Transplantation of a severely lacerated liver – a case report with review of the literature

Abstract:  Using lacerated livers for liver transplantation (LTx) can add an option to the extended donor criteria. We present an LTx case using a severely lacerated liver and review of the literature for reported cases. We used a high-grade lacerated liver from a 19-yr-old brain-dead patient caused by traffic accident. The liver had grade IV and II lacerations in the right and left lobe, respectively. Lacerations were managed by sealants, stitching and perihepatic packing. The liver was transplanted to a 49-yr-old man suffering from hepatocellular carcinoma on hepatitis C-induced liver cirrhosis. The two-yr follow-up was uneventful. All published LTx cases using traumatized livers (n = 18) were analyzed. The liver injury ranged from subcapsular hematoma to deep ruptures. Most reported lacerations were in the right lobe, which were managed by digital compression, suturing, electrocautery, and perihepatic packing. The reported complications were primary non- (18%), or poor function, liver abscess, bilioma, and subhepatic hematoma each in one case (5.5%). Six-month graft and patient survival were 71% and 88%, respectively. With meticulous management lacerated livers can be transplanted successfully. Because of complexity of the management, procurement and transplantation should be done by experienced liver surgeons. These organs are marginal grafts and should be offered to selected patients.     

Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin

To determine the role of recombinant human erythropoietin as a possible treatment option in Friedreich's ataxia, we performed an open-label clinical pilot study. Primary outcome measure was the change of frataxin levels at week 8 versus baseline. Twelve Friedreich's ataxia patients received 5,000 units recombinant human erythropoietin three times weekly subcutaneously. Frataxin levels were measured in isolated lymphocytes by enzyme-linked immunosorbent assay. In addition, urinary 8-hydroxydeoxyguanosine and serum peroxides, were measured. Treatment with recombinant human erythropoietin showed a persistent and significant increase in frataxin levels after 8 weeks (p < 0.01). All patients showed a reduction of oxidative stress markers.     

Markers of inflammation and fibrosis are related to cardiovascular damage in hypertensive patients with metabolic syndrome

BACKGROUND: Previous studies have shown that metabolic syndrome (MS) is associated with an increased susceptibility to develop cardiovascular damage (CD). Experimental evidence indicates that inflammation and fibrosis could play a critical role in the development of CD in hypertension. This issue has not been clarified yet in patients with MS. The aim of our study was to investigate the relationship between markers of inflammation and fibrosis with CD in hypertensive patients with and without MS. METHODS: One hundred twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, biochemical parameters, 24-h urinary albumin excretion rate (UAER), levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and procollagen type 1 carboxy-terminal propeptide (PICP) were measured. All patients underwent an echocardiographic examination with transmitral Doppler and tissue Doppler imaging (TDI). RESULTS: Left ventricular mass indexed by height(2.7) (LVM/h(2.7)) (P < .001), early diastolic peak flow velocity/early myocardial diastolic velocity ratio (E/Em ratio), a TDI index of diastolic function (P < .001), and 24-h UAER (P < .05) were significantly higher in the group with MS, whereas peak myocardial systolic velocity (Sm), a TDI index of systolic function (P < .001), was lower. Serum levels of CRP (P < .001), TNF-alpha (P < .05), TGF-beta (P < .01), and PICP (P < .001) were significantly increased in MS. These markers were significantly related to higher LVMI(2.7), higher E/Em ratio, and increased 24-h UAER and a lower Sm in the whole population, with a further significant enhancement in MS. CONCLUSIONS: Cardiovascular damage is more frequent in hypertensives with MS than in hypertensives without MS, and this is significantly related to the increased levels of inflammation and fibrosis found in hypertensives with MS.     

Exclusion of patients with arteriosclerosis reduces long-term recurrence rate of presumed arterial embolism after PFO closure

BACKGROUND: Percutaneous transcatheter closure of patent interatrial communications after presumed paradoxical embolism is used as an alternative to surgery or long-term anticoagulation for the treatment of patients who are at risk for recurrent thromboembolism. To avoid atherosclerotic events to be judged as recurrent paradoxical embolism, we prospectively excluded all patients with detectable arteriosclerosis from our series and investigated long-term results. METHODS AND RESULTS: We report the outcome of 180 patients who underwent percutaneous transcatheter closure of patent foramen ovale (PFO), PFO like atrial septal defect (ASD), or an ASD because of paradoxical embolism. One hundred four patients had cerebral embolism, 57 had transient ischemic attacks, 16 coronary embolism, and 3 had peripheral embolism. Twenty-three patients experienced multilocal arterial embolism. One hundred twenty-five patients had a PFO, 63 of them with an atrial septal aneurysm (ASA), 24 a PFO-like ASD (7 of them with an ASA), and 31 had an ASD. After 18 months, only 5 patients (2.8%) showed a trivial residual shunt. At a mean follow-up of 40 months (range 4 to 88), resulting in 602 observed patient-years, only 1 patient experienced a presumed paradoxical (coronary) embolism (calculated annual risk to suffer a recurrent thromboembolic event: 0.16%). CONCLUSIONS: Percutaneous transcatheter closure of PFO/ASD is a safe and effective therapeutic option for the secondary prevention of presumed paradoxical embolism. It is associated with a high success rate, low incidence of hospital complications, and very low frequency of recurrent systemic embolic events.     

The presence of antibodies recognizing a peptide derived from the second conserved region of HIV-1 gp120 correlates with non-progressive HIV infection

The C-terminus of the second conserved region of HIV-1 gp120 represents a functionally important domain, as it encompasses amino acids directly involved in the binding to the CD4 receptor and in post-receptor binding events. Previous studies have suggested that antibodies with specific affinity to a 23 amino acids-long NTM polypeptide, derived from this HIV-1 gp120 domain, may be involved in the control of HIV disease progression. In the current work, we searched for NTM-recognizing antibodies in specific cohorts of HIV-1 infected individuals, including long-term nonprogressors (LTNP) and progressors. For this purpose, we employed a previously defined bioinformatics criterion for design of an NTM peptide mimetic to select an octapeptide, NTMs (FTDNAKTI), which is more suitable for use in a solid-state enzyme-linked immunosorbent assay (ELISA). Our results show that NTMs-reactive antibodies are significantly more prevalent (p < 0.01) in LTNP as compared to progressors and healthy control subjects, indicating their association with non-progressive infection. The presence of antibodies recognizing the second conserved region of the HIV-1 gp120 derived peptide, NTMs, in LTNP sera suggest that these antibodies could be of considerable interest for development of anti-HIV immune-based therapies and vaccines.     

AMP-activated protein kinase: a physiological off switch for murine gastric acid secretion

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been shown to be a metabolic energy regulator in various cells. Activation is a direct result of rising AMP concentration coupled with falling adenosine triphosphate (ATP). AMPK activation during metabolic stress consequently reduces cellular ATP consumption. The gastric parietal cell has a large abundance of mitochondria per cell volume due to the numerous energy-dependent transporters and channels responsible for acid secretion. We identified AMPK in the parietal cell as a metabolic energy regulator that can switch acid secretion off as cellular ATP levels fall. AMPK presence in murine gastric glands was evaluated by immunofluorescent localization. We used a digital imaging system to monitor acid secretion as observed by proton efflux from parietal cells in hand-dissected gastric glands loaded with the pH-sensitive dye 2′,7′-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein. Individual murine gastric glands were exposed to histamine, pentagastrin, or carbachol. AMPK was pharmacologically activated with 5-aminoimidazole-4-carboxamide-1-β-d-riboside (AICAR) monophosphate or inhibited with 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (compound C) or ATP. Acid secretion was evaluated under these conditions as the rate of intracellular pH recovery. In addition, whole-stomach pH measurements were performed. Immunofluorescent localization confirmed the presence of AMPK in gastric mucosa. Exposure to AICAR monophosphate significantly reduced secretagogue-induced acid secretion; addition of compound C or ATP restored acid secretion. Our results indicate that secretagogue-induced acid secretion could be significantly reduced with AMPK activation and restored with its deactivation. We therefore propose the AMPK as a cellular metabolic off switch for gastric acid secretion.     

Mesenteric Lymph Nodes Confine Dendritic Cell-Mediated Dissemination of Salmonella enterica Serovar Typhimurium and Limit Systemic Disease in Mice

In humans with typhoid fever or in mouse strains susceptible to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, bacteria gain access to extraintestinal tissues, causing severe systemic disease. Here we show that in the gut-draining mesenteric lymph nodes (MLN), the majority of S. Typhimurium-carrying cells show dendritic-cell (DC) morphology and express the DC marker CD11c, indicating that S. Typhimurium bacteria are transported to the MLN by migratory DCs. In vivo FLT-3L-induced expansion of DCs, as well as stimulation of DC migration by Toll-like receptor agonists, results in increased numbers of S. Typhimurium bacteria reaching the MLN. Conversely, genetically impaired DC migration in chemokine receptor CCR7-deficient mice reduces the number of S. Typhimurium bacteria reaching the MLN. This indicates that transport of S. Typhimurium from the intestine into the MLN is limited by the number of migratory DCs carrying S. Typhimurium bacteria. In contrast, modulation of DC migration does not affect the number of S. Typhimurium bacteria reaching systemic tissues, indicating that DC-bound transport of S. Typhimurium does not substantially contribute to systemic S. Typhimurium infection. Surgical removal of the MLN results in increased numbers of S. Typhimurium bacteria reaching systemic sites early after infection, thereby rendering otherwise resistant mice susceptible to fatal systemic disease development. This suggests that the MLN provide a vital barrier shielding systemic compartments from DC-mediated dissemination of S. Typhimurium. Thus, confinement of S. Typhimurium in gut-associated lymphoid tissue and MLN delays massive extraintestinal dissemination and at the same time allows for the establishment of protective adaptive immune responses.Infection with Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever that, following consumption of contaminated food or water, starts with an intestinal phase characterized by colonization of the intestine and transepithelial uptake that provides the pathogen with access to the intestinal mucosa. Disease then progresses to a systemic phase as bacteria spread from the intestine to the spleen and liver. Infection with another Salmonella enterica serovar, S. Typhimurium, in most cases causes locally restricted enteritis in humans without eliciting systemic disease. In contrast, oral infection of susceptible mice with S. Typhimurium, but not S. Typhi, leads to a fatal systemic disease resembling the human disease and is used as a model of human typhoid fever. Notably, susceptible mouse strains that develop fatal systemic disease carry a mutation in the Slc11a1 (formerly natural resistance-associated macrophage protein-1, Nramp-1) gene and include widely used laboratory strains, such as C57BL/6 and BALB/c. In contrast, resistant mouse strains, such as 129Sv, express increased levels of Slc11a1 in infected cells (3, 35), thereby controlling the intracellular replication of S. Typhimurium and surviving infection. Thus, care needs to be taken when comparing the pathomechanisms in susceptible mouse strains infected with S. Typhimurium and human typhoid fever.Exploiting the M-cell gateway to the gut mucosa is thought to be an important way in which S. Typhimurium overcomes the tight intestinal epithelial barrier (17). M cells continuously sample the gut lumen and transport particulate antigens, including live microbes, across the epithelium to immune cells located in the underlying mucosal tissue. The majority of M cells are located within the follicle-associated epithelia of the gut-associated lymphoid tissue (GALT), such as Peyer''s patches (PP), and solitary intestinal lymphoid tissue (SILT) (13). Consistently, in early phases of infection the highest bacterial loads and levels of inflammation are observed at these sites (10). Uptake of S. Typhimurium via PP M cells was shown to cause local damage in the follicle-associated epithelium within 30 min of infection, thus generating gaps in the epithelium that allow rapid bacterial spread to the organs before an immune response can be initiated (17). Apart from M cells associated with lymphoid follicles, a low number of M cells is interspersed throughout the normal epithelium and has been associated with the invasion of S. Typhimurium in mice lacking organized lymphoid tissue in the intestine (15). In addition to the exploitation of these active sampling mechanisms, S. Typhimurium can breach the intestinal barrier through the normal absorptive epithelium (32).Two major virulence determinants of S. Typhimurium are encoded by pathogenicity islands SPI-1 and SPI-2 that translate into two separate type-III secretion systems (TTSS). The SPI-2-encoded secretion system TTSS-2 mediates the intracellular survival of the pathogens and their persistence in systemic target organs, like the liver and spleen. Consequently, TTSS-2-deficient S. Typhimurium strains cannot establish persistent infection and mice infected intraperitoneally with these strains will clear the infection (12, 25, 31).In contrast, TTSS-1-defective strains are not reduced in virulence when administered intraperitoneally but are clearly attenuated following oral infection, demonstrating that TTSS-1 is essential for the efficient entry of S. Typhimurium into host tissues (7). Still, TTSS-1-deficient mutants are capable of gaining access to the mucosal tissues, presumably via host-directed sampling mechanisms that act independently of S. Typhimurium-encoded virulence genes. There is evidence for active M-cell-independent bacterial uptake performed by dendritic cells (DC) residing in the lamina propria directly underneath the intestinal epithelium (28). These DC express the chemokine receptor CX₃CR1 that is essential for the formation of transepithelial extensions by these cells that allow the capture of bacteria directly from the gut lumen (24). Hapfelmeier and colleagues showed that conditional depletion of DC during the phase of transepithelial pathogen uptake strongly reduced the colonization of the lamina propria by TTSS-1-deficient S. Typhimurium (11). In contrast, depleting these DC at later phases of infection, i.e., after epithelial transmigration had occurred, did not influence the systemic spread of the pathogen. Similarly, depletion of DC had no significant influence on the outcome of oral infection with a TTSS-1-sufficient wild-type S. Typhimurium strain (11).Whatever mechanism allows S. Typhimurium to enter host tissues, a central issue in understanding systemic disease development relates to the mechanisms that enable S. Typhimurium to disseminate from the intestine. In tissue, S. Typhimurium infects monocytes/macrophages and neutrophils that show potent antibacterial activity (8, 29, 30) and are essential for host survival. In contrast, S. Typhimurium infection of DC induces their maturation and antigen presentation, thereby initiating adaptive immune responses (for a recent review, see reference 33). Moreover, S. Typhimurium has been observed in B cells, and carriage by any of these cells might allow S. Typhimurium to reach extraintestinal tissues. Indeed, experiments using mice deficient in β2-integrin, a molecule associated with cell migration, showed reduced numbers of S. Typhimurium bacteria in the spleen and liver after oral but not intraperitoneal infection. In particular, cells of the myeloid lineage have been suggested to confer β2-integrin-dependent S. Typhimurium dissemination (36).Thus, at present, multiple mechanisms have been shown to allow for the initial uptake of S. Typhimurium, as well as for the dissemination of the pathogen. However, the actual contributions of the various mechanisms remain enigmatic. In this study, we demonstrate that after oral infection, DC chiefly contribute to S. Typhimurium progression from the intestine to the mesenteric lymph nodes (MLN) but not to hepatosplenic infection. Furthermore, we show that the MLN serve as a vital barrier preventing lethal systemic infection.     

High-risk multiple myeloma: does it still exist?

Major improvement milestones in the treatment of patients with multiple myeloma (MM) include the introduction of the melphalan/prednisone combination in the 1960s, high-dose chemotherapy supported by autologous stem cell transplant in the 1980s, and the more recent introduction of the novel agents thalidomide, lenalidomide, and bortezomib. Historically, age and eligibility for autologous stem cell transplantation were the primary basis for treatment selection, but, from a biologic standpoint, MM therapy was "one size fits all," in that therapy was not tailored based on molecular or other features that define subtypes of MM. Recently, novel therapies have extended overall survival for the broad spectrum of patients with myeloma. Moreover, newer data demonstrate that novel therapies may ameliorate the prognostic impact of predictors of high risk and poor outcome in MM, which suggests that patients with MM and with high-risk disease should receive novel agents. Such approaches may constitute nascent steps toward individualized therapy, ie, the selection of highly effective therapies based on specific features exhibited by an individual patient's MM. However, prospective data that demonstrate the validity of these approaches are lacking. Definitive, multi-institutional clinical trials are required before redefining standards of myeloma care based on this approach.