The effects of arginine and selective inducible nitric oxide synthase inhibitor on pathophysiology of sepsis in a CLP model

BACKGROUND: Sepsis is an arginine-deficient state and is associated with overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). It has been indicated that low plasma levels of arginine are related to high mortality rates in sepsis. Arginine, however, is also known to be a precursor of NO. Therefore, administration of arginine in septic patients remains controversial. We examined the effects of co-administration of arginine and aminoguanidine, a selective iNOS inhibitor, on sepsis, using rat models. METHOD: Sepsis was induced in rats by cecal ligation and puncture (CLP). Effects of separate and combined administration of arginine and aminoguanidine were investigated by comparing plasma levels of arginine, expressions of heme oxygenase (HO)-1 and HO-2 in liver and lung, and nitrite + nitrate (NOx) excretion in urine, as well as neuroendocrine responses in urine in the early phase of sepsis. Seven-day survival rates were also examined. RESULTS: A combination of arginine and aminoguanidine recovered the plasma level of arginine at 6 h post-CLP, decreased expression of HO-1 in liver and lung at 24 h post-CLP, decreased urinary excretion of epinephrine, norepinephrine, dopamine, and 17-hydroxycorticosteroid in the first 24 h post-CLP, and increased 7-d survival. CONCLUSION: It is demonstrated that administration of arginine together with the selective iNOS inhibitor in the early phase of sepsis restores plasma arginine, reduces oxidative stress by probably maintaining NO derived from constitutive NOS, and attenuates neuroendocrine stress responses. This co-administration may be a beneficial treatment approach against sepsis.     

The risks and benefits of percutaneous nucleotomy for lumbar disc herniation. A 10-year longitudinal study

Percutaneous nucleotomy is a relatively new technique for treating lumbar disc herniation. There is no agreement as to the volume of disc material to be removed. A long-term study of clinical and radiological data from patients treated by percutaneous nucleotomy was designed to identify the factors associated with favourable and unfavourable outcomes. We studied 42 patients for at least ten years; the mean follow-up was 10.9 years. They were divided into two subgroups to assess the value of preserving the nucleus pulposus in the central area of the disc. The overall success rate for both subgroups was 50%. A decrease in disc height on plain radiography and a decrease in signal intensity on MRI were observed more infrequently in patients in whom the nucleus pulposus in the central area of the disc had been preserved, than in those in whom it had been extensively removed. These adverse radiological findings correlated closely with increased low back pain during the first one to two years after operation and a poorer overall outcome. We conclude that percutaneous nucleotomy is most likely to be successful when the central area of the disc is preserved.     

Effects of Hot shot on recovery after hypothermic ischemia in neonatal lamb heart

BACKGROUND: Terminal warm blood cardioplegia, "Hot shot", is the method for providing an energy replenishment and/or early recovery of aerobic metabolism without electromechanical activity at initial reperfusion. The mechanism of beneficial effects of this Hot Shot is multifactorial. This study was designed to assess the effects of terminal warm blood cardioplegia by comparing with oxygenated terminal warm crystalloid cardioplegia. METHODS: In Group HS-B, n=8 (oxygenated blood; 37 degrees C, Ht: 20%, K+ 20 mEq/l, pH 7.237, PO2 219 mmHg) and in Group HS-C, n=8 (bloodless oxygenated (5% CO2+95%O2) crystalloid, 37 degrees C, K+ 20 mEq/l, pH 7.435, PO2 624 mmHg), terminal warm cardioplegia (20 ml/kg for 5 minutes) was studied in the isolated blood perfused neonatal lamb heart following 2 hr of cardioplegic ischemia. Another eight hearts served as control without any kind of terminal cardioplegia. After 60 min of reperfusion, LV function was measured. Coronary blood flow (CBF), oxygen content, and oxygen consumption (MVO2) were measured and the oxygen extraction ratio was calculated in Group HS-B and HS-C during terminal cardioplegia and/or reperfusion. Results are given as % recovery of preischemic values. RESULTS: HS-B as well as HS-C groups showed better functional recovery in maximum developed pressure (DP: 78.0+/-8.3 in HS-B vs 65.2+/-9.2%; p=0.018), maximum dp/dt (67.3+/-6.2 in HS-B, 65.3+/-7.4 in HS-C vs 55.8+/-5.0%; p=0.003, p=0.02), DP V10 (87.1+/-8.5 in HS-B vs 67.2+/-9.9%; p=0.0001), and peak dp/dt V10 (76.4+/-7.6 in HS-B, 69.8+/-8.1 in HS-C vs 58.6+/-6.9 %; p=0.0001) than the control group. Between the HS-B and HS-C groups, HS-B showed better functional recovery in terms of DP V10 (p=0.01). Oxygen delivery of terminal cardioplegia was almost four times higher in HS-B group (90.4+/-17.7 vs 18.7+/-1.1 mcl/ml), contrarily, HS-C group showed four times higher oxygen extraction ratio compared to HS-B group (0.78+/-0.06 vs 0.18+/-0.11), thus oxygen consumption during hot shot was maintained at the same level in both groups. CBF in the control group was lower than that in the other groups at 60 min of reperfusion. CONCLUSIONS: Reperfusion with both terminal warm cardioplegia including blood and oxygenated crystalloid cardioplegia resulted in better recovery of function and higher levels of CBF with slightly better function in terminal warm blood cardioplegia.     

Effects of allopurinol on renal stone formation and osteopontin expression in a rat urolithiasis model

BACKGROUND: The inhibitory effect of allopurinol on calcium oxalate urolithiasis has been reported, but its effect on stone matrix proteins has not been studied in vivo. To clarify the effect of allopurinol on the matrix, we investigated its effect on the expression of osteopontin (OPN), which we previously identified as an important stone matrix protein. METHODS: Control rats were not treated. Rats of the stone group were given ethylene glycol (EG) and vitamin D(3), while the allopurinol groups (low-dose group and high-dose group) were treated with allopurinol in addition to receiving EG and vitamin D(3). RESULTS: The rate of renal stone formation was lower in the allopurinol groups than in the stone group. This was associated with a low expression of OPN mRNA in allopurinol-treated rats relative to that in the stone group. CONCLUSION: Allopurinol was effective in preventing calcium oxalate stone formation and reduced OPN expression in rats. Our results suggest that allopurinol prevents renal stone formation by acting against not only the control of oxalate but also OPN expression.     

Serial neuroimaging of a growing thrombosed giant aneurysm of the distal anterior cerebral artery--case report

An 81-year-old female presented with a giant aneurysm of the distal anterior cerebral artery (A3) which grew from a small saccular aneurysm to a huge aneurysm within 36 months before manifesting as a mass lesion. The thrombosed portion of the aneurysm showed growth, whereas the aneurysmal cavity did not change in size. Computed tomography and magnetic resonance imaging showed new bleeding in the thrombosed portion. Hemorrhage into the thrombus and/or aneurysmal wall might have caused the aneurysmal growth. She refused surgery and was discharged with no deficits. Distal anterior cerebral artery aneurysm which shows neuroimaging signs of growth requires regular follow up as such lesions may become giant before manifesting clinical symptoms.     

Right ventricular dynamic cardiomyoplasty for the univentricular heart with pulmonary hypertension

OBJECTIVES: We conducted an acute experimental study to test the feasibility of dynamic cardiomyoplasty in a setting of modified Fontan procedure for univentricular heart with pulmonary hypertension to obtain a possible proxy for high-risk Fontan candidates. METHODS: After electrical preconditioning of the left latissimuss dorsi for 6 weeks in 8 dogs, the right ventricular cavity was totally obliterated with concomittent closure of the tricuspid valve and right pulmonary artery. Modified Fontan circulation was established with the aortic homograft anastomosed between the right atrium and pulmonary trunk, incorporated with a pericardial pouch as a compression chamber (neoright ventricle) fixed onto the epicardial surface of the ventricle. After cardiopulmonary bypass termination, a latissimus dorsi was applied to wrap the pericardial pouch and ventricle clockwise and stimulated with a trained-pulse (25 Hz) at 1:1 synchronization ratio with cardiac beats. RESULTS: Profound right heart failure was noted during Fontan circulation in increased pulmonary vascular resistance (11 +/- 3.2 Wood units), whereas graft pacing showed significant augmentation of systolic pulmonary pressure by 54 +/- 12%, the mean pulmonary flow by 68 +/- 23%, and aortic pressure by 23 +/- 5% at a physiological range of central venous pressure (13.2 +/- 0.7 mmHg). Right heart function curve analysis confirmed marked augmentation of right heart performance, restoring almost normal pulmonary circulation. These functional benefits were sustained up to 4 hours in 4 animals until experiments were terminated. CONCLUSIONS: Dynamic cardiomyoplasty in a modified Fontan procedure is a viable surgical option for univentricular heart, not a Fontan candidate.     

Ectopic cystic thymoma associated with Raynaud's phenomenon.

Mediastinal cystic tumors are well-marginated round lesions that comprise 12% to 18% of all mediastinal masses. These lesions include a variety of diseases with overlapping radiologic appearances and variable prognoses. Pathological examinations are almost always required for differential diagnosis. We encountered a case of anterior mediastinal tumor discovered in the process of investigation of Raynaud's phenomenon. Taking into account the tumor location, a pericardial cyst was initially suspected. However, the tumor was surgically resected and histopathological examinations demonstrated thymus-like tissue in the cyst walls. Raynaud's phenomenon greatly improved after surgery. These findings suggested that cystic thymoma originated from ectopic thymic tissue and is accompanied by paraneoplastic syndrome.     

Use of ultrasound for thoracic paravertebral block

Thoracic paravertebral block is the technique of injecting local anesthetic adjacent to the intervertebral foramina, resulting in unilateral somatic and sympathetic nerve blockade. Previous studies have reported its effectiveness for thoracic surgery including breast surgery and relief of postoperative and chronic pain of unilateral origin from the chest and abdomen. The technique is relatively easy to learn and safer than thoracic epidural. Its clinical advantages include the inhibition of stress and pressor responses to surgical stimuli, maintenance of hemodynamic stability, low incidence of complication, long duration of analgesia, and few contraindications. Recent advances in ultrasound technology can further increase the effectiveness and the safety of thoracic paravertebral block, although identification of the nerve and needle is not still possible.     

Hepatectomy-Related Hypophosphatemia: A Novel Phosphaturic Factor in the Liver-Kidney Axis

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na⁺-dependent phosphate (Pi) uptake decreased by 50%–60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na⁺-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.Inorganic phosphate (Pi) absorption in the renal proximal tubules and small intestine is important for Pi homeostasis.¹ The Na⁺-dependent Pi (Na/Pi) transport system includes type IIa and type IIc Na/Pi transporters, which are localized in the apical membrane of the proximal tubular cells, and type IIb Na/Pi transporters, which are localized in the apical membrane of the intestinal epithelial cells.^1,2 Pi (re)absorption is regulated by the dietary Pi content, parathyroid hormone (PTH), and the active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)₂D₃].³ Other phosphaturic hormones, termed phosphatonins, also control renal Pi handling.⁴ The discovery that fibroblast growth factor (FGF) 23, the first identified phosphatonin,⁵ originated from osteocytes established the concept of the bone-kidney axis.^6,7The incidence of liver transplantation has steadily increased and the incidence of partial hepatectomy (PH) has also consequently increased.⁸ Hypophosphatemia frequently occurs after liver resection.^9–11 Acute hypophosphatemia causes septicemia and is associated with a poor prognosis.^11,12 Acute hypophosphatemia is of considerable clinical relevance because many hepatectomized patients develop marked hypophosphatemia and, thus, large doses of Pi replacement are required to maintain metabolic homeostasis.¹³ Urinary Pi excretion is markedly increased in many patients. After hepatectomy, hypophosphatemia is associated with hyperphosphaturia.¹³For many years, the increased metabolic demand of the regenerating liver was considered the underlying pathologic mechanism of hypophosphatemia. The magnitude of Pi uptake by the recovering liver, however, cannot explain the severity of the resulting hypophosphatemia.¹¹ Hepatectomy-induced hypophosphatemia is associated with an increased renal fractional excretion index for Pi unrelated to intact FGF23, FGF7, or secreted frizzled-related protein 4 as a phosphaturic factor,¹⁴ indicating that other factors have a role in the pathogenesis of hypophosphatemia.Nicotinamide (NAM) inhibits intestinal and renal Na/Pi transport activity in normal rats.^15–17 Administration of NAM to rats produces a specific dose-dependent inhibition of Na/Pi transport across the renal brush-border membrane (BBM) and an increase in urinary Pi excretion.^16,17 NAM suppresses hyperphosphatemia in hemodialysis patients.¹⁸ Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the first rate-limiting step in converting NAM to NAD,^19,20 which is essential for cellular metabolism, energy production, and DNA repair.^20–22 Nampt exists in two known forms: intracellular Nampt (iNampt) and secreted extracellular Nampt (eNampt).²³ eNampt also generates an intermediate product, nicotinamide mononucleotide (NMN).²³Our findings indicate that the acceleration of NAM metabolism through Nampt function in the kidney is involved in the hepatectomy-induced hypophosphatemia in rodent models. This study also suggests that NAM metabolism through the liver-kidney axis is important in Pi homeostasis.     

Laparoscopic Repair of a Diaphragmatic Hernia Associated with Radiofrequency Ablation for Hepatocellular Carcinoma: Lessons from a Case and the Review of the Literature

We describe the case of a patient with a diaphragmatic hernia associated with radiofrequency ablation for hepatocellular carcinoma who was successfully treated by laparoscopic surgery. A 62-year-old man with a long history of hepatitis C-induced liver cirrhosis was admitted to our institution because of recurrent postprandial periumbilical pain. Eight years earlier, he had undergone radiofrequency ablation for hepatocellular carcinoma at hepatic segment VIII. Computed tomography, gastrografin enema examination revealed transverse colon obstruction because of a diaphragmatic hernia. We diagnosed diaphragmatic hernia associated with the prior radiofrequency ablation treatment. The patient underwent laparoscopic repair of the diaphragmatic hernia. Though the patient experienced the recurrence once, relaparoscopic treatment has improved the patient''s conditions. Thus, diaphragmatic hernia can develop as a complication of radiofrequency ablation treatment. A laparoscopic approach is safe, feasible, and minimally invasive, even in patients with cirrhosis who develop iatrogenic diaphragmatic hernia as a complication of radiofrequency ablation treatment.Key words: Diaphragmatic hernia, Radiofrequency ablation, Complication, Laparoscopic surgeryAlthough surgery is accepted as the first-line treatment for hepatocellular carcinoma (HCC) and colorectal metastases that are limited in number, radiofrequency ablation (RFA) is an effective treatment option for patients with primary and metastatic liver tumor, who are not surgical candidates because of tumor location, poor hepatic reserve, or advanced age.^1,2,3 Chen et al conducted a prospective randomized trial comparing RFA with hepatectomy; however, they were not able to determine whether on treatment alternative was superior to the other.⁴ RFA treatment is the best option among the locoregional treatments for HCC.^5,6 According to the HCC treatment algorithm in the National Comprehensive Cancer Network guideline, RFA treatment should be chosen as a locoregional therapy depending on the degree of liver damage. Tumors ≤ 3 cm are optimally treated with ablation.⁷ RFA for hepatic tumors is a relatively safe modality with a reported overall complication rate of 7.1% and a very low mortality rate (0.3%);⁸ however, the guideline reinforces awareness of the major vessels, major bile ducts, diaphragm, and other intra-abdominal organs.⁷Diaphragmatic hernia is defined as out-pocketing of abdominal contents into the thoracic cavity, through a defect in the diaphragm. However, most of the acquired diaphragmatic hernias are caused by penetrating or blunt traumatic injury and are rarely caused by surgical procedures such as gastric banding or abdominal surgeries (e.g., nephrectomy).^4,9 Especially, the appearance of a diaphragmatic hernia after RFA treatment is quite rare and clinically unrecognized as a complication of RFA.¹⁰ Surgical intervention is the best single treatment for the permanent cure of a diaphragmatic hernia. Among the surgical procedures, open laparotomy for diaphragmatic hernia has been widely accepted; however, only 1 case of liver cirrhosis and HCC has been reported, in which a laparoscopic approach was used to treat the diaphragmatic hernia associated with RFA treatment.¹⁰ We report the case of a patient with a diaphragmatic hernia caused by RFA treatment for HCC with cirrhosis, who was successfully treated with laparoscopic surgery.