Correlation Between Splenectomy and Portal Vein Complications in Living Donor Liver Transplantation.

OBJECTIVES: In adults undergoing living donor liver transplantation (LDLT), the transplanted livers are partial grafts, and the portal venous pressure is higher than that observed with whole liver grafts. In patients undergoing LDLT concomitant with splenomegaly, portal venous flow is often diverted to collateral vessels, leading to a high risk of portal vein thrombosis. In such cases, occlusion of the collateral veins is important; however, complete occlusion of all collaterals without blocking the blood flow through the splenic artery causes portal hypertension and liver failure. We aimed to examine the effect of performing a splenectomy concomitant with LDLT to reduce portal vein complications. METHODS: Between 1991 and 2017, we performed 170 LDLT operations, including 83 in adults. For this cohort study, adult cases were divided into 2 groups. Group I was those who underwent LDLT without splenectomy (n = 60); Group II was those who underwent LDLT with splenectomy for the reduction of portal hypertension (n = 23). We investigated the incident rates of complications, including blood loss, lethal portal vein thrombosis (intrahepatic thrombosis), acute rejection, and so on. We also investigated the survival rates in both groups. RESULTS: The incident rate of lethal portal vein thrombosis in Group II was significantly lower than that observed in Group I (4.4% vs 21.7%, respectively, P = .0363). There were no statistically significant differences observed between the groups with respect to blood loss, survival rates, and other such parameters. CONCLUSION: LDLT concomitant with splenectomy might effectively reduce the occurrence of portal vein complications in adults.

Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation from Donors After Cardiac Death in Rats.

BACKGROUND: Liver transplantation from donors after cardiac death (DCD) might increase the pool of available organs. Recently, some investigators reported the potential use of mesenchymal stem cells (MSCs) to improve the outcome of liver transplantation from DCD. The aim of this study was to evaluate the cytoprotective effects and safety of MSC transplantation on liver grafts from DCD. METHODS: Rats were divided into 4 groups (n = 5) as follows: 1. the heart-beating group, in which liver grafts were retrieved from heart-beating donors; 2. the DCD group, in which liver grafts were retrieved from DCD that had experienced apnea-induced agonal conditions; 3. the MSC-1 group, and 4. the MSC-2 group, in which liver grafts were retrieved as with the DCD group, but were infused MSCs (2.0 × 105 or 1.0 × 106, respectively). The retrieved livers were perfused with oxygenated Krebs-Henseleit bicarbonate buffer (37°C) through the portal vein for 2 hours after 6 hours of cold preservation. Perfusate, bile, and liver tissues were then investigated. RESULTS: Bile production in the MSC-2 group was significantly improved compared with that in the DCD group. Based on histologic findings, narrowing of the sinusoidal space in the both MSC groups was improved compared with that in the DCD group. CONCLUSIONS: MSCs could protect the function of liver grafts from warm ischemia-reperfusion injury and improve the viability of DCD liver grafts. In addition, we found that the infusion of 1.0 × 106 MSCs does not obstruct the hepatic sinusoids of grafts from DCD.

Effects of Subnormothermic Perfusion Before Transplantation for Liver Grafts from Donation After Cardiac Death: A Simplified Dripping Perfusion Method in Pigs.

BACKGROUND: Liver transplantation from donors after cardiac death (DCD) provides a solution to the donor shortage. However, DCD liver grafts are associated with a high incidence of primary graft nonfunction. We investigated the effectiveness of subnormothermic porcine liver perfusion, before transplantation from DCD, on graft viability. METHODS: Landrace pigs (25-30 kg) were randomly allocated to 3 groups (5 per group): heart-beating (HB) graft, transplanted after a 4-hour period of cold storage (CS); DCD graft, retrieved 20 minutes after apnea-induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-hour period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs-Henseleit buffer (21-25°C, 10-15 cm H2O) for 30 minutes in a simplified dripping manner, without a machine perfusion system, after the 4-hour period of CS, and subsequently transplanted. RESULTS: Although all animals in the HB group survived for >7 days, all animals in the DCD group died within 12 hours after transplantation. In the SELP group, 2 recipients survived for >7 days and another 2 recipients were killed on day 5. The survival rate was significantly better for SELP than for DCD grafts (P = .0016). The values of tumor necrosis factor α were not significantly different between the SELP and HB groups. Preserved structure of the parenchyma was observed in the SELP group on histologic examination. CONCLUSIONS: A simplified subnormothermic perfusion before liver transplantation is expected to improve graft viability and survival.

Further evidence for a significant participation of the melanocortin 4 receptor in the preovulatory prolactin surge in the rat.

We previously reported that the melanocortin 4 receptor may play a significant role in mediating the preovulatory surges of luteinizing hormone and prolactin in the rat. In order to confirm this previous finding, in the present study we examined and compared the effects of intracerebroventricular administrations of 1.0 nmol of MT II (a non-selective melanocortin 3 and 4 receptor agonist) and 10 nmol of gamma(1)-melanocyte-stimulating hormone (a selective melanocortin 3 receptor agonist) on luteinizing hormone and prolactin surges in starved, gonadal steroid-primed ovariectomized female rats, which is a model deprived of inherent surges of the two hormones. MT II significantly recovered the surge of prolactin, but not of luteinizing hormone (although a tendency to increase was seen), and gamma(1)-melanocyte-stimulating hormone was without effect on both hormones. This study corroborated our previous report through a different and direct approach that the melanocortin 4 receptor, but not the melanocortin 3 receptor, plays a significant role in mediating the preovulatory prolactin surge in the rat.

Normalization of circulating leptin levels by fasting improves the reproductive function in obese OLETF female rats.

In order to examine a possible detrimental effect of hyperleptinemia on the reproductive system, we examined whether a decrease in circulating leptin levels by fasting affects the estradiol/progesterone-induced luteinizing hormone (LH) and prolactin (PRL) surges in genetically obese OLETF (Otsuka-Long-Evans-Tokushima-Fatty) rats. Experiments were performed on both normally fed and 3-day starved groups from ovariectomized OLETF rats and their controls LETO (Long-Evans-Tokushima-Otsuka). Starved LETO rats, whose leptin levels were less than 0.5 ng/ml, did not show a significant surge of either LH or PRL. Normally fed OLETF rats, whose leptin levels were 9.7 +/- 1.8 ng/ml, showed a significant but small surge for both LH and PRL. Interestingly, starved OLETF rats, whose leptin levels (4.1 +/- 0.7 ng/ml) were similar to those in normally fed LETO rats (3.3 +/- 0.4 ng/ml), had significantly greater surges of both hormones than normally fed OLETF group. This study demonstrates for the first time that the normalization of circulating leptin levels in female OLETF rats augments the steroid-induced LH and PRL surges, and also suggests a deleterious effect of hyperleptinemia on the reproductive axis.

A significant participation of orexin-A, a potent orexigenic peptide, in the preovulatory luteinizing hormone and prolactin surges in the rat.

Orexins are novel hypothalamic peptides which stimulate food intake. In view of the well-known tight connection between the nutritional state and the reproductive function, in this study we examined a possible role of orexin-A in the generation of ovarian steroid-induced luteinizing hormone (LH) and prolactin (PRL) surges in ovariectomized rats. Experiments were performed on both normally-fed and 3-day-fasted rats. Although fasting led to abolition of both LH and PRL surges, intracerebroventricular administration of orexin-A (0.3 and 3.0 nmol) resulted in a dose-dependent recovery of the hormonal surges. In addition, anti-orexin-A antisera given to normally-fed rats completely abrogated the surges of both hormones. These results demonstrate for the first time a significant participation of orexin-A in the preovulatory LH and PRL surges in the rat.

Agouti-related peptide prevents steroid-induced luteinizing hormone and prolactin surges in female rats.

We studied the effect of Agrp (agouti-related peptide) on LH (luteinizing hormone) and PRL (prolactin) surges in ovariectomized rats primed with estradiol and progesterone. The rats displayed characteristic LH and PRL surges that were completely abolished by starving. Injection of either 1 nmol or 3 nmol Agrp (83-132), a potent antagonist of the orexigenic MC3 and MC4 receptors, completely prevented both the LH and PRL surges. We also investigated the effects of either a single or double injection of anti-Agrp serum to fasted animals, which were without LH and PRL surges. A single injection of the antiserum was without effect, but the rats that received double injection of anti-Agrp serum partially reinstated both the LH and PRL surges. Although the onset of LH and PRL surges was significantly delayed in the double treated group, the highest levels of the surges for both hormones were statistically indistinguishable compared with the control group. These data give a clear indication that endogenous Agrp may be involved in LH and PRL surges during starvation, providing further evidence that the melanocortin system is important for these hormonal surges in female rats.

Interstitial cystitis and ileus in pediatric-onset systemic lupus erythematosus.

A girl aged 11 years presented with autoimmune hemolytic anemia with thrombocytopenia, and subsequently developed severe abdominal pain, vomiting, and pollakiuria. X-ray findings of her abdomen demonstrated paralytic ileus with intestinal wall thickening. Intravenous pyelography revealed bilateral hydroureter with mild hydronephrosis and contracted bladder. Pathological examination of her bladder revealed interstitial cystitis, with evidence of focal deposition of IgG and C3 in a granular pattern on small blood vessel walls. She was diagnosed as having systemic lupus erythematosus (SLE) associated with paralytic ileus and chronic interstitial cystitis. Although initiation of high-dose prednisolone therapy resulted in a gradual improvement in clinical symptoms, reducing the dosage of prednisolone caused a relapse. To our knowledge, the combination of paralytic ileus and chronic interstitial cystitis is quite uncommon in pediatric-onset SLE.

Complete occulusion of left renal artery in pediatric-onset Takayasu's arteritis.

A-16-year-old male adolescent with a 4-year history of protean clinical manifestations such as fever, abdominal pain, back pain, erythema nodosum and uveitis developed complete occlusion of left renal artery. Although he had been suspicious of having an autoimmune disease and treated with prednisolone, a definite diagnosis was not made. Finally, an angiography disclosed stenosis of abdominal aorta just beneath the origin of the renal arteries as well as complete occlusion of left renal artery. It has been reported that pediatric-onset Takayasu's arteritis sometimes shows protean clinical manifestations as in ours. Takayasu's arteritis should be considered as one of the underlaying disease, when a child develops protean manifestations suggesting an autoimmune disease.

Temporal profiles of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in the plasma and hypothalamic paraventricular nucleus after intravenous or intraperitoneal administration of lipopolysaccharide in the rat: estimation by push-pull perfusion.

Lipopolysaccharide (LPS) is known to stimulate the synthesis and secretion of various proinflammatory cytokines in both the peripheral immune cells and the brain. Yet, the relative contribution of peripheral and central cytokines to the LPS-induced activation of the hypothalamo-pituitary-adrenal axis is still poorly understood. In this study, utilizing the push-pull perfusion technique of the rat brain, we attempted to characterize in detail the temporal profiles of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha after intravenous (i.v.) or intraperitoneal (i.p.) administration of LPS in both the general circulation and the hypothalamic paraventricular nucleus (PVN), which is the primary source of corticotropin releasing hormone (CRH). Temporal changes in plasma adrenocorticotropic hormone (ACTH) and CRH levels in the PVN were also monitored. We collected blood and perfusates every 30 min from 11:00 to 17:00 h. At 12:00 h, 1.0 or 2.5 mg/kg body weight of LPS was given via an i.v. or i.p. route, respectively. Peak ACTH response occurred 30 min after i.v. LPS and 1.5 h after ip LPS. Of the three cytokines measured in the plasma, TNF-alpha showed the fastest rise in synchrony with peak ACTH secretion after both i.v. and i.p. LPS. Although plasma IL-6 also showed a robust rise, its peak level occurred later than the ACTH peak. Elevation of plasma IL-1beta was the smallest among the three cytokines. CRH levels in the PVN reached their peaks 1 and 2.5 h after the ACTH peak following i.p. and i.v. LPS, respectively. Irrespective of the route of LPS administration, IL-6 and TNF-alpha levels in the PVN showed significant rises 1-2 h after the ACTH peak, but IL-1beta in the PVN did not significantly change during the entire period of observation. The results of the present study suggest that circulating TNF-alpha may play the most important role in triggering the early, peak phase of ACTH secretion after both i.v. and i.p. LPS. Although it is possible that brain TNF-alpha, IL-6, and circulating IL-6, may be involved in the later, protracted phase of ACTH secretion induced by LPS, IL-1beta in both the brain and peripheral circulation seems to play the smallest role in ACTH secretion. This is the first study to characterize the LPS-induced temporal changes in IL-1beta, IL-6, and TNF-alpha in both plasma and PVN simultaneously in conscious, freely moving rats.

A comparative study of the effects of nitric oxide and carbon monoxide on the in vivo release of gonadotropin-releasing hormone and neuropeptide Y from rat hypothalamus during the estradiol-induced luteinizing hormone surge: estimation by push-pull perfusion.

Recent evidence suggests that nitric oxide (NO), a free radical gas, plays an important role in regulating the function of a variety of neuroendocrine systems. With respect to the hypothalamo-pituitary-gonadal axis, a stimulatory effect of NO on the release of gonadotropin-releasing hormone (GnRH) from rat hypothalamus has been demonstrated in vitro. However, no previous study has reported NO-stimulated secretion of GnRH from in vivo hypothalamus, and also the precise cellular site of action of NO within the GnRH neuronal system remains to be elucidated. In the present study, utilizing the push-pull perfusion technique of rat hypothalamus, we examined the effect of L-arginine (L-Arg), an NO donor, on the release of GnRH, neuropeptide Y and cyclic GMP (c-GMP), which is a pivotal second messenger molecule of the NO system. For comparison, we also examined the effect of carbon monoxide (CO), another putative gaseous neurotransmitter, using hematin, a CO donor. During the period of 11.00-18.00 h, we collected blood and hypothalamic perfusates from ovariectomized adult rats that had been implanted with an estradiol capsule 2 days before. During the entire period of observation, L-Arg (1.0 or 10 mM), hematin (10 or 100 microM) or artificial cerebrospinal fluid alone (as the control) was infused into the medial preoptic area (MPOA) where there are cell bodies of GnRH neurons, or the median eminence-arcuate nucleus complex (ME-ARC) where axon terminals of GnRH neurons are localized. Although 10 mM of L-Arg significantly stimulated GnRH and c-GMP, but not neuropeptide Y, levels in both the MPOA and ME-ARC, GnRH and c-GMP in the ME-ARC were already increased by 1.0 mM of L-Arg. By contrast, both concentrations of hematin were without effect at either site of the hypothalamus. This study is the first to demonstrate that NO is capable of stimulating GnRH release from rat hypothalamus in vivo. Our data also suggests that both cell bodies and axon terminals of GnRH neurons may be sites of action of NO. Our data do not support a previous study by other investigators that reported a stimulatory effect of CO on the GnRH release.

IgA interaction with carboxy-terminal 43-kD fragment of fibronectin in IgA nephropathy.

IgA deposition in the glomerular mesangial matrix is a prerequisite for the diagnosis of IgA nephropathy, and circulating IgA-containing complex has been implicated in this process. Since fibronectin is known to be involved in the assembly of extracellular matrix, this study was conducted to investigate whether fibronectin and its fragments are present in sera of patients and are capable of binding IgA1. Sera from patients with IgA nephropathy were purified by heparin-affinity chromatography, and column eluate were analyzed for the presence of fibronectin using Western blot and a set of anti-fibronectin monoclonal antibodies. Native fibronectin was digested with cathepsin D to obtain fragments similar to those of serum fibronectin. The capacity of fibronectin to bind IgA was examined with a mixture of purified IgA1 and cathepsin D-digested fibronectin fragments. A 43-kD carboxy-terminal fragment of fibronectin was detected in samples derived from sera of patients with IgA nephropathy but not in healthy control subjects. A similar-sized fragment was generated by cathepsin D digestion of the native molecule and was shown to bind to IgA1 in vitro. Since the carboxy-terminal domain is known to be critical in assembling exogenous fibronectin into the extracellular matrix, the affinity to IgA1 to a fragment found in patients may have pathogenic potential to mediate extracellular IgA deposition in IgA nephropathy.

A significant role of leptin in the generation of steroid-induced luteinizing hormone and prolactin surges in female rats.

Recent evidence suggests that leptin, the product of obese (ob) gene, may play an important role in the regulation of reproductive function. However, a possible role of leptin in the preovulatory surges of luteinizing hormone (LH) and prolactin (PRL) in rodents has yet to be explored, and thus examined in this study. Experiments were performed on both normally fed and 3-day starved rats, which were ovariectomized and primed with estradiol and progesterone. At 11:00 h on the day of the experiments, normally fed rats received an intracerebroventricular injection of artificial cerebrospinal fluid, anti-leptin serum, or normal rabbit serum. Three-day starved rats were given artificial cerebrospinal fluid or recombinant human leptin (2.5 microgram) via the same route. From 11:00 to 18:00 h, blood was collected every 30 min to measure LH and PRL. The 3-day starvation completely abolished both LH and PRL surges, but leptin resumed these hormonal surges to the levels of normally fed rats. In addition, anti-leptin serum given to normally fed rats significantly depressed LH surge and delayed the onset of PRL surge. This study is the first to demonstrate that leptin plays a physiologically important role in the generation of steroid-induced LH and PRL surges in female rats.

Acute tubulointerstitial nephritis following intravenous immunoglobulin therapy in a male infant with minimal-change nephrotic syndrome.

A boy aged 4 years with nephrotic syndrome (NS) was referred to our hospital because of the third relapse of NS. Hypogammaglobulinemia associated with massive proteinuria was observed at the presentation. Residual urinary tract infection required intravenous piperacillin and immunoglobulin therapy (IVIG). Soon after IVIG, he complained of high fever with chills, bilateral knee joint pain, dry cough and chest discomfort. Although he did not develop renal insufficiency, a transient increase in the urinary beta2-microglobulin and decrease in the serum complement hemolytic activity were observed. These clinical manifestations spontaneously ceased. A percutaneous renal biopsy for his NS performed 19 days after the episode of allergic reaction revealed tubulointerstitial nephritis (TIN) with marked eosinophil infiltrates. Glomeruli showed minor glomerular abnormalities. Renal complications associated with IVIG treatment have been reported to date, however, acute TIN has rarely been seen.

Measurement of cytokines in the cavernous sinus plasma from patients with Cushing's disease.

In order to know more about the in vivo secretion of various cytokines from the human pituitary, this study measured the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, tumor necrosis factor-alpha and IL-1 receptor antagonist (ra) in both the peripheral blood and the cavernous sinus (CS) plasma from six patients with Cushing's disease before and after an intravenous bolus injection of human corticotropin-releasing hormone (CRH, 100 microg). As a routine procedure for the diagnosis of Cushing's disease, adrenocorticotropin (ACTH) levels were also determined in the same samples. In four of the six patients, unstimulated levels of IL-1ra in the CS ipsilateral to the ACTH-secreting adenoma were higher than those in the peripheral blood, with a ratio of > or = 1.5:1, even though CRH was without effect on the cytokine's concentration in the CS. In contrast, no consistent data were obtained for any of the remaining five cytokines. These results demonstrate for the first time that the in vivo release of IL-1ra is detectable in at least some corticotroph adenomas, and also suggest a possible role of the cytokine in physiological and pathophysiological processes occurring in the human pituitary.

Chronic urticaria associated with aseptic meningitis: an atypical urticarial vasculitis?

The patient was a 7-year-old girl with early onset urticarial cutaneous lesions and was later complicated with aseptic meningitis. Her skin lesions occurred in the infantile period and were diagnosed as urticaria, but did not disappear with antihistamines and were recurrent and persistent. In addition, she had experienced an episode of headache about once a month since 1991, when she was 4 years old, and was diagnosed as aseptic meningitis. All studies including skin biopsy for urticarial vasculitis (UV) and systemic lupus erythematosus (SLE) were negative except for the data from non-specific inflammations. A systemic corticosteroid therapy dramatically reduced her symptoms. An unusual clinical course for this patient is described. It might suggest that this case is a presentation of the disease entity of UV, chronic urticaria and possibly SLE. To our knowledge, a similar case has not been previously reported.

Acute tubulointerstitial nephritis associated with piperacillin therapy in a boy with glomerulonephritis.

An 11-year-old boy with glomerulonephritis developed acute renal failure 4 days after beginning piperacillin (PIPC) treatment. Renal biopsy revealed acute tubulointerstitial nephritis (ATIN) with marked eosinophils. A lymphocyte stimulation test (LST) for PIPC demonstrated an extremely high LST index of 626%. The serum levels of immunoglobulin E and eosinophil cationic protein also showed a significant increase at 9021 IU/mL and greater than 150 micrograms/L, respectively. These observations suggest that a hypersensitivity reaction might play a role in the pathogenesis of ATIN. This is the first report to describe PIPC-induced ATIN in a child.

An adolescent case of anti-neutrophil cytoplasmic autoantibodies-associated crescentic glomerulonephritis complicated with subclinical autoimmune thyroiditis.

We report here a 15-year-old girl with myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated crescentic glomerulonephritis (CreGN) and subclinical autoimmune thyroiditis. She was found to have proteinuria and hematuria by a school mass-screening a year before the first visit to the hospital, where a routine examination revealed blood urea nitrogen (BUN) 36.8 mg/dl and serum creatinine concentration of 1.63 mg/dl, although she had no apparent disabilities. On admission, the additional laboratory findings showed proteinuria of 1.06 g/day, hematuria of 3+, and a creatinine clearance of 30.1 ml/min. Hypocomplementemia was not observed. A renal biopsy revealed pauci-immune CreGN with 95% fibrocellular crescents, 84% sclerosis and/or hyalinosis and a massive cellular infiltration in the interstitium. She had MPO-ANCA of 865 EU/ml and an anti-thyroid microsome antibody titer of 1:1,600 without the detection of anti-glomerular basement membrane antibodies. Laboratory tests and scintigraphies for the thyroid gland did not show any abnormalities. Under the diagnosis of MPO-ANCA-associated CreGN, cocktail therapy consisting of prednisolone, cyclophosphamide, dilazep hydrochloride and warfarin was started. Improvement of urinary abnormalities and suppression of further deterioration of renal function were observed. Serial renal biopsy 6 months after the initiation of therapy showed decrement of interstitial cell infiltration and no generation of other crescentic glomeruli. The patient's serum titer of anti-thyroid microsome antibody was not affected by the adsorption of MPO-reacted IgG, suggesting that MPO-ANCA was not cross-reactive to thyroid microsome antigen.