Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets?

Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myofibroblast proliferation and collagen synthesis in vitro, but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-alpha given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 40-60%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-beta or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.     

Successful catheter ablation of left ventricular epicardial tachycardia originating from the great cardiac vein: a case report and review of the literature.

A patient underwent radiofrequency (RF) catheter ablation for a drug-refractory ventricular tachycardia, but RF energy application at an endocardial site of the left ventricular outflow tract and at the left sinus of Valsalva could not eliminate the tachycardia. The earliest ventricular activation during the arrhythmia, which preceded the onset of the QRS complex by 32 ms, was found within the great cardiac vein and complete elimination of the tachycardia was finally achieved with RF application at that site.     

The Clara cell10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.     

Prevalence of methicillin-resistant Staphylococcus aureus among veterinary staff in small animal hospitals in Sapporo,Japan, between 2008 and 2016: A follow up study

The aim of the present study was to determine and compare the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and their molecular characteristics among veterinary staff in Sapporo in 2008 and 2016. We isolated MRSA from veterinarians (Vet; n = 91), veterinary technicians (VT; n = 113), and other staff members (n = 24) from 45 small animal hospitals (animal hospitals), as well as from surface swabs (n = 123) obtained from 37 animal hospitals, in 2016. MRSA was observed in 14 Vets (15%), 7 VTs (6%), 2 other staff members (8%), and 6 environmental samples (5%). The prevalence of MRSA among veterinary staff tended to decrease, in comparison to 2008. All the MRSA isolates were classified as CC5/SCCmecII, which is commonly observed in medical settings in Japan. Upon performing pulse-field gel electrophoresis, with SmaI and EagI, and clfB sequence typing, it was observed that 16 of the MRSA isolates from 2016 were highly similar to those obtained in 2008. This suggests that some MRSA isolates persisted throughout 8 years, although their origins remain unclear. The continuation of education and monitoring of MRSA is necessary for the prevention and control of infection in these settings.     

Review on acute pancreatitis attributed to COVID-19 infection

The coronavirus disease 2019 (COVID-19) is known to cause gastrointestinal symptoms. Recent studies have revealed COVID-19-attributed acute pancreatitis (AP). However, clinical characteristics of COVID-19-attributed AP remain unclear. We performed a narrative review to elucidate relation between COVID-19 and AP using the PubMed database. Some basic and pathological reports revealed expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, key proteins that aid in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the pancreas. The experimental and pathological evaluation suggested that SARS-CoV-2 infects human endocrine and exocrine pancreas cells, and thus, SARS-CoV-2 may have a direct involvement in pancreatic disorders. Additionally, systemic inflammation, especially in children, may cause AP. Levels of immune mediators associated with AP, including interleukin (IL)-1β, IL-10, interferon-γ, monocyte chemotactic protein 1, and tumor necrosis factor-α are higher in the plasma of patients with COVID-19, that suggests an indirect involvement of the pancreas. In real-world settings, some clinical features of AP complicate COVID-19, such as a high complication rate of pancreatic necrosis, severe AP, and high mortality. However, clinical features of COVID-19-attributed AP remain uncertain due to insufficient research on etiologies of AP. Therefore, high-quality clinical studies and case reports that specify methods for differential diagnoses of other etiologies of AP are needed.     

Unilateral active adrenal tuberculosis featuring persistent intermittent fever

The adrenal gland is one of the organs which tuberculosis infects. In most clinical settings bilateral adrenal tuberculosis has been clarified after adrenal insufficiency is overt. On the contrary, active adrenal tuberculosis is rarely detected during the survey of infectious disease. A 68-year-old man was admitted because of intermittent fever. The fever had continued for the last 3 months. The intermittent fever was accompanied with leukocytosis and elevation of C-reactive protein. Serum soluble interleukin-2 receptor was 1920 U/ml, and beta2-microglobulin was 4.0 mg/l. Bacterial cultures of blood, sputa, urine, bone marrow and cerebrospinal fluid did not show any particular bacteria. Mycobacterium tuberculosis was negative in culture of sputa, and there was no tuberculin reaction. Plasma ACTH and serum cortisol were 18.5 pmol/l and 527.0 nmol/l, respectively. Abdominal CT scan showed right adrenal mass with a size of 28 x 20 mm, which was low density and had a well-encapsulated homogenous appearance. After the adrenalectomy, histology verified active adrenal tuberculosis. The intermittent fever disappeared, and white blood cells and C-reactive protein normalized. These findings indicate an atypical, rare case of unilateral, active adrenal tuberculosis closely linked to intermittent fever, and without any other organ involvement.     

Tube cholangio-jejunal bypass in unresectable hepatic hilar carcinoma for a better quality of life

A 76-year-old male patient with jaundice was diagnosed as having hepatic hilar cholangiocarcinoma. The patient underwent percutaneous transhepatic biliary drainage of the left and the right intrahepatic bile duct. He could not have a percutaneous transhepatic endoprosthesis placed because it was impossible to pass the guidewire through the stenotic portion of the lesion. The patient was operated, but the tumor was considered to be unresectable. Along the intrahepatic routes formed by the preexisting two percutaneous transhepatic biliary drainage tubes, silicon tubes were inserted. Through the lumen of a long jejunal limb, Roux-en-Y, the tubes with five to six side holes were passed in the distal direction and drawn out from the lumen of the jejunal limb and passed through the abdominal wall to outside. The tubes were occluded and buried in the subcutaneous space after a few clamping tests. He died of liver failure in his house four months after the operation without any symptoms of jaundice, fever or of obstruction of the tubes.     

Accelerated myocardial metabolic and functional recovery with terminal nicorandil-Mg cardioplegia in heart transplantation

Cardiac reperfusion injury after heart transplantation or cardiopulmonary bypass has been difficult to control due to the variable degree of myocardial damage with respect to the length of ischemia and the complexity of the surgical procedure. Here, we evaluated the myocardial metabolic and functional recovery of hearts infused with a nicorandil vasodilator-magnesium (Mg) solution just prior to reperfusion (terminal cardioplegia). Donor hearts (20 dogs) were removed and immersed in a 4 degrees C water bath containing 20 mEq/l KCL-5% glucose for 6 hours, and then were transplanted to recipient dogs. Orthotopically transplanted dog hearts were either reperfused without any further treatment or received a terminal cardioplegic solution containing 8 mg/l nicorandil, 30 mEq/l Mg, and 50 g/l glucose, which was infused at a pressure of 75 cm H2O for 2 minutes. During the reperfusion period, myocardial tissue PCO2 (t-PCO2) and calcium ion (t-Ca) were continuously monitored by an ISFET (ion-sensitive field effect transistor) sensor. Myocardial oxygen consumption and lactate flux were calculated/monitored at 5, 10, 20 and 40 minutes of reperfusion. Thereafter, myocardial function was evaluated at 45 minutes of reperfusion using LVSWI. Just after reperfusion, the treatment group (group B, n = 10) had a significantly greater coronary flow than the control group (Group A, n = 10, 35.0 +/- 10.1; group B, 47.4 +/- 8.5 ml/100 g/min, p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibrolamellar hepatocellular carcinoma: report of a case

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.     

A retrospective study of the preventive effect of transarterial chemotherapy for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy

A major problem in treating hepatocellular carcinoma (HCC) is intrahepatic recurrence after partial hepatectomy, despite the relatively early detection now possible due to recent developments in non-invasive diagnostic modalities. The present study evaluated the usefulness of preventive therapy for intrahepatic recurrence of HCC. In order to suppress intrahepatic recurrence in HCC patients at high risk of recurrence after tumor removal, we performed preventive transarterial chemotherapy in 23 such patients. Doxorubicin, at a dose of 0.5 mg/kg body weight, was administered, via a catheter inserted at the junction of the common hepatic artery and the gastroduodenal artery, every 2 weeks for the first 2 months, and every month thereafter for at least 1 year. The control group consisted of 30 patients with similar risk of recurrence who underwent partial hepatectomy during the same period without receiving transarterial preventive therapy. The 1-, 2-, 3-, and 5-year cumulative cancer-free survival rates in patients who received transarterial preventive chemotherapy after partial hepatectomy were 87.0%, 47.1%, 21.2%, and 21.2%, respectively, compared to 53.3%, 30.0%, 20.0%, and 13.3%, respectively, in the control group (P<0.05). The 1-, 2-, 3-, and 5-year cumulative overall survival rates were 95.7%, 81.2%, 58.4%, and 48.7%, respectively, in the preventive chemotherapy group, compared to 70.0%, 49.4%, 41.7%, and 19.5%, respectively, in the control group (P<0.05). Thus, the present study demonstrates the limited but significant effect of preventive transarterial chemotherapy for the intrahepatic recurrence of HCC after partial hepatectomy.