Serum free light chain assessment in type 1 autoimmune pancreatitis.

BACKGROUND: /Object: Some patients with type 1 autoimmune pancreatitis (AIP), the pancreatic manifestation of IgG4-related disease, have normal serum IgG4. The aim of this study is to investigate the diagnostic value of measuring serum free light chains (FLCs) in type 1 AIP. MATERIALS AND METHODS: Thirty-seven patients with type 1 AIP, and 21 healthy, 17 alcoholic chronic pancreatitis (ACP), 21 idiopathic chronic pancreatitis (ICP) and 20 pancreatic cancer (PC) patients were enrolled. Serum IgG4 and FLC concentrations were measured using sFLC Freelite assays on a nephelometric analyzer. RESULTS: Active AIP patients have significantly higher serum levels of κ (median 30.97 (12.3-227.0) mg/L) and λFLC (median 20.53 (12.36-102.7) mg/L)) than healthy controls (κFLC; median 12.5 (3.1-52.1) mg/L), λFLC: median 12.45 (5.4-39.5) mg/L) (p < 0.05) correlating with raised serum IgG4, and significantly higher summated FLCs (∑) (median 53.09 (25.0-218.0) mg/L) than ICP patients (median 26.77 (15.0-89.2) mg/L) and healthy controls (median 24.43 (8.5-91.6) mg/L) (p < 0.05). AIP patients (median 1.43 (0.84-3.24)) showed significantly higher κ/λ ratios than ACP (median 0.83 (0.42-1.18)), ICP (median 0.87 (0.47-2.16)), PC patients (median 0.90 (0.48-1.27)) and healthy controls (median 0.963 (0.51-1.32)). There was a correlation between increased κ and λ FLCs levels and the number of affected organs involved in IgG4 related disease. CONCLUSION: Patients with type 1 AIP have increased serum k and λ FLC concentrations, Σ FLC, and κ/λ ratios. These novel biomarkers may be useful in the diagnosis of type 1 AIP and in monitoring disease activity.

Liver Transection-First Approach in Hepatopancreatoduodenectomy for Hilar Cholangiocarcinoma: A Safe and Secure Technique for the Early Assessment of Curable Resection and Vascular Reconstruction.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) is often indicated in the resection of cholangiocarcinoma but is associated with high mortality.1-3 From a risk-benefit perspective, HPD can be justified only when curative resection is achievable.4-6 METHODS: A liver transection-first approach is a surgical technique in which liver transection precedes pancreatoduodenectomy (PD) and skeletonization of the hepatoduodenal ligament in HPD. This approach enables an early assessment of resectability and curability. RESULTS: A 64-year-old with jaundice had a tumor located mainly in the proximal bile duct, spreading from the confluence of hepatic ducts (dominant in the left hepatic duct) to the intrapancreatic bile duct. The right hepatic artery and portal vein existed in close proximity to the tumor. HPD (left hemi-hepatectomy and subtotal stomach-preserving PD) with vascular resection was performed. After liver transection along the Cantlie line, the right Glissonean pedicle was collectively secured inside the liver. The right hepatic artery, right portal vein, and right hepatic duct (RHD) were isolated, and the feasibility of vascular reconstruction was confirmed. After the RHD was divided and the negative margin was confirmed, we proceeded to perform PD. The portal vein was reconstructed between the right portal vein and the portal vein trunk. The right hepatic artery was anastomosed to the second jejunal artery of the jejunal loop with the right gastroepiploic artery as an interposition graft. CONCLUSION: The liver transection-first technique in HPD facilitates early assessment of curability and resectability as well as a safe and secure manipulation and reconstruction of the hepatic artery and portal vein.

Relationship between the Functional Independence Measure and Mann Assessment of Swallowing Ability in hospitalized patients with pneumonia.

AIM: Pneumonia ranks high among the causes of death worldwide. However, the predictive values of activities of daily living, the nutrition index and the aspiration index measured objectively remain unclear. The present study aimed to examine the associations of activity, nutrition and dysphagia with pneumonia. METHODS: We assessed 992 hospitalized patients. Logistic regression analysis was used to examine the predictors of pneumonia. Receiver operating characteristic curve analysis was used to determine the cut-off values of variables. Kaplan-Meier and Cox hazards regression analyses were used to examine the incidence of pneumonia and the factors associated with pneumonia. RESULTS: We finally enrolled 393 inpatients. Of the 393 patients, 102 (26.0%) had pneumonia. On logistic regression analysis, age, Functional Independence Measure (FIM)-motor score and Mann Assessment of Swallowing Ability (MASA) score were independent predictors of pneumonia. The FIM-motor and MASA cut-off values were 19.5 (area under the curve 0.83, P < 0.01) and 170.5 (area under the curve 0.82, P < 0.01), respectively. Kaplan-Meier analysis showed that the no pneumonia rate was significantly lower among patients with FIM-motor scores <20 than among those with FIM-motor scores ≥20 (log-rank test, P < 0.01), and was significantly lower among patients with MASA scores <171 than among those with MASA scores ≥171 (log-rank test, P < 0.01). Cox regression analysis showed that FIM-motor (hazard ratio 0.97, P = 0.009) and MASA scores (hazard ratio 0.99, P < 0.01) were significantly associated with pneumonia. CONCLUSIONS: In addition to the infectious risk, the FIM-motor and MASA scales are useful tools to predict the development of pneumonia in older adults. Geriatr Gerontol Int 2018; 18: 1620-1624.

Inter-individual variability of in vivo CYP2D6 activity in different genotypes.

Cytochrome P450 2D6 (CYP2D6), which has a large number of genetic polymorphisms, is involved in the metabolism of a wide range of substrates. Dextromethorphan (DM) is a well-known probe drug for CYP2D6 and metabolic ratio (MR) is often used to measure the enzyme activity in vivo. Using the literature values of DM MR, we estimated the inter-individual variability of CYP2D6 hepatic intrinsic clearance (CL(int,h,2D6)) in each genotype by Monte Carlo simulation and found that the homozygote of CYP2D6*1 and the heterozygote of CYP2D6*1 and null alleles had a coefficient of variation (CV) of 43% and 56%, respectively. The variability of homozygotes of CYP2D6*2 and CYP2D6*10 was 63% and 66%, while that of the heterozygotes of CYP2D6*2 and null alleles and CYP2D6*10 and null alleles was 125% and 109%, respectively. Based on the variability and reported frequency of the CYP2D6 genotype in Asians and Caucasians, the inter-individual variability of CL(int,h,2D6) of extensive metabolizers was estimated at 60-70%, which provided comparable variability of AUC with the literature values of DM, tolterodine, risperidone and atomoxetine. It is suggested that the produced inter-individual variability of CL(int,h,2D6) in each genotype is useful for estimating AUC variability of the CYP2D6 substrates in the regional population.

Prediction of interindividual variability in pharmacokinetics for CYP3A4 substrates in humans.

A method for predicting the interindividual variability of human exposure for CYP3A4 substrates using Monte Carlo simulation was developed based on relevant factors. The coefficient of variation (CV) values for CYP3A4 content in human liver microsomes, hepatic blood flow, liver volume and body weight, and the unbound blood fraction were collected from the published literature. The parallel tube and dispersion models were found to be appropriate mathematical models to describe the pharmacokinetics (PK). Simulation results using 33% as the CV for CYP3A4 content reflected reported CV values of the area under the curve (AUC) for 40 CYP3A4 substrates for both intravenous and oral administration. We also successfully predicted the clearance of midazolam in Japanese and in European American subjects. In all cases, the simulated mean and SD values reflected the reported values. Thus, the interindividual variability of the AUC of CYP3A4 substrates was predictable for both intravenous and oral administration.

Estimation of the interindividual variability of cytochrome 2D6 activity from urinary metabolic ratios in the literature.

Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its intrinsic metabolic activity (CL(int,CYP2D6,app)) relative to extensive metabolizers (EM) and its variability were estimated by analyzing the urinary metabolic ratios (MR) based on the well-stirred model. Sparteine and debrisoquine were considered to be appropriate probes for our methodology, whereas dextromethorphan was not appropriate since the formation of its metabolite of interest is not described by the well-stirred model. From the analysis of MRs of sparteine and debrisoquine for Caucasian subjects in the literature, CL(int,CYP2D6,app) for intermediate metabolizers (IM) was estimated to be approximately 15% of that for EM. The coefficient of variability (CV) of CL(int,CYP2D6,app) was estimated to be approximately 60% for both EM and IM and 100% for the combined population of ultrarapid metabolizer, EM and IM [i.e., the non-poor metabolizer (non-PM) population]. Simulation of exposure in the non-PM population showed that the CV of exposure was 140% for dextromethorphan and 71% for metoprolol, which reflected the reported values of 110% and 53% for dextromethorphan and metoprolol, respectively. The present study should be useful for predicting the interindividual variability in exposure to investigational drugs that are metabolized by CYP2D6.

Questionnaire-based assessment of pelvic organ dysfunction in multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized clinically by any combination of autonomic, cerebellar, and extrapyramidal symptoms. Autonomic symptoms are usually severe, and urinary symptoms are one of the cardinal features of MSA. Bowel dysfunction and sexual dysfunction are also common in MSA. Quality of life (QOL) in patients with MSA is severely impaired by the presence of pelvic organ dysfunction. Therefore, we aimed to examine the prevalence of pelvic organ dysfunction in patients with MSA. We recruited 256 patients with MSA seen at our neurology clinic. The mean age was 62 years. The control group comprised 158 individuals, and the mean age was 52 years. We administered a questionnaire on pelvic organ dysfunction to the MSA and control groups. The questionnaire had sections focusing on the bladder, bowel, and sexual function. Dysfunction, as described in the responses, was evaluated as normal, mild (>once a month), moderate (>once a week), or severe (>once a day). The Mann-Whitney's U-test was used for statistical analysis. When compared with the control group, the prevalence of pelvic organ dysfunction in the MSA group was significantly higher for urinary storage and voiding dysfunction, bowel dysfunction, and sexual dysfunction. QOL in the MSA group was therefore significantly impaired because of urinary dysfunction (70%, 76%), bowel dysfunction (40% of the men), and sexual dysfunction (26%, 45%). Pelvic organ dysfunction is common in MSA, and QOL is severely impaired in patients with MSA.

Effects of milnacipran and paroxetine on overactive bladder due to neurologic diseases: a urodynamic assessment.

AIMS: To determine the effects of milnacipran hydrochloride, a serotonin-norepinephrine reuptake inhibitor (SNRI), or paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on overactive bladder (OAB) in neurologic diseases, given by objective measures of urodynamic studies. METHODS: This is a prospective open trial, and we enrolled 24 patients (16 men, 8 women; mean age, 63.9 years) with OAB in a neurology clinic. They were randomly allocated into two groups: the milnacipran group (11 patients), and paroxetine group (13 patients). We started with 100 mg/day of milnacipran or 40 mg/day of paroxetine. Before and 3 months after the treatment, we performed a urinary questionnaire and urodynamic studies. RESULTS: Milnacipran reduced daytime urinary frequency (average, from 9.4 to 7.1 times, p < 0.001), improved the quality of life index (p = 0.023), and increased bladder capacity (average, from 289 to 377 ml, p = 0.009) as shown in urodynamic studies. No such changes were noted in the other categories of the lower urinary tract symptoms questionnaire or urodynamic studies, or in the paroxetine group. One male patient complained of mild voiding difficulty. Other adverse effects were not seen during the observation period. CONCLUSION: Milnacipran, an SNRI, increased bladder capacity as shown in urodynamic studies, and thereby ameliorated OAB in patients with neurologic diseases without serious adverse effects.

Psychogenic urinary dysfunction: a uro-neurological assessment.

AIMS: The diagnosis of psychogenic urinary dysfunction (PUD) is one of exclusion, particularly from urologic and neurologic causes, and is usually accompanied by more obvious psychologic/ psychiatric features. We here describe patients with PUD who were diagnosed in our uro- neurological laboratory. MATERIALS AND METHODS: We reviewed the digitized records of 2,300 urodynamic cases treated in the past 6 years to identify patients who fulfilled the diagnostic criteria of PUD. All 2,300 patients had completed a urinary questionnaire and undergone both electromyography (EMG)-cystometry and a detailed neurological examination. In addition, pressure-flow analysis, neurophysiology tests including sphincter EMG analysis, and MRI of the brain and spinal cord were performed as applicable. RESULTS: PUD was seen in 16 cases (0.7%): 6 men, 10 women, mean age 37 years. Lower urinary tract symptoms (LUTS) included overactive bladder (OAB) alone in 5, difficult urination alone in one, and both in 10. LUTS commonly occurred in particular situations, for example, OAB only while riding the train. Some patients showed extremely infrequent toileting. The urodynamic findings were normal except for increased bladder sensation (50%) for OAB and acontractile detrusor (31%) for difficulty. The final diagnosis was conversion reaction in six followed by anxiety in four. CONCLUSIONS: PUD patients experienced the situational occurrence of OAB and/or difficult urination and, in some patients, extremely infrequent toileting. The main urodynamic abnormalities were increased bladder sensation and acontractile detrusor. However, even in cases suggestive of PUD, a non-PUD pathology behind the symptoms should be explored.