Inhibitory effect of angiotensin Ⅱ receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis

AIM: To investigate the efficacy of angiotensin II receptor antagonist on hepatic stellate cells (HSCs) activation in the patients with non-alcoholic steatohepatitis (NASH). METHODS: Seven patients with NASH were prescribed losartan, a selective angiotensin II type 1 receptor antagonist (50 mg/d) for 48 wk. Liver biopsies were performed both at the entry and end of the study in all patients. Quiescent and activated HSCs were identified by double immunostaining using anti-p75 and -smooth muscle actin antibodies, and the number of each phenotype was counted. Similarly, the liver specimens obtained from the eight patients with non-alcoholic fatty liver (NAFL) were also examined as controls. RESULTS: In NASH hepatic tissues, activated HSCs were dominantly distributed as compared with those in NAFL. The 48-wk losartan treatment induced a remarkable decrease in activated HSCs and a mild increase in quiescent phenotypes. CONCLUSION: Our data suggest the crucial involvement of HSCs in anti-fibrotic effect of angiotensin II receptor antagonist on patients with NASH.     

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

The objective of this study was to evaluate the efficacy and safety of an additive combination of a disease-modifying antirheumatic drug (DMARD) actarit and low-dose methotrexate (MTX) in patients with active rheumatoid arthritis (RA) unresponsive to MTX. Thirty-four patients with active RA, who had been unsuccessfully treated with MTX for at least 3 months were enrolled on a 24-week course of actarit (300 mg/day) and MTX (2.5–10 mg/week). Disease activity was evaluated by physical global assessments using conventional measures (Japan Rheumatism Association), and the American College of Rheumatology (ACR) criteria of improvements in RA. Thirty-two patients completed this study. No severe adverse drug reactions were seen. Patients whose RA did not respond to MTX alone responded to the combination therapy, with a significant improvement in the duration of morning stiffness, grip strength, swollen joint counts, patient's articular pain score, modified health assessment questionnaire (M-HAQ) score, score of both patient's and physician's global assessments, and C-reactive proteins (CRP). Sixteen patients (50.0%) and 9 patients (31.0%) showed a significant improvement in overall conventional measures, and ACR response criteria, respectively, and 60.0% of RA patients who received MTX for more than 1 year showed improvement in ACR definition. Patients who responded to the combination treatment within the first 12 weeks showed persistent improvement for the remaining part of the 24 week period. Our results indicate that the additive combination of actarit and MTX is safe, and without serious adverse effects, and has an excellent efficacy in patients with active and refractory RA. Received: July 28, 1999 / Accepted: January 28, 2000     

Updates in diabetic neuropathy: A call for new diagnostic and treatment approaches

Diabetic polyneuropathy (DPN) is a serious complication of both type 1 and type 2 diabetes. The major clinical manifestations of DPN are neuropathic pain, diabetic foot (which is associated with ulcers, gangrene and amputation) and autonomic neuropathy. Diabetic sensorimotor peripheral neuropathy (DSPN) is the most common form of DPN and affects approximately 50% of people with type 1 or 2 diabetes during their lifetime ¹ . Despite its major clinical impact, DPN remains underdiagnosed and undertreated. To reduce the burdens of DPN, there is an urgent need to develop both novel diagnostic procedures that enable improvement in the early detection of the disease and new treatments that address multiple mechanistic pathways (Figure 1) ² .Open in a separate windowFigure 1Mechanisms of diabetic neuropathy. Chronic hyperglycemia induces an excessive activation of the polyol, protein kinase C and hexosamine pathways. In addition, chronic hyperglycemia leads to an increased production of advanced glycation end‐products (AGEs), which induces functional and structural neuronal damage through interaction with the AGE‐specific receptors. Hyperglycemia, insulin resistance and dyslipidemia contribute synergistically to mitochondrial dysfunction, overproduction of reactive oxygen species, inflammation, endoplasmic reticulum stress and deoxyribonucleic acid (DNA) damage, leading to neuronal cell damage. Both neuronal damage (demyelination and axonal loss) and endoneurial microvascular damage cause diabetic neuropathy in people with diabetes. AGE‐RAGE, advanced glycation end‐product–specific receptors; ER, endoplasmic reticulum; ROS, reactive oxygen species.Nerve conduction studies are the current gold standard for diagnosing DSPN, but they are labor intensive, time‐consuming, costly and impractical to implement in routine clinical care ³ . Therefore, DSPN is primarily diagnosed by a clinical examination that uses simple evaluation tests. They consist of assessing both small and large nerve fiber function, including temperature and pinprick perception (small fiber function); vibration sensation (with a 128‐Hz tuning fork) and Achilles tendon reflexes (large fiber function); and protective sensation (with a 10‐g monofilament; large fiber function) ⁴ .Recently, some new diagnostic point‐of‐care devices that enable early detection of DPN have been developed ⁵ . DPNCheck is a handheld point‐of‐care device that measures sural nerve amplitude and conduction velocity without the need for physiologist expertise or expensive equipment. DPNCheck measurements of sural nerve amplitude show strong agreement with standard nerve conduction studies ⁵ . Kamiya et al. ^{6 , 7} showed that parameters of the sural nerve obtained by DPNCheck were significantly associated with the severity of DSPN categorized by the Baba classification, suggesting that DPNCheck could provide comprehensive management of DSPN ⁶ . However, further research is required to determine whether routine use can be used as a reliable assessment for DSPN, and whether it can prevent clinical outcomes, such as foot ulcers, amputation and cardiovascular disease.I anticipate that future research will establish novel biomarkers for DSPN, painful neuropathy and autonomic neuropathy ⁸ . Novel biomarkers derived from the current pathogenic concepts show promise in the early detection of DPN, and in predicting its development and progression, with biomarkers of oxidative stress and inflammation being very promising candidates ⁸ . Other biomarkers, such as serum bilirubin, platelet size and complement C1q tumor necrosis factor‐related protein 9, are promising candidates for diagnosing DSPN and cardiovascular autonomic neuropathy (CAN) ^{9 , 10 , 11} . However, large prospective studies are required to further validate whether these biomarkers can predict the unwanted outcomes of diabetic neuropathy, such as neuropathic pain, ulcers, amputations or even death.Diabetic autonomic neuropathy affects the autonomic neurons (parasympathetic and/or sympathetic) and is associated with a variety of organ‐specific symptoms. Clinical manifestations of autonomic neuropathy include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea and fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction ³ .CAN is associated with the development of cardiovascular disease, and has a high risk of lethal arrhythmias and sudden death ³ . A post‐hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial showed beneficial effects of intensive glycemic or blood pressure control on the development of CAN in high‐risk patients with type 2 diabetes ¹² . Identifying CAN by assessing heart rate variability as early as possible is important and clinically relevant, because it allows physicians to decide when and how to implement optimal strategies for risk factor management ¹³ .A review article mentioned the possibility that continuous glucose monitoring could help improve hypoglycemia awareness, because it is effective in reducing hypoglycemia and severe hypoglycemic episodes in patients with type 1 diabetes and hypoglycemia unawareness ¹⁴ .Management of DSPN consists of three major principles: (i) causal treatment, including lifestyle modification, intensive glucose control and multifactorial cardiovascular risk intervention; (ii) pathogenesis‐based therapy; and (iii) relief of pain ¹⁵ . A better understanding of the underlying pathophysiology is required to enable new diagnostic and treatment approaches to be developed.Some drugs derived from research on the pathogenetic concepts of DSPN are being used in several countries around the world. Aldose reductase is a key enzyme of the polyol pathway, which has been shown to be enhanced and a possible factor in DSPN (Figure 1). Aldose reductase inhibitors aim to inhibit the activation of the polyol pathway induced by chronic hyperglycemia. In a 3‐year randomized study, the aldose reductase inhibitor, epalrestat, was well tolerated, and hindered the deterioration in median motor nerve conduction velocity, minimum F‐wave latency and vibration sensation seen in an untreated group of patients with DSPN ¹⁶ . A growing body of evidence suggests that oxidative stress resulting from enhanced free‐radical formation and/or defects in anti‐oxidant defense is implicated in the pathogenesis of DSPN (Figure 1). Several meta‐analyses suggested that anti‐oxidative therapy with α‐lipoic acid might be effective in treating DSPN ¹⁵ , and it has been used to treat symptomatic DSPN for a couple of decades.For the initial symptomatic treatment of neuropathic pain, α2δ ligands for voltage‐dependent Ca2⁺ channels, such as pregabalin, and norepinephrine reuptake inhibitors, such as duloxetine, are the two classes of analgesic drugs recommended, and they can also be used in combination ¹⁵ . In a study of Asian patients with diabetic neuropathy, mirogabalin, a new α2δ ligand, relieved neuropathic pain in a dose‐dependent manner and showed statistically significant pain relief (vs placebo) at a dose of 30 mg/day ¹⁷ . However, the efficacy of symptomatic treatments for neuropathic pain is limited, so there is a continuing need for novel drugs to be developed for painful neuropathy that target the pathogenesis.The current management strategy for diabetic neuropathy is focused on its early diagnosis, and prevention of diabetic foot and cardiovascular disease. In future, novel diagnostic techniques and criteria for classifying the severity of diabetic neuropathy might be developed, and their usefulness in evaluating the prognosis of diabetic neuropathy might be examined in large‐scale clinical studies. I also expect that basic research will lead to the development of new, more efficacious compounds (drugs) that ideally address multiple mechanistic pathways.     

Primary signet ring cell carcinoma of the urinary bladder successfully treated with intra-arterial chemotherapy alone

A 65-year-old man presented with the complaint of gross hematuria. Cystoscopy revealed a sessile tumor on the left bladder wall. It was diagnosed as primary signet ring cell carcinoma of the bladder (T3bN0M0). The patient did not want surgical treatment. Therefore, three courses of arterial infusion of carboplatin were administered at 3-week intervals. Complete remission was obtained and has been maintained for 44 months. Our case appears to be the first report of successful treatment with chemotherapy alone of an infiltrating signet ring cell carcinoma of the bladder.     

Short-lasting impairment of tactile perception by 0.9Hz-rTMS of the sensorimotor cortex

To test whether low-frequency repetitive transcranial magnetic stimulation (rTMS) of sensorimotor cortex (SM1) has prolonged effects on somatosensory function, eight subjects were given 900 TMS pulses over the left hand SM1 (0.9Hz, 90% of the resting motor threshold) or at sites 3 cm anterior or posterior to it. Tactile threshold of the right hand was increased for a short duration after rTMS over SM1, but two-point discrimination and median nerve SEPs were unaffected after rTMS at any sites.     

Habitual intake of lactic acid bacteria and risk reduction of bladder cancer

INTRODUCTION: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. METHODS: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). RESULTS: The OR of smoking was 1.61 (95% confidence interval: 1.10-2.36). Those of previous (10-15 years ago) intake of fermented milk products were 0.46 (0.27-0.79) for 1-2 times/week and 0.61 (0.38-0.99) for 3-4 or more times/week, respectively. CONCLUSION: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.     

Two cases of thoracopancreatic fistula in alcoholic pancreatitis: clinical and CT findings

We report two patients who were long-time habitual consumers of alcohol and suffered from thoracopancreatic fistula. The first patient, a 52-year-old man with no symptoms, underwent chest CT scan for a medical check-up and was revealed to have left small pleural effusion. A month later, he suddenly experienced severe cough and back pain. The immediate CT scan showed massive pleural effusion and mediastinal pseudocyst, and the amylase level in the aspirated pleural effusion proved to be elevated. He was successfully treated with medication and drainage of the effusion. The second patient, a 39-year-old woman, underwent CT scan for a medical check-up, and it disclosed that she had a small pleural effusion in the left lower thorax. Follow-up CT two months later revealed the pleural effusion to be resolved, however, it demonstrated that a narrow tract derived from the pancreatic secretion located just posterior to the pancreatic tail extended to the mediastinum along the left hemidiaphragmatic crus. She experienced severe cough and sputum four months later. CT scan showed massive pleural effusion in the left thorax and revealed that the pancreaticopleural fistula was located in the same position as the small tract that had been detected by the previous CT scan. The patient received conservative treatment and eventually recovered from the severe chest complications. We consider that asymptomatic left small pleural effusion in these patients who were habitual drinkers is a potential precursor to symptomatic pancreatitis. The patients developed mediastinal pseudocyst and pancreaticopleural fistula in association with chronic pancreatitis within a few months, and therefore intensive follow-up should be undertaken to minimize or prevent chest complications in association with the subsequent symptomatic pancreatitis.     

Nuclear cardiology: technical bases and clinical applications

Although the role of nuclear cardiology is currently well consolidated, the addition of new radiotracers and modern techniques makes it necessary to continuously update the requirements, equipment and clinical applications of these isotopic tests. The characteristics of the radioisotopic drugs and examinations presently used are explained in the first part of this text. In the second, the indications of them in diagnostic and prognostic evaluation of the different coronary diseases are presented.