) toxicity will provide further insight into the processes by which hH(e) may increase atherosclerosis.

Hyperhomocyst(e)inemia induces accelerated transplant vascular sclerosis in syngeneic and allogeneic rat cardiac transplants.

Chronic rejection (CR) and transplant vascular sclerosis (TVS) cause the majority of graft failures in cardiac transplantation. Hyperhomocyst(e)inemia [hH(e)] is associated with human TVS without a proven causal relationship. This study investigated the effect of hH(e) on graft survival and TVS in allogeneic and syngeneic rat cardiac transplants. Lewis recipients of heterotopic F344 heart allografts, received normal or hH(e)-inducing (folate, methionine) diets [controls: syngeneic transplanted [+/- hH(e), + CsA] and nontransplanted rats [+/- hH(e), +/- CsA]]. Serial plasma homocyst(e)ine [H(e)] levels were measured. TVS was assessed in clinically rejected grafts and a subset of pre-rejection normal diet allografts (day 64) (neointimal index, NI). The hH(e) diet elevated plasma H(e) levels. When compared with normal diet controls (n = 9), hH(e) diet allografts (n = 9) had decreased time to onset of CR (40 +/- 9 vs. 72 +/- 10d, p = 0.02), and graft failure (64 +/- 10 vs. 107 +/- 12d, p = 0.009). hH(e) diet allografts at rejection (n = 9, 64d) had more severe TVS (NI = 68 +/- 2) than both time-matched normal diet allografts (NI = 49 +/- 6, n = 8, 64d, p <0.001) and normal diet allografts at rejection (NI = 58 +/- 5, n = 9, 107d, p = 0.007). hH(e) induced TVS in syngeneic grafts (NI=50 +/- 3, n = 10 vs. NI = 5 +/- 3, n = 10, 130d, p <0.001). hH(e) accelerated rejection and increased the severity of TVS in allogeneic cardiac transplants, and induced TVS in syngeneic cardiac transplants.

Elimination of donor-specific alloreactivity prevents cytomegalovirus-accelerated chronic rejection in rat small bowel and heart transplants.

BACKGROUND: The primary cause for late failure of vascularized allografts is chronic rejection (CR) characterized by transplant vascular sclerosis (TVS). Cytomegalovirus (CMV) infection accelerates TVS and CR by unclear mechanisms involving direct effects of CMV, indirect effects of the recipient's immune response to CMV, or interactions between CMV and the recipient's alloreactivity. This study examined the role of CMV and the alloreactive response in the development of TVS using bone marrow chimerism (BMC) in rat small bowel (SB) and heart transplantation models. METHODS: Fisher 344 (F344) rat heart or SB grafts were transplanted into F344/Lewis bone marrow chimera. F344 heart or SB grafts transplanted into Lewis recipients (low-dose cyclosporine) were positive controls for the development of TVS. Lewis heart or SB grafts transplanted into Lewis recipients (+/-cyclosporine) were transplantation controls. The effect of rat CMV (RCMV) (5x105 plaque-forming units) on TVS (neointimal index, NI) and graft survival was studied in these groups. RCMV infection was assessed by serologic analysis and quantitative polymerase chain reaction techniques (TaqMan). RESULTS: RCMV infection accelerated the time to graft CR (SB 70-38 days; hearts 90-45 days) and increased the severity of TVS in both the SB allografts (day 38, NI=27 vs. 52) and the heart allografts (day 45, NI=43 vs. 83). Grafts from CMV-infected syngeneic recipients failed to develop TVS and CR. Donor-specific tolerance induced by BMC prevented allograft TVS and CR in both transplant models. In contrast to naïve Lewis recipients, RMCV infection failed to cause allograft TVS and CR in bone marrow (BM) chimeras. CONCLUSIONS: The events in CMV-induced acceleration of TVS involve a crucial interplay between CMV infection and the recipient's alloreactive immune response.

Neointimal hyperplasia in balloon-injured rat carotid arteries: the influence of hyperhomocysteinemia.

PURPOSE: Hyperhomocyst(e)inemia (hH[e]) is a risk factor for atherosclerosis. Neointimal hyperplasia (NH) after vessel injury can contribute to atherosclerosis. In this study, we investigated the effects of hH(e) on NH formation after arterial balloon injury in rats. METHODS: Lewis rats that were given a hH(e)-inducing (high methionine, low folate) or normal diet for 150 days underwent common carotid artery (CCA) balloon injury. Two and 4 weeks after injury, CCAs were formalin perfusion-fixed, sectioned, and stained for elastin. Neointimal index (NI, percent lumen occlusion) and neointima (N) and media (M) area were measured by using computer-interfaced microscopy. RESULTS: Plasma homocyst(e)ine (H[e]) levels were elevated in rats given the study diet compared with rats given the normal diet at days 40 and 90 (69 +/- 8 and 73 +/- 9 micromol/L vs 4 +/- 0.4 and 4 +/- 0.6 micromol/L, P <.001). After balloon injury, the CCA NI and N/M ratio, but not the M area, were increased by hH(e) compared with normal plasma H(e) (2 weeks [n = 6,7]: NI = 7.3 +/- 1.7 vs 2.9 +/- 0.7, P =.002, and N/M = 0.31 +/- 0.08 vs 0.08 +/- 0.02, P <.001; 4 weeks [n = 4,7]: NI = 13.1 +/- 2.2 vs 6.3 +/- 1.3, P =.002, and N/M = 0.36 +/- 0.08 vs 0.17 +/- 0.03, P <.001). CONCLUSION: hH(e) accelerates NH in a rat CCA balloon-injury model. The effect of hH(e) on NH may contribute to increased atherosclerosis in humans with hH(e).