Percentage of urinary albumin excretion and serum-free light-chain reduction are important determinants of renal response in myeloma patients with moderate to severe renal impairment.

Reversal of renal dysfunction significantly affects the prognosis of multiple myeloma (MM) with renal impairment (RI). There is no reliable test for predicting reversibility of RI in MM patients. We postulated that MM with high albuminuria may reflect glomerular disease that is difficult to reverse. Here, we examined the impact of urinary albumin excretion. We retrospectively analyzed 279 patients admitted to our hospital from April 2000 to December 2013. Clinical variables and laboratory data that may affect myeloma treatment response were extracted. The results were examined for relationship to renal response by univariate and multivariate analysis. RI (estimated glomerular filtration rate ≦50 ml/min per 1.73 m(2)) was observed in 116 patients (46%) and renal responses of renal complete response, renal partial response, renal minor response and no response were obtained in 46 (40%), 15 (13%), 13 (11%) and 42 (36%) patients, respectively. Although renal recovery was significantly associated with Durie-Salmon 1 or 2 (P=0.02), myeloma response better than very good partial response (P=0.03), involved free light-chain (iFLC) reduction from baseline 80% at day 12 (P=0.005), ≧95% at day 21 (P<0.001) and urinary albumin ≦25% on admission (P<0.001) on univariate analysis, only reduction of iFLC 95% at day 21 (P=0.015) and urinary albumin ≦25% (P=0.007) remained significant for any renal response. Our observation indicates that increased urinary albumin excretion >25% and reduction of iFLC ≦95% on day 21 were associated with favorable renal recovery in MM patients with RI, and were considered as negative predictors for renal response.

The relationship of brachial-ankle pulse wave velocity to future cardiovascular disease events in the general Japanese population: the Takashima Study.

Brachial-ankle pulse wave velocity (baPWV) is a non-invasive measure of arterial stiffness obtained using an automated system. Although baPWVs have been widely used as a non-invasive marker for evaluation of arterial stiffness, evidence for the prognostic value of baPWV in the general population is scarce. In this study, we assessed the association between baPWV and future cardiovascular disease (CVD) incidence in a Japanese population. From 2002 to 2009, baPWV was measured in a total of 4164 men and women without a history of CVD, and they were followed up until the end of 2009 with a median follow-up period of 6.5 years. Hazard ratios (HRs) for CVD incidence according to baPWV levels were calculated using a Cox proportional hazards model adjusted for potential confounding factors, including seated or supine blood pressure (BP). During the follow-up period, we observed 40 incident cases of CVD. In multivariable-adjusted model, baPWV as a continuous variable was not significantly associated with future CVD risk after adjustment for supine BP. However, compared with lower baPWV category (<18 m s(-1)), higher baPWV (< or = 18.0 m s(-1)) was significantly associated with an increased CVD risk (HR: 2.70, 95% confidence interval: 1.18-6.19). Higher baPWV (< or = 18.0 m s(-1)) would be an independent predictor of future CVD event in the general Japanese population.

[Barrett's esophagus: analyses from human and experimental animal studies]. / Barrett-Ösophagus: Erkenntnisse beim Menschen und aus experimentellen Tierstudien.

Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett's esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.

Is there any circadian variation consequence on acute case fatality of stroke? Takashima Stroke Registry, Japan (1990-2003).

BACKGROUND: Circadian periodicity in the onset of stroke has been reported. However, it is unclear whether this variation affects the acute stroke case fatality. Time of the day variation in stroke case fatality was examined using population-based stroke registration data. METHODS: Stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During the period of 1990-2003, there were 1080 (549 men and 531 women) cases with classifiable stroke onset time. Stroke incidence was categorized as occurring at night (midnight-6 a.m.), morning (6 a.m.-noon), afternoon (noon-6 p.m.), and evening (6 p.m.-midnight). The 28-day case fatality rates and 95% confidence intervals (95% CI) were calculated by gender, age, and stroke subtype across the time blocks. After adjusting for gender, age at onset, and stroke severity at onset, the hazard ratios for fatal strokes in evening, night, and morning were calculated, with afternoon serving as the reference. RESULTS: For all strokes, the 28-day case fatality rate was 23.3% (95% CI:19.4-27.6) for morning onset, 16.9% (95% CI:13.1-21.6) for afternoon onset, 18.3% (95% CI:13.6-24.1) for evening onset, and 21.0% (95% CI:15.0-28.5) for the night onset stroke. The case fatality for strokes during the morning was higher than the case fatality for strokes during afternoon. This fatality risk excess for morning strokes persisted even after adjusting for age, gender, and stroke severity on onset in multivariate analysis. CONCLUSION: In the examination of circadian variation of stroke case fatality, 28-day case fatality rate tended to be higher for the morning strokes.

Trend of stroke incidence in a Japanese population: Takashima stroke registry, 1990-2001.

BACKGROUND: In Japan, stroke mortality and incidence started to decline during the 1960s. The recent unfavourably diverging trends in risk factors make it uncertain whether the decline will continue. Few comprehensive stroke registries of long research duration exist in Japan to illustrate the trends in stroke incidence. OBJECTIVE: We examined 12-year stroke registration data to evaluate the current trend in a Japanese population. METHODS: Data were obtained from the Takashima Stroke Registry, covering approximately 55 000 residents of Takashima County in central Japan. We calculated the age-adjusted stroke incidence rates (/100 000 person-years) and 95% confidence intervals for 1990-1992, 1993-1995, 1996-1998, and 1999-2001. We applied the direct method to adjust for the age distribution among the four periods. The incidence time trend was determined by calculating the average annual change across the study years using negative binomial regression analysis. RESULTS: There were 1453 (men: 771 and women: 682) registered first-ever stroke cases during 1990-2001. The diagnosis was established by neuro-imaging in 93.6% of the cases. The average age was 69.4 years in men and 74.2 years in women. The age-adjusted incidence rates of stroke across the four observation periods were 143.1 (confidence interval: 127.4-158.8) in 1990-1992, 147.4 (confidence interval: 131.9-162.8) in 1993-1995, 120.4 (confidence interval: 106.7-134.0) in 1996-1998, and 122.9 (confidence interval: 109.6-136.2) in 1999-2001. The stroke incidence across the study years showed an insignificant time trend, with an average annual change of -0.33% (confidence interval: -2.44 to 1.78) per year. Similar trends were observed for both men and women and stroke subtypes. CONCLUSIONS: The previously reported declining trend in stroke incidence may have levelled off or slowed down considerably in the Japanese population.

Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990-2003.

BACKGROUND: We examined the circadian periodicity of ischaemic stroke (IS) onset and its relationship with conventional risk factors using 14-year stroke registration data. METHODS: Ischaemic stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. During 1990-2003 there were 637 (353 men and 284 women) cases with classifiable onset time. IS incidence was categorized as occurring at night (midnight to 6 am), morning (6 am to noon), afternoon (noon to 6 pm), and evening (6 pm to midnight). The OR (with 95% CI) of having an IS in the morning, afternoon, and evening were calculated, with night serving as reference. RESULTS: There was significant diurnal variation in IS incidence (P < 0.001). The proportion of events was highest in the morning (40.7; 95% CI: 36.9-44.5), and lowest in the night (14.0; 95% CI: 11.5-16.9). In the morning an excess incidence of IS was observed in both genders, in subjects <65 years and > or =65 years, and in all IS subtypes. The morning excess of IS incidence was similar across seasons and days of the week. For all IS, morning excess was higher (odds ratio: 2.91; 95% CI: 2.29-3.70) compared to the night period. Similar trends persisted after adjusting for age, gender, and risk factors. CONCLUSION: In the examination of circadian variation of IS onset, a predominant morning peak independent of conventional risk factors was observed in a Japanese population with similar pattern across seasons of the year and days of the week.

An animal model of intrinsic dental erosion caused by gastro-oesophageal reflux disease.

OBJECTIVES: To explore the association between dental erosion and gastro-oesophageal reflux disease (GORD), we used an animal model of GORD. MATERIALS AND METHODS: We performed an operation to force gastro-duodenal contents reflux in male Wistar rats, and examined the teeth in the reflux rats at 15 or 30 weeks postoperatively. Dental erosion was evaluated based on a slightly modified index from a previous report. Estimation of pH was employed in the oesophageal and gastric contents. RESULTS: Macroscopically, dental erosion was only detected in the reflux rats. Histopathologically, dentin exposure was detected in three of the seven cases after 30 weeks. Alveolar bone destruction and osteomyelitis were also noted in severe cases. The pH of the oesophageal and stomach contents was 6.93 +/- 0.15 and 3.7 +/- 0.39, respectively. CONCLUSIONS: We confirmed the relationship between dental erosion and GORD. First step of dental erosion caused by GORD is the loss of surface enamel induced by regurgitation of an acidic liquid and acidic gas. Subsequently, further destruction of dental hard tissues and tooth supporting structure is accelerated by mixed juice with gastric and duodenal contents. The reflux animal model is a useful tool to examine the mechanism of dental erosion in GORD.

PGE2 signal via EP2 receptors evoked by a selective agonist enhances regeneration of injured articular cartilage.

OBJECTIVE: The effect of the prostaglandin E2 (PGE2) signal through prostaglandin E receptor 2 (EP2) receptors on the repair of injured articular cartilage was investigated using a selective agonist for EP2. METHODS: Chondral and osteochondral defects were prepared on the rabbit femoral concave in both knee joints, and gelatin containing polylactic-co-glycolic acid microspheres conjugated with or without the EP2 agonist was placed nearby. Animals were sacrificed at 4 or 12 weeks post-operation, and regenerated cartilage tissues and subchondral structure remodeling were evaluated by histological scoring. The quality of regenerated tissues was also evaluated by the immunohistochemical staining of EP2, type II collagen, and proliferating cell nuclear antigen (PCNA). As an evaluation of side effects, the inflammatory reaction of the synovial membrane was analyzed based on histology and the mRNA expression of matrix metalloproteinase3 (MMP3), tissue inhibitor of metalloproteinase 3 (TIMP3), and interleukin-1 beta (IL-1 beta). Also, the activity of MMP3 and the amount of tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein in joint fluid were measured. RESULTS: In both models, the EP2 agonist enhanced the regeneration of the type II collagen-positive tissues containing EP2- and PCNA-positive chondrocytes, and the histological scale of regenerated tissue and subchondral bone was better than that of on the control side, particularly at 12 weeks post-operation. No inflammatory reaction in the synovial membrane was observed, and no induction of pro-inflammatory cytokines was found in joint fluid. CONCLUSION: Selective stimulation of the PGE2 signal through EP2 receptors by a specific agonist promoted regeneration of cartilage tissues with a physiological osteochondral boundary, suggesting the potential usefulness of this small molecule for the treatment of injured articular cartilages.

Intratumoural heterogeneity of intestinal expression reflects environmental induction and progression-related loss of induction in undifferentiated-type gastric carcinomas.

AIMS: Gene expression in tumours is regulated by environmental as well as genetic/epigenetic factors. This study assessed the environmental factors in intestinal expression of gastric cancers. METHODS AND RESULTS: We immunohistochemically examined intratumoural heterogeneity in the expression of Cdx2, MUC2, MUC5AC and MUC6 in 39 intramucosal and 49 extramucosally invasive undifferentiated-type gastric carcinomas (UGCs), consisting of signet ring cell carcinomas showing a layered structure (LS) in the mucosa and dedifferentiated tubular adenocarcinomas without LS and with minor tubular components (TC). The LS retains mucosal vertical polarity with superficial MUC5AC expression. Loss of this polarity was independent of intestinal expression and associated with extramucosal invasion. In LS(+) UGCs, intestinal expression was enhanced as the size of mucosal spread increased and was significantly reduced with deeper extramucosal invasion, whereas, in LS(-)/TC(+) UGCs, intestinal expression was frequent and predominant in the mucosa and was insignificantly reduced with deeper extramucosal invasion. CONCLUSIONS: In LS(+) UGCs, intestinal expression showed dynamic alteration probably by environmental induction and progression-related loss of induction, whereas it was relatively stable in LS(-)/TC(+) UGCs. Thus, intestinal expression in UGCs is not useful as a marker of tumour progression because it is also affected by environmental factors and genetic lineage.

A non-acromegalic case of multiple endocrine neoplasia type 1 accompanied by a growth hormone-releasing hormone-producing pancreatic tumor.

Cases of acromegaly due to GHRHproducing pancreatic endocrine tumors have been reported. Here we present a case of a 31-yr-old nonacromegalic man with hyperparathyroidism and elevated serum IGF-I with normal serum GH levels. Serum GH was not suppressed below 1 ng/ml by the glucose tolerance test and increased in response to TR H and GHRH administration. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia and an abdominal computed tomography (CT ) scan showed a tumor in the pancreatic tail. Plasma concentration of GHRH was elevated. Based on these clinical data, multiple endocrine neoplasia (MEN) type 1 was suspected. Three enlarged parathyroid glands were removed and a distal pancreatectomy was performed. Pathological examination of the parathyroid glands and pancreatic tumor showed nodular hyperplasia and a well-differentiated endocrine tumor, respectively, both compatible with MEN features. Immunohistochemistry revealed positive immunoreactivity for GHRH, SS , insulin, glucagon, chromogranin A, and pancreatic polypeptide in the pancreatic tumor. After pancreatic surgery, elevated levels of GHRH and IGF-I were normalized and pituitary hyperplasia definitely decreased in size. In cases of pituitary hyperplasia with elevated IGF-I, ectopic GHRH syndrome must be considered even if physical features of acromegaly are absent. It is also important to measure plasma GHRH concentrations in order to give a diagnosis.

Enhanced vagal modulation and exercise induced ischaemia of the inferoposterior myocardium.

OBJECTIVE: To determine whether the Bezold-Jarisch reflex or enhancement of vagal nerves, which are preferentially distributed in the inferoposterior myocardium, results from exercise induced ischaemia in this region. METHODS: On the basis of exercise myocardial scintigraphy and coronary angiography, 145 patients were classified as follows: group I, 34 patients with inferoposterior ischaemia; group A, 32 with anterior ischaemia; and control, 79 without ischaemia. The relation between ischaemic areas and ECG leads with ST segment changes and vagal modulation assessed by heart rate variability (HRV) (high frequency (HF) component (0.15-0.40 Hz) and coefficient of HF component variance (CCVHF), which is the square root of HF divided by mean RR interval) were assessed. RESULTS: The rate of ST segment depression in any lead did not differ between group I and group A. HF and CCV(HF) were similar before exercise but higher in group I than in group A and the control group after exercise (mean (SEM) HF: 94 (17) ms2, 41 (7) ms2, and 45 (6) ms2, respectively, p = 0.021; CCV(HF): 1.18 (0.09)%, 0.81 (0.07)%, and 0.89 (0.05)%, p = 0.0053). Furthermore, the percentage change in CCV(HF) before and after exercise was higher in group I than in group A or controls (mean (SEM) 22 (10)%, -24 (4)%, and -21 (3)%, p < 0.0001). The optimal cut off for diagnosis of inferoposterior ischaemia was -5% with a sensitivity of 74%, specificity 75%, and accuracy 75%. CONCLUSIONS: Vagal modulation as assessed by HRV analysis was enhanced in association with exercise induced inferoposterior ischaemia. Exercise ECG testing combined with HRV analysis would increase accuracy in the diagnosis of ischaemic areas in selected patients with angina pectoris.

New antibody immobilization method via functional liposome layer for specific protein assays.

A specific protein assay system based on functional liposome-modified gold electrodes has been demonstrated. To fabricate such assay system, a liposome layer was initially grown on top of a gold layer. The liposome layer contained two kinds of functional molecules: biotin molecules for the binding sites of streptavidin and N-(10,12-pentacosadiynoic)-acetylferrocene molecules for the facile redox probe in electrochemical detections. Then, streptavidin was attached on the functional liposme-modified layer using the interaction of streptavidin-sbiotin complex. On the streptavidin-attached surface, antibody molecules, anti-human serum albumin antibodies could be immobilized without any secondary antibodies. AFM imaging of the streptavidin-attached liposome surface revealed a uniform distribution of closely packed streptavidin molecules. In situ quartz-crystal microbalance and electrochemical measurements demonstrated that the wanted antibody-antigen reactions should occur with high specificity and selectivity. Our specific antibody assay system, based on a functional liposome modified electrode, can be developed further to yield sophisticated structures for numerous protein chips and immunoassay sensors.

Characterization of novel squamous cell carcinoma antigen-related molecules in mice.

The squamous cell carcinoma antigen 1 (SCCA1) and SCCA2 are unique serpins that can inhibit cysteine proteinases. SQN-5, their mouse ortholog, has already been identified, and its inhibitory property has been characterized; however, its biological role has remained undefined. Furthermore, no other mouse homolog of SQN-5 has been known. We characterize three mouse members of SCCA-related molecules including SQN-5 in this article. Serpinb3a (SQN-5) and Serpinb3b, but not Serpinb3c, were functional, inhibiting both serine and cysteine proteinases with different inhibitory profiles due to the difference of two amino acids in their reactive site loops. Serpinb3a was ubiquitously expressed in most tissues, whereas expression of Serpinb3b was limited to keratinocytes. Keratinocytes secreted both SCCA-related proteins, Serpinb3a and Serpinb3b. These results indicate that Serpinb3a and Serpinb3b may play different roles by inhibiting intrinsic or extrinsic proteinases with different expression distributions and different inhibitory profiles.

Usefulness of switching to cabergoline from other dopamine agonists in patients with advanced Parkinson's disease.

Problems associated with long-term treatment of advanced Parkinson's disease (PD) include motor complications and psychotic and autonomic symptoms. We switched patients from bromocriptine (BR) or pergolide (PER) to cabergoline (CB) therapy and investigated CB's usefulness in alleviating such problems. Subjects were 30 patients (mean age 68.2 years; 13 receiving BR, 17 PER) with PD complicated by effects of long-term treatment but in whom their dose of dopamine (DA) agonist was contraindicated due to adverse reactions. Patients were switched to CB over a 2-4-week period. Hoehn-Yahr and Unified Parkinson Disease Rating Scale (UPDRS) I-IV "on" and "off" scores improved in both the BR and PER groups. CB was not discontinued due to adverse reactions in any patient. In conclusion, switching to CB is useful in patients in whom it is problematic to increase their dose of DA agonist due to motor complications or psychotic symptoms of advanced PD.

Probing feature selectivity of neurons in primary visual cortex with natural stimuli.

One way to characterize neural feature selectivity is to model the response probability as a nonlinear function of the output of a set of linear filters applied to incoming signals. Traditionally these linear filters are measured by probing neurons with correlated Gaussian noise ensembles and calculating correlation functions between incoming signals and neural responses. It is also important to derive these filters in response to natural stimuli, which have been shown to have strongly non-Gaussian spatiotemporal correlations. An information-theoretic method has been proposed recently for reconstructing neural filters using natural stimuli in which one looks for filters whose convolution with the stimulus ensemble accounts for the maximal possible part of the overall information carried the sequence of neural responses. Here we give a first-time demonstration of this method on real neural data, and compare responses of neurons in cat primary visual cortex driven with natural stimuli, noise ensembles, and moving gratings. We show that the information-theoretic method achieves the same quality of filter reconstruction for natural stimuli as that of well-established white-noise methods. Major parameters of neural filters derived from noise ensembles and natural stimuli, as well as from moving gratings are consistent with one another. We find that application of the reverse correlation method to natural stimuli ensembles leads to significant distortions in filters for a majority of studied cells with non-zero reverse-correlation filter.

Cell kinetic study on histogenesis of Barrett's esophagus using rat reflux model.

BACKGROUND: To elucidate the histogenesis of Barrett's esophagus and esophageal adenocarcinoma, we designed a duodeno-gastric reflux model in which normal stomach function and normal nutritional status are retained. METHODS: Male Wistar rats were used in the experiment. The esophago-gastric junction was side-to-side anastomosed to a loop of jejunum about 3 cm distal to Treitz's ligament. The animals were not exposed to any known carcinogens during the experiment. Sequential morphological changes were studied for up to 50 weeks after surgery. Serial sections were made and stained with hematoxylin and eosin (H&E). In addition, immunohistochemical staining for bromodeoxyuridine (BrdU) was performed along with histochemical staining for mucins using paradoxical concanavalin A (ConA), galactose oxidase Schiff (GOS), and high-iron diamine-alcian blue (HID-AB). RESULTS: Severe esophagitis with squamous cell hyperplasia was noted in all animals after surgery. At week 20 after surgery, glandular metaplastic cells positive for ConA first appeared within the basal cell layer of esophageal squamous cell epithelium, and then GOS-positive cells and HID-AB goblet cells appeared. This is a characteristic of the specialized columnar epithelium of Barrett's esophagus. We detected esophageal adenocarcinomas in 1 out of 8 subjects at week 40 and in 3 out of 8 subjects at week 50 after surgery. CONCLUSIONS: Reflux of duodenal contents causes specialized columnar epithelium of Barrett's esophagus and esophageal adenocarcinoma. As part of the sequence of events leading to the development of Barrett's esophagus, pyloric-foveolar metaplasia was observed followed by the appearance of intestinal goblet cells. The pyloric-foveolar metaplasia appears to be associated with chronic mucosal damage and regeneration. This multiplastic cell lineage is referred to as 'gut-regenerative cell lineage' (GRCL).

Prostate cancer cell growth is modulated by adipocyte-cancer cell interaction.

OBJECTIVE: To assess whether adipocytes (mesenchymal stromal cells thought to affect the proliferation and differentiation of epithelial cells) affect the behaviour of prostate cancer cells in vitro, as prostate cancer metastasizes to the bone, which is an adipocyte-rich environment. MATERIALS AND METHODS: The human bone-metastatic prostate carcinoma cell line PC3 was cultured with or without adipocytes in a three-dimensional collagen gel matrix. Histological and immunohistochemical assays were used to evaluate the proliferation and differentiation of PC3 cells. The cytokine expression of this culture assembly was also examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The proliferation and differentiation of cancer cells were clearly changed on co-culture with adipocytes compared with the control cultures. The mean (range) bromodeoxyuridine (BrdU) indices estimated (according to uptake) to evaluate the growth of the cultured cells were 36.3 (8.55)% in the co-culture and 26.95 (10.50) in the control (P < 0.02). PC3 cells in co-culture formed larger clusters than in the control, at 16.0 (11.0) vs 14.0 (10.0), respectively (P < 0.01). Cancer cells also showed pleomorphism, varying from cuboidal to spindle-shaped. The expressions of vascular endothelial and platelet-derived growth factor were greater in co-culture than in the control. CONCLUSION: These findings suggest that adipocytes modulate the growth, morphology and cytokine expression of prostate cancer cells. This specific mesenchymal stromal cell type is important in the biological behaviour of prostate cancer cells.