En Bloc Multivisceral and Kidney Transplantation in an HIV Patient: First Case Report.

The continual improvement in outcome with highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection and visceral transplantation for gut failure stimulated our interest in lifting HIV infection as a contraindication for intestinal and multivisceral transplantation. This report is the first to describe visceral transplantation in a patient with HIV infection. A HAART regimen was introduced in the setting of short-gut syndrome with successful suppression of HIV viral load. The indication for en bloc multivisceral and kidney transplantation was end-stage liver failure with portomesenteric venous thrombosis and chronic renal insufficiency. The underlying hepatic pathology was alcoholic and home parenteral nutrition-associated cirrhosis. Surgery was complicated due to technical difficulties with excessive blood loss and long operative time. The complex posttransplant course included multiple exploratory laparotomies due to serious intra-abdominal and systemic infections. Heavy immunosuppression was required to treat recurrent episodes of severe allograft rejection. Posttransplant oral HAART successfully sustained undetectable viral load. Unfortunately, the patient succumbed to sepsis 3 months posttransplant. With new insights into the biology of gut immunity, mechanisms of allograft tolerance, and HIV-associated immune dysregulation, successful outcome is anticipated, particularly in patients who are in need of isolated intestinal and less-organ-contained visceral allografts.

Split liver transplantation using Hemiliver graft in the MELD era: a single center experience in the United States.

Under the "sickest first" Model for End-Stage Liver Disease (MELD) allocation, livers amenable to splitting are most often allocated to patients unsuitable for split liver transplantation (SLT). Our experience with SLT using hemilivers was reviewed. From April 2004 to June 2012, we used 25 lobar grafts (10 left lobes and 15 right lobes) for adult-sized recipients. Twelve recipients were transplanted with primary offers, and 13 were transplanted with leftover grafts. Six grafts were shared with other centers. The data were compared with matched whole liver grafts (n = 121). In 92% of donors, the livers were split in situ. Hemiliver recipients with severe portal hypertension had a greater graft-to-recipient weight ratio than those without severe portal hypertension (1.96% vs. 1.40%, p < 0.05). Hemiliver recipients experienced biliary complications more frequently (32.0% vs. 10.7%, p = 0.01); however, the 5-year graft survival for hemilivers was comparable to whole livers (80.0% vs. 81.5%, p = 0.43). The secondary recipients with leftover grafts did not have increased incidences of graft failure (p = 0.99) or surgical complications (p = 0.43) compared to the primary recipients. In conclusion, while routine application is still controversial due to various challenges, hemiliver SLT can achieve excellent outcomes under the MELD allocation.

Adjuvant treatment of hepatocellular carcinoma after orthotopic liver transplantation: do we really need this?

Hepatocellular carcinoma (HCC) continues to rise and is still a major cause of mortality. Orthotopic liver transplantation (OLT) continues to give patients the best chance for cure, but recurrence of the disease remains a problem. Even with the implementation of the Milan criteria, recurrence rates have been shown to be 8-15% in most studies and even higher in patients who are beyond the Milan criteria. Therefore, several investigators have looked into the value of adjuvant therapy using systemic cytotoxic chemotherapy in HCC after OLT. Unfortunately, most of the trials are very small, and the results have been disappointing. But trials using Licartin seem to be promising, and other drugs such as FOLFOX and sorafenib warrant further investigation based on their efficacy in the advanced disease. In this review, we will review the current data on efficacy and rationale of adjuvant treatment for HCC after OLT including novel biomarkers.

Use of tissue plasminogen activator in liver transplantation from donation after cardiac death donors.

Ischemic-type biliary stricture (ITBS) occurs in up to 50% after liver transplantation (LT) from donation after cardiac death (DCD) donors. Thrombus formation in the peribiliary microcirculation is a postulated mechanism. The aim was to describe our experience of tissue plasminogen activator (TPA) administration in DCD-LT. TPA was injected into the donor hepatic artery on the backtable (n = 22). Two recipients developed ITBS including one graft failure. Although excessive postreperfusion bleeding was seen in 14 recipients, the amount of TPA was comparable between those with and without excessive bleeding (6.4 ± 2.8 vs. 6.6 ± 2.8 mg, p = 0.78). However, donor age (41 ± 12 vs. 29 ± 9 years, p = 0.02), donor BMI (26.3 ± 5.5 vs. 21.7 ± 3.6 kg/m(2) , p = 0.03), previous laparotomy (50% vs. 0%, p = 0.02) and lactate after portal reperfusion (6.3 ± 4.6 vs. 2.8 ± 0.9 mmol/L, p = 0.005) were significantly greater in recipients with excessive bleeding. In conclusion, the use of TPA may lower the risk of ITBS-related graft failure in DCD-LT. Excessive bleeding may be related to poor graft quality and previous laparotomy rather than the amount of TPA. Further studies are needed in larger population.

Significance of des-gamma-carboxy prothrombin in selection criteria for living donor liver transplantation for hepatocellular carcinoma.

Des-gamma-carboxy prothrombin (DCP) levels reportedly correlate with histological features of hepatocellular carcinoma (HCC). We examined serum DCP as a predictor of HCC recurrence in 144 patients who underwent living donor liver transplantation. Receiver operating characteristics (ROC) analysis revealed superiority of DCP and AFP over preoperative tumor size or number for predicting recurrence. Multivariate analysis revealed tumor size >5 cm, > or =11 nodules, and DCP >400 mAU/mL as significant independent risk factors for recurrence. Incidence of microvascular invasion (62% vs. 27%, p = 0.0003) and poor differentiation (38% vs. 16%, p = 0.0087) were significantly higher for patients with DCP >400 mAU/mL than for patients with DCP < or =400 mAU/mL. In ROC analysis for patients with < or =10 nodules all < or =5 cm to predict recurrence, area under the curve was much higher for DCP than for AFP (0.84 vs. 0.69). Kyoto criteria were thus defined as < or =10 nodules all < or =5 cm, and DCP < or =400 mAU/mL. The 5-year recurrence rate for 28 patients beyond-Milan but within-Kyoto criteria was as excellent as that for 78 patients within-Milan criteria (3% vs. 7%). The preoperative DCP level offers additional information regarding histological features, and thus can greatly improve patient selection criteria when used with tumor bulk information.

Neuroprotective effects of edaravone, a free radical scavenger, on the rat hippocampus after pilocarpine-induced status epilepticus.

PURPOSE: Edaravone (MCI-186) is a newly developed antioxidative radical scavenger for the treatment of acute cerebral infarction, exerting neuroprotective effects against ischemic insult. The neuroprotective effects of edaravone on pilocarpine-induced seizures in rats were investigated. METHODS: Rats were treated intraperitoneally with saline or edaravone (1-30 mg/kg), applied 30 min before pilocarpine hydrochloride (330 mg/kg). The onset of status epilepticus (SE) and mortality were recorded for a period of at least 3 days. The cell loss and immunoreactivities of nitric oxide synthase (NOS) in the hippocampus from control and the day 3 rats after SE, treated with saline or edaravone, were evaluated. RESULTS: Edaravone (1mg/kg) significantly prevented cell loss in the hippocampus after SE while easier inducing SE. The higher dose of drug could not induce SE significantly but tended to increase the rate of mortality. Inducible NOS (iNOS) expression was significantly decreased in the hippocampus from day 3 rats treated with 1mg/kg edaravone, compared with saline group, while neuronal NOS (nNOS) and iNOS significantly increased in the hippocampus treated with saline, compared with control group. Significant alteration of endothelial NOS (eNOS) expression in the hippocampus among control group, saline group, and edaravone group was not shown. CONCLUSIONS: Edaravone may act as a neuroprotector for the hippocampus after SE by reducing at least iNOS although the low dose of drug easier induces SE because of preventing an endogenous antiepileptic effect of NO.

The association between high VEGF levels and multiple probable punctuate cavernous malformations.

Cerebral cavernous malformations (CCMs) are congenital abnormalities of the cerebral vessels. The de novo development of new lesions in this disease has been reported. However, the underlying mechanism of progressive CCMs in such patients remains unclear. This report documents two cases of multiple probable CCMs that showed a progressive behaviour. The plasma levels of vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGF-beta1) were measured using an enzyme-linked immunosorbent assay (ELISA). The concentration of both VEGF and TGF-beta1 in plasma was increased in these patients. A relationship was observed between high concentrations of growth factors and progressive CCMs. Even though a causal linkage between these conditions cannot be confirmed, a continuous high VEGF level in plasma could be a possible clinical indicator for subsequent intracerebral haemorrhages in the CCM patients.

Hyperhomocysteinaemia is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients.

The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Plasma total homocysteine (tHcy), which increases with diabetes, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of WML correlates with tHcy and insulin resistance in type 2 diabetic patients not receiving insulin treatment. Based on brain magnetic resonance imaging findings, 81 type 2 diabetic patients were divided into two groups, with-WML group (57 +/- 8 years, mean +/- standard deviation, n = 31) and without-WML group (57 +/- 6 years, n = 50). The blood glucose level was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, Homeostasis Model Assessment (HOMA) Index and hemoglobin A1c. The body mass index was higher in the with-WML group than in the without-WML group (P < 0.05). Plasma levels of triglyceride were higher whilst high-density lipoprotein cholesterol was lower in the with-WML group than in the without-WML group (P < 0.05 and P < 0.0001 respectively). FPG (P < 0.005), insulin concentrations (P < 0.0001), HOMA Index (P < 0.0001) and tHcy (<0.0001) levels were higher in the with-WML group than in the without-WML group. Multivariate logistic analysis revealed that WML was independently predicted by the high tHcy and insulin resistance. Our findings indicate that the presence of WML was associated with the high tHcy and insulin resistance in these Japanese patients with type 2 diabetes mellitus.

Aberrant expression of microRNAs and the miR-1/MET pathway in canine hepatocellular carcinoma.

Canine hepatocellular carcinoma (HCC) is the most common primary hepatic tumour in dogs. MicroRNA (miRNA) dysregulation has been reported in human HCC and shown to have diagnostic and prognostic value; however, there are no data on miRNA expression in canine HCC. The aim of the present study was to investigate differentially expressed miRNAs in canine HCC. Analysis of miRNA expression in canine HCC tissues and cell lines by quantitative reverse transcription PCR showed that miR-1, miR-122, let-7a, and let-7g were downregulated, whereas miR-10b and miR-21 were upregulated in canine HCC. MET is one of the target genes of miR-1. MET was upregulated in canine HCC at the gene and protein levels, and a significant correlation between the concomitant downregulation of miR-1 and upregulation of MET was observed. Fast/intermediate-proliferating canine HCC cell lines had higher MET gene and protein expression levels than the slow-proliferating cell line. These findings suggest that miRNAs are differentially expressed in canine HCC, and that the miR-1/MET pathway may be associated with canine HCC cell proliferation.

The relationship between paired pulse magnetic MEP and surgical prognosis in patients with intractable epilepsy.

PURPOSE: To assess whether paired pulse magnetic motor evoked potential (MEP) can predict surgical prognosis in patients with intractable epilepsy. METHODS: MEP of the unilateral hand muscles were recorded following paired pulse transcranial magnetic stimulation (TMS) of the motor cortex. The interstimulus intervals of paired stimulation were 1-16 ms with a conditioning stimulus that was 90% active motor threshold. Subjects were six patients with temporal lobe epilepsy (TLE) scheduled for anterior temporal lobectomy and three patients with myoclonic or head-drop seizures scheduled for anterior corpus callosotomy, resulting in the unilateralization of epileptic discharges. The hemisphere showing unilateral discharges was defined as the affected hemisphere. The intracortical inhibition and facilitation curve was drawn based on MEP before and after surgery and the relationship between MEP and surgical prognosis was investigated. RESULTS: In five patients with TLE showing class I surgical results (Engel's classification), the affected hemisphere showing cortical hyperexcitability preoperatively was almost normalized after surgery. However, in a patient with class III, the unaffected hemisphere showed cortical hyperexcitability before and after surgery. In the callosotomy group, two patients with excellent outcomes showed the same results as TLE group with class I. CONCLUSIONS: Paired pulse magnetic MEP may provide predictive value in terms of surgical outcome in those patients with intractable epilepsy.

Spontaneous chronic head and spinal subdural haematoma.

Spinal chronic subdural haematomas (SSDH) are extremely rare. We report a case of a SSDH combined with intracranial SDH. After tapping the SSDH in addition to the evacuation of SDH, the clinical symptoms dramatically improved. SSDH are considered to have an uncertain prognosis; however, good results can be obtained with an early diagnosis and prompt treatment.

Overlapping free bone graft with galea-pericranium in reconstruction of the anterior skull base to prevent CSF leak and sequestrum formation.

Background. Reconstruction of the skull base after resection of a tumour is important to prevent postoperative complications such as infectionsand cerebrospinal fluid (CSF) leakage. Several reconstructive methods of the anterior skull base have been reported but, their long-term results are not clear. Methods. We describe a technique used after removal of an olfactory neuroblastoma with infiltration of the skull base. The reconstructed dura was covered with a galeal patch, a replicated galeal-pericranial flap, a graft from the inner table of skull, and a vascularised galeal-pericranial flap placed on the skull base defect. All layers were fixed with fibrin glue. Conclusion. Three dimensional computed tomography (3D-CT) at bone window settings demonstrated the bone graft covered the bone defect and was not absorbed and after 11 years there have been no signs of tumour regrowth or complications.

Longitudinal and long-term effects of radiotherapy on swallowing function after tongue reconstruction.

OBJECTIVE: This study evaluated the longitudinal and long-term effects of radiotherapy on swallowing function after tongue reconstruction. METHODS: The study comprised 16 patients who had: undergone glossectomy and tongue reconstruction with free flap transfer, received adjuvant radiotherapy, and survived without recurrence for at least 1 year. Swallowing function, as indicated by tolerance of oral intake, was evaluated before radiotherapy, at radiotherapy completion, and at 6 and 12 months after radiotherapy completion. RESULTS: Before radiotherapy, all patients could tolerate oral intake. At radiotherapy completion, only three patients could consume all nutrition orally. However, swallowing function improved over time, and by 12 months after radiotherapy completion it had returned nearly to that before radiotherapy. CONCLUSION: Acute dysphagia due to radiotherapy after tongue reconstruction is severe, but can improve gradually. Multidisciplinary support of patients during percutaneous endoscopic gastrostomy dependence is important to improve long-term functional outcomes.

Lateral supraorbital approach as an alternative to the classical pterional approach.

OBJECTIVE: The standard pterional approach has been used to approach aneurysms of the anterior circulation and the basilar tip, suprasellar tumors, cavernous lesions. The senior author (JH) established a lateral supraorbital approach as an alternative to the pterional approach after continuous trial and error. We describe the techniques of this approach based on clinical experiences. METHODS: The lateral supraorbital approach is more subfrontal and anterior than the pterional approach. This approach has been regularly used by the senior author (JH) in the last decade in more than 2000 operations for mostly aneurysms of anterior circulation, but also for tumors of the anterior fossa and parasellar area as well as the sphenoid wing area. RESULTS: This approach can be used to operate on most cases, in which the classical pterional approach would be used. There are almost no craniotomy-related complications with this approach. This approach is not suitable in certain lesions which need to be exposed from a more temporal perspective. CONCLUSION: This approach is simpler, faster, safer and less invasive than the classical pterional approach.

Subtemporal approach to basilar bifurcation aneurysms: advanced technique and clinical experience.

OBJECTIVE: The surgical treatment of basilar bifurcation aneurysms is challenging, and many of these aneurysms are currently treated by endovascular means. However, the complete closure of the aneurysm by surgical clipping still remains the best and most permanent cure for the aneurysm. The "gold standard", subtemporal approach was established and introduced by Drake and it has been adapted by the senior author Hernesniemi. We describe our present modified technique of this approach based on clinical experience. METHODS: The subtemporal approach to basilar bifurcation aneurysms has been regularly used by the senior author Hernesniemi in recent 15 years in over 200 operations in Kuopio and Helsinki, Finland. RESULTS: This approach is suitable in most basilar bifurcation aneurysms except for those high above the posterior clinoid process. To avoid temporal lobe damage, cerebrospinal fluid drainage is necessary. Benefits of subtemporal approach are short operative and retraction times, and no need for skull base resection. CONCLUSION: The subtemporal approach is simple and safe in experienced hands, and should be considered the standard method to approach most basilar bifurcation aneurysms.

Analysis of cartilage oligomeric matrix protein (COMP) degradation and synthesis in equine joint disease.

REASONS FOR PERFORMING STUDY: Cartilage oligomeric matrix protein (COMP) is abundant within cartilage; its turnover and/or degradation have been investigated in various equine joint diseases and it has been suggested that COMP fragmentation might be useful for monitoring such conditions. OBJECTIVES: To determine whether COMP metabolism is compromised in equine osteoarthritis (OA) and whether COMP degradation is a useful joint marker representing cartilage destruction. HYPOTHESIS: A monoclonal antibody (mAb) with a higher affinity for degraded COMP allows discrimination of diseased joints by quantifying COMP levels and fragmentation. METHODS: A mAb (clone14G4) was generated against equine cartilage COMP. The NH2-terminal sequence of enzyme-cut COMP fragments recognised by 14G4 was determined, as was the efficiency of binding to COMP (using a generated COMP peptide). COMP concentration and fragmentation were analysed in synovial fluid (SF) from normal horses and those with OA. RESULTS: The mAb 14G4 had a higher affinity for the smaller fragments of equine COMP, compared with a mAb (clone 12C4) generated against human COMP. The 14G4 epitope was identified as between C134 and F147. The COMP values in OA (mean +/- s.d. 205.8 +/- 90.9 microg/ml) were significantly higher than in the normal (133.1 +/- 31.5 microg/ml) SF. On the immunoblots of OA sample, the proportions of intact COMP were significantly lower, while smaller fragments ranging from 75 to 290 kDa were higher compared with the normal SF. CONCLUSIONS AND POTENTIAL RELEVANCE: The mAb 14G4 reliably detects COMP degradation as well as synthesis, and fragmentation analysis combined with quantification in SF could be useful to study equine OA.

Genetic influences on cellular reactions to spinal cord injury: activation of macrophages/microglia and astrocytes is delayed in mice carrying a mutation (WldS) that causes delayed Wallerian degeneration.

Reactive changes in macrophages/microglia and astrocytes were evaluated following spinal cord injury in normal mice of the C57BL/6J strain and in mice carrying a mutation (WldS) which delays the onset of Wallerian degeneration in damaged axons. Crush injuries were produced at the T8 level by using an extradural approach; animals were allowed to survive for 2 days to 12 weeks, and spinal cords were prepared for immunocytochemistry using antibodies against Mac1 and glial fibrillary acidid protein (GFAP). In normal mice, Mac1-positive macrophages accumulated at the injury site by 4 days and immunostaining of these cells peaked at 6-8 days. Cells in the gray matter near the crush site and in the ascending dorsal column also exhibited increased Mac1 staining that was prominent at 1 week and remained high at 2-4 weeks. In mice carrying the WldS mutation, the accumulation of macrophages at the injury site and the increase in immunostaining of these cells were delayed, as were the increases in immunostaining in the gray matter and dorsal columns. Both normal and mutant mice exhibited pronounced increases in glial fibrillary acidic protein immunostaining at the edge of the crush site and for some distance both rostral and caudal to the injury; increased immunostaining was also prominent along the ascending dorsal columns. The center of the crush site, which contained connective tissue, remained completely unstained for GFAP. In normal mice, immunostaining for GFAP reached a peak at 1 week postinjury and then declined. In mice carrying the WldS mutation, increases in GFAP immunostaining did not reach a peak until 2-3 weeks postinjury. These results indicate that activation of macrophages, microglia, and astrocytes is delayed and prolonged in mice carrying the WldS mutation.

Genetic influences on cellular reactions to spinal cord injury: a wound-healing response present in normal mice is impaired in mice carrying a mutation (WldS) that causes delayed Wallerian degeneration.

Progressive tissue necrosis is a process unique to the injured mammalian spinal cord which often leads to gradually increasing cavitation and enlargement of the lesion. To evaluate the role of neuronal degeneration in initiating this response, histopathological changes were compared in C57BL and WldS (delayed Wallerian degeneration mutation) mice. The spinal cord was crushed at T8, producing a primary lesion at the site of the trauma and a secondary lesion extending rostrocaudally in the dorsal columns (where long ascending and descending fiber tracts undergo Wallerian degeneration). Cavitation was relatively mild at both sites and developed mainly at the margins of the lesions. In striking contrast to spinal cord injury in rats, progressive necrosis did not occur in mice; instead, the primary and secondary lesion sites became filled in by macrophages and fibroblasts embedded in a well-vascularized collagenous stroma. Quantitative image analysis revealed that the primary lesion decreased dramatically in size and cavitation between 2 and 3 weeks in C57BL, whereas in WldS the reduction in size and cavitation began later (at 4 weeks) and was less complete. The initial development of the secondary lesion began later and its healing was less complete in WldS than C57BL. These results are consistent with the hypothesis that neuronal damage, including Wallerian degeneration, triggers inflammatory responses leading to tissue repair. For this reason, any delay in neuronal degeneration, as in the WldS mutation, results in deficient tissue repair as reflected in the larger size of both primary and dorsal column lesions.

High frequency transcranial magnetic stimulation mimics the effects of ECS in upregulating astroglial gene expression in the murine CNS.

The present study evaluates the consequences of high frequency (25 hz) trans-cranial magnetic stimulation on the expression of glial fibrillary acidic protein (GFAP) in the murine CNS. Trains of transcranial magnetic stimulation (1-30 trains at 25 Hz, 10 s duration) were delivered to mice via 5-cm diameter round coils. The stimulation produced stimulus-locked motor responses but did not elicit behavioral seizures. GFAP mRNA levels were evaluated 12, 24, 36, 48 h, 4 days, and 8 days following stimulation by in situ hybridization. Following multiple 25 Hz trains, there were dramatic increases in the levels of GFAP mRNA in the hippocampal dentate gyrus; more modest increases were observed in the cerebral cortex. The selective increases in GFAP mRNA in the dentate gyrus were similar to those observed following single electroconvulsive seizures (ECS). These results indicate that trans-cranial magnetic stimulation can be used to modulate astroglial gene expression, inducing the first stage of a reactive response that is similar to what occurs following nervous system injury.

Evidence of apoptotic procedure in deafferented striatum after cortical injury in young adult rats.

In denervated striatum after excitotoxic cortical lesion in young adult rats, apoptotic cells, though quite few, were observed by TUNEL 2 weeks after surgery. Also, prominent expressions of p53 were observed at the same time. These data indicate that apoptotic procedure may be involved in the denervation-induced degeneration even in young adults.