Prognosis and incidence of immunological and oncological complications after direct-acting antiviral therapy for chronic hepatitis C.

Background and study aims: The long-term comprehensive prognosis of chronic hepatitis C after direct-acting antiviral (DAA) therapy is unclear. This study aimed to investigate the prognosis and incidence of immunological and oncological complications after DAA therapy. Patients and methods: The study included a total of 1461 patients who received DAA therapy in our university hospital and affiliated hospitals between September 3, 2014 and September 30, 2018. Results: The incidence rates of total malignancies in overall or female patients after DAA therapy were significantly greater than expected in the corresponding general population. The same was true for lung malignancies. Predictive risk factors associated with the occurrence and recurrence of hepatic malignancies after DAA therapy in patients with sustained virological response were cirrhosis and insulin use, protein induced by vitamin K absence or antagonist-II level, and albumin-bilirubin score, respectively. Eight (0.5%) patients were diagnosed with autoimmune diseases after starting DAA therapy. Importantly, the attending physician considered a possible causal relationship between DAA therapy and these autoimmune diseases in five cases (four rheumatoid arthritis and one membranoproliferative glomerulonephritis). The 5-year overall survival rate was 91.6%. The most frequent primary cause of death was malignancy in 41 (60.2%) patients, including 25 with hepatic malignancies. Lung and colorectal cancers were the next most common. Conclusions: Given that the incidence of total and lung cancers might increase and DAA-related autoimmune diseases might emerge after DAA therapy, we should be alert for the development of these diseases as well as hepatic malignancies.

Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites : a multicenter retrospective propensity score-matched cohort study.

Background: The aim of this retrospective study was to determine whether tolvaptan treatment reduces the amount of albumin administered, volume of ascites removed, and frequency of paracentesis procedures in patients with decompensated cirrhosis with uncontrolled ascites with conventional diuretics. Patients and methods: The control (C) group included patients treated with conventional diuretics. The tolvaptan (T) group included patients treated with both tolvaptan and conventional diuretics. Both groups were matched according to baseline parameters. The amount of albumin administered, volume of ascites removed, and frequency of paracentesis within 30 days of onset of uncontrolled ascites were compared between the two groups. Results: After matching, 74 patients (C=37, T=37) were included. Baseline parameters (C vs. T group) were as follows: age, 69.5 ± 9.3 vs. 70.4 ± 11.0 years (p = 0.702) ; males, 24 (64.9%) vs. 25 (67.6%) (p = 0.999) ; patients with hepatocellular carcinoma, 17 (45.9%) vs. 18 (48.6%) (p = 0.999) ; serum albumin levels at treatment initiation, 2.76 ± 0.48 vs. 2.73 ± 0.49 g/dL (p = 0.773), and serum creatinine levels at treatment initiation, 1.18 ± 1.23 vs. 1.09 ± 0.48 g/dL (p = 0.679). In the C vs. T groups, respectively, mean amount of albumin administered was 51.0 ± 31.4 vs. 33.4 ± 29.8 g/month (p = 0.016) ; mean volume of ascites removed was 2,905 ± 4,921 vs. 1,824 ± 3,185 mL/month (p = 0.266) ; and mean frequency of paracentesis was 0.92 ± 1.46 vs. 0.89 ± 1.45 procedures (p = 0.937). Conclusions: Tolvaptan reduced the use of albumin infusion in patients with decompensated cirrhosis and was effective and acceptable for uncontrolled ascites.

Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2.

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E-dependent and E-independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas-related G protein-coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin-10 fragment) that act as bioactive peptides and induce immunoglobulin E-independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as-yet-unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells.

Inverted internal limiting membrane flap technique as a useful procedure for macular hole-associated retinal detachment in highly myopic eyes.

PurposeTo determine whether the inverted internal limiting membrane (ILM) flap technique contributes to high reattachment and closure rates in patients with macular hole-associated retinal detachment (MHRD).Patients and methodsIn all, 15 eyes of 15 patients with MHRD undergoing 25-gauge pars plana vitrectomy with the inverted ILM flap technique or ILM peeling. The patients were divided into the inverted ILM flap technique group (6 eyes) and ILM peeling group (9 eyes). The logarithm of minimal angle of resolution best-corrected visual acuity (BCVA) and retinal attachment and macular hole closure rates were compared between the two groups before and after surgery.ResultsNo significant differences were found in the pre- and postoperative BCVA at 1 and 3 months after surgery in either group (inverted ILM flap technique group, preoperatively 1.04±0.55, 1 month 0.95±0.30, 3 months 0.83±0.22; ILM peeling group, preoperatively 1.00±0.44, 1 month 1.05±0.38, 3 months 1.06±0.49; P>0.05, respectively). The postoperative BCVA at 6 months after surgery was significantly better in the inverted ILM flap technique group than in the ILM peeling group (inverted ILM flap technique group, 0.62±0.35; ILM peeling group, 1.02±0.41, P=0.045). The improvement in BCVA was significantly better in the inverted ILM flap technique group than in the ILM peeling group (inverted ILM flap technique group, -0.41±0.29; ILM peeling group, 0.02±0.36; P=0.021). The primary macular hole closure rates were 100% in the inverted ILM flap technique group and 55.5% in the ILM peeling group. The primary reattachment rates were 100% in the inverted ILM flap technique group and 55.5% in the ILM peeling group. The primary macular hole closure and reattachment rates were not significantly different in both groups (P=0.056, respectively).ConclusionThe inverted ILM flap technique is a useful procedure for MHRD in highly myopic eyes.

Comparative study of 27-gauge vs 25-gauge vitrectomy for epiretinal membrane.

PURPOSE: The purpose of this study was to compare 27-gauge (27G) with 25-gauge (25G) microincision vitrectomy in patients with epiretinal membrane (ERM).ParticipantsSeventy-four eyes of 66 patients undergoing 3-port pars plana vitrectomy using 27G or 25G instrumentation. METHODS: Seventy-four eyes of 66 patients with ERM, who underwent 27G or 25G microincision vitrectomy were prospectively evaluated. RESULTS: The mean operation time for vitrectomy was significantly longer in the 27G group than in the 25G group (9.9±3.5 vs 6.2±2.7 min, respectively, P<0.0001). No statistically significant difference was found between the two groups in terms of the mean operation time for ERM-inner limiting membrane peeling (27G vs 25G: 20.2±9.9 vs 16.1±9.3 min, P=0.14), although the time for vitreous cutting was longer in the 27G group (9.9±3.5 vs 6.2±2.7 min, respectively, P<0.0001). The flare value, intraocular pressure (IOP), and rate of hypotony 1 day after surgery did not differ between the 27G and 25G groups (flare value: 18.7 vs 17.2; IOP: 8.8 vs 9.7 mm Hg; rate of hypotony: 30 vs 35%, respectively). There was no significant difference in the surgically induced astigmatism between the two groups in the follow-up period. The mean time required for wound closure did not show a significant difference between the 27G and 25G groups (7.7 vs 8.6 weeks, respectively). CONCLUSION: The 27G system is as safe and useful for ERM vitrectomy as the 25G system. Based on its potential, further improvement of 27G instruments could result in greater efficiency.

A large ovarian leiomyoma discovered incidentally in a 76-year-old woman: case report.

BACKGROUND: Ovarian leiomyoma is very rare type of ovarian tumor. This benign tumor is seen in the pediatric age group to premenopausal women. CASE: A 76-year-old woman had a huge leiomyoma (19 x 11 x 10 cm) of the right ovary. The preoperative diagnosis was difficult to distinguish from a broad ligament leiomyoma or ovarian cancer. CONCLUSIONS: Although theses tumors are benign, its extreme rarity led us to report an additional and rather unusual case of ovarian leiomyoma, and to focus some attention on this type of tumor.

Efficacy and Safety of Lixisenatide in Japanese Patients with Type 2 Diabetes Insufficiently Controlled with Basal Insulin±Sulfonylurea: A Subanalysis of the GetGoal-L-Asia Study.

The aim of the study was to evaluate the efficacy and safety of once-daily lixisenatide 20 µg as add-on to basal insulin with or without sulfonylurea in Asian patients with type 2 diabetes mellitus. The study as a subanalysis of the 159 Japanese patients from the 24-week double-blind GetGoal-L-Asia study (NCT00866658) who received once-daily lixisenatide or placebo. The primary endpoint was change from baseline in HbA1c evaluated using analysis of covariance. Once-daily lixisenatide significantly reduced mean HbA1c [least squares mean difference vs. placebo - 1.1% (- 12 mmol/mol); p<0.0001]. Significantly more patients in the lixisenatide group reached HbA1c targets of < 7% (53 mmol/mol; 31.4 vs. 2.3% for placebo; p<0.0001) and ≤ 6.5% (48 mmol/mol; 12.9 vs. 1.2% for placebo; p=0.0028). Lixisenatide significantly reduced 2-h postprandial plasma glucose (least squares mean difference vs. placebo-8.64 mmol/l; p<0.0001), glucose excursion (least squares mean difference vs. placebo - 7.80 mmol/l; p<0.0001) and fasting plasma glucose (least squares mean difference vs. placebo - 0.96 mmol/l; p=0.0126). Body weight was reduced with lixisenatide but with no significant difference vs. placebo. Gastrointestinal adverse events were more frequent with lixisenatide (61.1 vs. 11.5% for placebo) but were generally transient and mild-to-moderate in intensity. The incidence of symptomatic hypoglycemia was 39.0 vs. 13.5% in patients receiving sulfonylureas and 32.3 vs. 22.9% in those not receiving sulfonylureas, for lixisenatide and placebo, respectively. In Japanese patients with type 2 diabetes mellitus, once-daily lixisenatide was well tolerated and led to significant and clinically relevant improvement in glycemic control, with a pronounced effect on postprandial plasma glucose.

Premenstrual syndrome: management and pathophysiology.

Premenstrual syndrome (PMS) is triggered by hormonal events ensuing after ovulation. The symptoms can begin in the early, mid, or late luteal phase and are not associated with defined concentrations of any specific gonadal or non-gonadal hormone. Women with PMS experience affective or somatic symptoms that cause severe dysfunction in social or occupational realms. Although evidence for a hormonal abnormality has not been established, the symptoms of the premenopausal disorders are related to the production of progesterone by the ovary. The progesterone metabolites may bind to a neurosteroid-binding site on the membrane of the neurotransmitters. Thus, ovulation suppression is an area of focus for diagnostic and treatment options. Many treatment studies have focused on suppression of ovulation with gonadotropin-releasing hormone analogs (GnRHa), high doses of transdermal estrogen, and bilateral oophorectomy all have positive evidence as treatment options for prevention of PMS. However, because of these limitations and their substantial intensive care, these do not appear to be appropriate methods for conventional treatment of PMS. Serotonergic antidepressants, selective serotonin reuptake inhibitors, are well-established, highly effective, and first-line pharmacologic therapy.

Mesenteric malperfusion complicated with type A acute aortic dissection.

Type A acute aortic dissection (AAAD), involving the ascending aorta, is one of life-threatening disorders. Emergent surgery, such as graft replacement of the aortic root, ascending aorta, aortic arch, or these combinations, is routinely performed to avoid sudden death due to free rupture, cardiac tamponade, or coronary obstruction. Even though appropriate surgery is immediately completed, however, operative mortality remains high, between 15% and 30%. Furthermore, mesenteric malperfusion, bringing about enteric ischemia, occurs unusually in AAAD with far and away higher mortality. In the present article, we reviewed contemporary evidence regarding incidence, mortality, and treatment of mesenteric malperfusion complicated with AAAD. The incidence and early mortality rate of mesenteric malperfusion complicated with AAAD was 4% and 68%, respectively. Patients with mesenteric malperfusion had a 9.7-fold risk of mortality relative to those without it. Evidence regarding optimal treatment of mesenteric malperfusion complicated with AAAD is very limited.

Meteorology in ruptured abdominal aortic aneurysm: an institutional study and a meta-analysis of published studies reporting atmospheric pressure.

The aim of this paper was to determine whether weather factors including atmospheric pressure are associated with the occurrence of ruptured abdominal aortic aneurysm (RAAA). We investigated our institutional experiences of RAAA in more than 150 patients during 8 years. Further, we performed a meta-analysis of published studies reporting the influence of atmospheric pressure on RAAA. We retrospectively evaluated 152 patients who underwent surgery for RAAA (including ruptured iliac arterial aneurysm) at our institute between 1 January 2006 and 31 December 2013. Daily regional meteorological data (in the nearest weather station located 3.5 km from the hospital) were obtained online from Japan Meteorological Agency. To identify comparative studies of mean atmospheric pressure on the day with RAAA versus that on the day without RAAA, MEDLINE and EMBASE were searched through January 2014 using Web-based search engines (PubMed and OVID). Mean sea level atmospheric pressure, delta mean atmospheric pressure (difference between mean sea level atmospheric pressure on the day and that on the previous day), and sunshine duration on the day with RAAA were significantly lower than those on the day without RAAA: 1012.43±7.44 versus 1013.71±6.49 hPa, P=0.039, -1.18±5.15 versus 0.05±5.62 hPa, P=0.005; and 4.76±3.76 versus 5.47±3.88 h, P=0.026; respectively. A pooled analysis of 8 studies (including our institutional study) demonstrated that mean atmospheric pressure on the day with RAAA was significantly lower than that on the day without RAAA: standardized mean difference, -0.09; 95% confidence interval, -0.14 to -0.04; P=0.0009. Atmospheric pressure on the day with RAAA appears lower than that on the day without RAAA. Atmospheric pressure may be associated with the occurrence of RAAA.

Levonorgestrel-releasing intrauterine device used for dysmenorrhea: five-year literature review.

Intrauterine devices (IUDs) provide highly effective, long-term, safe, reversible contraception, and are the most widely used reversible contraceptive method worldwide. The levonorgestrel-releasing IUD (LNG-IUD), originally designed for long-term contraceptives, is now recognized to provide non-contraceptive health benefits. These include severe dysmenorrhea and/or heavy menstrual bleeding associated with uterine myoma, endometriosis, and adenomyosis. This report aims to review the last five-year literature on the efficacy and safety of the LNG-IUD in women with dysmenorrhea. Dysmenorrhea has been reported to decrease in all women. LNG-IUD seems to be superior over copper-releasing IUD for improving dysmenorrhea. The LNG-IUD is beneficial for symptom recurrence and endometriotic cyst recurrence after conservative surgery for patients with severe pain related to endometriosis. There is also evidence to support its role in menstrual problems of severely obese adolescent females. Expulsion, one of the important factors for IUD acceptability, is rare but more common in women with distorted uterine cavity. In the treatment of dysmenorrhea, the LNG-IUD is equal or superior to treat with systemic progestins or oral contraceptives even in adolescent or menopausal women.

Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration.

Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.

Intestinal mast cells and eosinophils in relation to Strongyloides ratti adult expulsion from the small and large intestines of rats.

Mucosal mast cells (MMC) play a crucial role in the expulsion of Strongyloides ratti adults from the small intestine of mice. We reported the large intestinal parasitism of S. ratti in rats, and there has been no report on MMC in the large intestine of the natural host. We studied kinetics of MMC, together with eosinophils, in the upper and lower small intestines, caecum and colon of infected rats. Two distinct phases of mastocytosis were revealed: one in the upper small intestine triggered by stimulation of 'ordinary' adults, and the other in the colon stimulated by 'immune-resistant' adults that started parasitizing the colon around 19 days post-infection. In all 4 intestinal sites, the MMC peaks were observed 5-7 days after the number of adult worms became the maximum and the height of MMC peaks appeared to be dependent on the number of parasitic adults, suggesting an important role played by worms themselves in the MMC buildup.

Improvement in skin color achieved by smoking cessation.

It has been well known that habitual smoking accelerates premature skin ageing recognized as 'smoker's face'. However, the effect of smoking cessation on the appearance of skin has not been elucidated. The aim of this study was to evaluate objectively the effect of smoking cessation on the skin's appearance. The stratum corneum carbonyl protein level and skin colour of the cheek and the hand were measured. The change before and during the smoking cessation treatment (0, 2, 4, 8 and 12 weeks), and the success or failure in smoking cessation, was compared and examined. Eighty-four cases who had smoking cessation treatment were examined. The level of the stratum corneum carbonyl protein did not show any difference comparing before and after treatment for the smoking cessation success group and the failure group. The lightness of skin colour showed an upward tendency 4-12 weeks after starting the treatment in the success group and increased significantly compared with the failure group. The redness showed a significant decrease in comparison with before the treatment, and it also showed a significant decrease compared with the failure group. The yellowness did not show any clear tendency. Also, the haemoglobin showed a decreased tendency. Furthermore, multivariate statistical analysis showed a possibility that the lightness and haemoglobin could be changed by smoking cessation treatment. In conclusion, our study showed that an upward tendency of skin lightness was seen to correspond with a haemoglobin decrease accompanied by smoking cessation. If we can easily measure skin improvement as an effect of smoking cessation, it is thought to be a useful aid for smoking cessation support.

Effects of statin therapy on abdominal aortic aneurysm growth: a meta-analysis and meta-regression of observational comparative studies.

OBJECTIVE: To determine whether statin therapy reduces the growth rate of small abdominal aortic aneurysms (AAAs). DESIGN: A meta-analysis and a meta-regression of comparative studies. MATERIALS: Eligible studies were randomized controlled trials or observational comparative studies of statin therapy versus placebo or no statin, enrolling individuals with small (<55 mm in diameter) AAAs and reporting AAA growth rate as an outcome. METHODS: Study-specific estimates (standardized mean differences [SMDs]) were combined in the fixed- and random-effects model. RESULTS: Seven adjusted and 4 unadjusted observational comparative studies enrolling 4647 patients with a small AAA were identified. Pooled analysis of all 11 studies suggested a significant reduction in AAA growth rate among patients assigned to statin therapy versus no statin (SMD, -0.420; 95% confidence interval [CI], -0.651 to -0.189). Combining the 7 high-quality studies providing adjusted data for growth rates generated an attenuated but still statistically significant result favoring statin therapy (SMD, -0.367; 95% CI, -0.566 to -0.168). The meta-regression coefficient for the baseline diameter was statistically significant (-0.096; 95% CI, -0.132 to -0.061). CONCLUSION: Statin therapy is likely effective in prevention of the growth of small AAAs, and may be more beneficial as the baseline diameter increases.

Novel [corrected] medical management of primary bladder endometriosis with dienogest: a case report.

BACKGROUND: Because of its low incidence, medical treatment of has not yet been well established although surgical excision is generally considered effective. We report the first case of primary bladder endometriosis successfully managed with a novel progestin dienogest. CASE: A 39-year-old woman, nulligravida, presented with lower urinary tract symptoms, especially during menstruation. Cystoscopy, with subsequent cold cup biopsy, revealed a solitary submucosal mass (2 x 2 cm) in the bladder on the posterior wall; histopathology revealed the diagnosis of extraperitoneal endometriosis. MRI and laparoscopy confirmed no peritoneal endometriosis implants or adenomyosis. She was treated with oral 2 mg/day dienogest for six months. The measurable lesion exhibited a remarkable reduction in its size, accompanied with immediate relief of the lesion-related symptoms. At one year after medication cessation, she is well and symptom-free. CONCLUSION: Dienogest may be a novel conservative alternative for bladder endometriosis, in particular for women who wish to avoid surgical intervention.

Peptide YY producing strumal carcinoid tumor of the ovary.

BACKGROUND: Primary ovarian carcinoid tumor is uncommon and represents less than 0.1% of ovarian malignancies. The strumal carcinoid may be complicated by carcinoid syndrome induced by peptide YY (PYY). CASE REPORT: We describe a 45-year-old woman with a bilateral ovarian tumor diagnosed through periodical gynecological examination. She presented with severe constipation. Right ovarian cyst laparoscopically resected was diagnosed as a strumal carcinoid tumor; the left one was mature cystic teratoma. No metastatic findings were seen macroscopically on the ovarian surface and pelvic peritoneum. Constipation was drastically improved by resecting the tumor. The carcinoid tumor cells were positive for tumor-producing PYY by mRNA analysis. CONCLUSION: It is important to be aware of this entity in the pathological diagnosis of ovarian tumors, in the presence of any clinical indicator of carcinoid tumor/syndrome, as it carries a markedly better prognosis and clinical outcome in comparison with most other malignant ovarian tumors.

Ovarian torsion; early diagnosis by MRI to prevent irreversible damage.

BACKGROUND: Early diagnosis of ovarian torsion can help prevent irreversible damage to the adnexal structures in women desiring to maintain fertility. CASE: The patient was transferred by ambulance for a six-hour history of severe lower abdominal pain. Magnetic resonance imaging (MRI) revealed bilateral enlarged ovaries measuring 5 x 6 cm (right) and 4 x 5 cm (left) with a right twisted and thickened peduncle. Ultrasonography failed to detect the peduncle changes. At surgery, the right adnexa was twisted 180 degrees in a clockwise direction with no findings suggestive of gangrenous change, hemorrhagic infarction or ischemic change. Detorsion of the twisted ovary was performed. CONCLUSION: Detection of tube torsion at MRI may be useful in the preoperative evaluation for surgical detorsion of twisted adnexa encountered in enlarged ovaries.