Shinichi Hosokawa

Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine

The liver and exocrine pancreas share a common structure, with functioning units (hepatic plates and pancreatic acini) connected to the ductal tree. Here we show that Sox9 is expressed throughout the biliary and pancreatic ductal epithelia, which are connected to the intestinal stem-cell zone. Cre-based lineage tracing showed that adult intestinal cells, hepatocytes and pancreatic acinar cells are supplied physiologically from Sox9-expressing progenitors. Combination of lineage analysis and hepatic injury experiments showed involvement of Sox9-positive precursors in liver regeneration. Embryonic pancreatic Sox9-expressing cells differentiate into all types of mature cells, but their capacity for endocrine differentiation diminishes shortly after birth, when endocrine cells detach from the epithelial lining of the ducts and form the islets of Langerhans. We observed a developmental switch in the hepatic progenitor cell type from Sox9-negative to Sox9-positive progenitors as the biliary tree develops. These results suggest interdependence between the structure and homeostasis of endodermal organs, with Sox9 expression being linked to progenitor status.

Validity of 99mTc Dimercaptosuccinic Acid Renal Uptake for an Assessment of Individual Kidney Function

99mTc dimercaptosuccinic acid is a new renal scanning agent that provides a good quality of renal image as a result of preferential cortical accumulation and also makes feasible a quantitative assessment of separate kidney function, correlating well with renal plasma flow obtained from a 131I hippuran renogram of each kidney. By measuring the dimercaptosuccinic acid uptake, the cortical functioning nephrons can be determined independent of the activity from the urinary outflow tract. Such evaluations may replace the conventional split renal function study in which traumatic procedures, such as cystoscopy and ureteral catheterizations, are required. 99mTc dimercaptosuccinic acid scintigraphy causes less discomfort to the patient and can be performed repeatedly and routinely even in children and debilitated geriatric patients.

Trace Elements and Complications in Patients Undergoing Chronic Hemodialysis

Abnormalities of trace elements such as aluminum, silicon, zinc, manganese and nickel were found in chronic hemodialysis (HD) patients. The relationship between serum concentration of trace elements and complications such as anemia bone disease, neurological disorder and nutritional disorder in 100 chronic HD patients was examined. Serum Al and Si levels were very high in these patients, and were negatively correlated with indicators of anemia such as RBC, hemoglobin and hematocrit values. Serum Al and Si levels in the HD patients with peripheral neurological disorder (excluding encephalopathy) and with bone disease were significantly high. The levels of serum Zn, Mn and Ni were low, and were correlated with total serum protein levels. In summary, in order to prevent some complications in chronic HD patients, it is very important to regulate levels of trace elements.

Renal function studies using 99mTc-dimercaptosuccinic acid.

99mTc-dimercaptosuccinic acid (DMSA), provides both a well defined renal image via preferential cortical accumulation, and a quantitative assessment of separate kidney function, correlating well with renal plasma flow obtained from the 131I-Hippuran renogram of each kidney. 99mTc-DMSA is capable of labeling the functioning nephrons in the cortex without interference by the activity of urine flow, suggesting that DMSA should be termed a cortical tubular marker. 99mTc-DMSA scintigraphy has advantages over conventional methods in that it can be performed repeatedly with little discomfort to the patients, as a routine clinical examination.

Serum and corpuscular nickel and zinc in chronic hemodialysis patients

Serum and corpuscular nickel and zinc concentrations in 30 chronic hemodialysis patients were examined. Serum nickel and zinc levels before dialysis were 0.22 +/- 0.03 microgram/dl (normal value: 0.56 +/- 0.08 microgram/dl) and 70.0 +/- 13.4 micrograms/dl (normal value: 96 +/- 8 micrograms/dl) low, respectively. However, corpuscular nickel and zinc levels before dialysis were high: 1.25 +/- 0.24 microgram/dl (normal value: 0.88 +/- 0.17 microgram/dl) and 1,299 +/- 146 micrograms/dl (normal value: 1,120 +/- 80 micrograms/dl). Serum zinc levels significantly increased after dialysis, but serum nickel concentrations did not significantly increase during dialysis. Corpuscular nickel and zinc concentrations did not significantly change during dialysis.

Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice

In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions.

Effects of Erythropoietin on Trace Elements in Patients with Chronic Renal Failure Undergoing Hemodialysis

We examined the relationship between recombinant human erythropoietin (rHuEPO) therapy and serum levels of the trace elements aluminum, silicon, zinc, nickel, and manganese in 55 patients undergoing chronic hemodialysis (HD) in whom rHuEPO (for 12 weeks) was effective in reducing anemia, and in 55 patients undergoing HD without rHuEPO treatment. In the rHuEPO group, serum Al level was significantly decreased and Si level showed a tendency to decrease. Zn, Ni, and Mn levels, however, were significantly increased.

Clinical studies on molybdenum in patients requiring long-term hemodialysis

Molybdenum is an essential trace element in humans. However, the serum molybdenum level or its role in patients with chronic renal failure or those requiring long-term hemodialysis remains unknown. The authors examined the serum molybdenum levels and studied the role of hemodialysis in 60 patients requiring long-term hemodialysis. The serum molybdenum levels of the 60 patients with chronic renal failure were examined before and after hemodialysis. The authors also studied the relationships between serum molybdenum levels and beta 2-microglobulin (beta 2-MG) levels, c-parathyroid hormone (C-PTH) levels, and dialysis related arthritis in the 60 patients. Molybdenum was measured with a flameless atomic absorption spectrophotometer equipped with an autobackground corrector. The level of molybdenum in serum significantly (P < 0.01) decreased from 2.7 +/- 1.9 micrograms/dl (normal value, 0.02-0.13 micrograms/dl) before hemodialysis to 1.4 +/- 0.7 micrograms/dl after hemodialysis. The correlation between serum molybdenum value and serum beta 2-MG level was significant (P < 0.01). The authors also found significant correlations between serum molybdenum level and C-PTH value, serum calcium ion (C++) level in serum, and duration of hemodialysis. Serum molybdenum levels were high (12.8 +/- 0.96 micrograms/dl) in nine patients with dialysis related arthritis. In conclusion, serum molybdenum levels are high in patients undergoing long-term hemodialysis, and abnormal molybdenum accumulation may contribute to dialysis related arthritis.

Successful immunoadsorption with membrane plasmapheresis for multiple sclerosis

Sixteen patients (mean age, 36.4 years) with multiple sclerosis were treated with immunoadsorption membrane plasmapheresis (IAP). Using an immunoadsorption column containing polyvinyl alcohol gel, IAP was performed two times a week for 2 weeks, followed by once a week for 2 months, and then every 2 weeks. The volume of perfused plasma was 3 liters for each IAP. Activity of natural killer (NK) cells and helper T cells was significantly (p less than 0.01) increased after IAP therapy. In addition, muscle power improved in all patients. Walking ability improved in four patients, standing ability in six, and sitting ability improved in seven. Most patients showed improvements in ability to lie still, sensory disturbance, visual disturbance, and urinary complications. No adverse effects were associated with IAP treatment. These findings indicate that IAP therapy is effective for multiple sclerosis.

Serum Copper Concentration Changes in Chronic Hemodialyzed Patients

We studied the behavior of copper during hemodialysis and the relationship between serum copper levels and hematologic parameters such as red blood cell count (RBC), hematocrit (Hct), hemoglobin (Hb), and serum iron in 48 hemodialyzed patients. To study diffusion, we measured copper in the arterial blood and in the dialysate at the inflow and outflow sites of the dialyzer. To study hemoconcentration, the change in hematocrit values and total serum protein values were examined. To study liberation of copper from the dialyzer membrane, copper concentrations in normal saline were measured before and after the saline was used to wash dialyzers of various kinds. We found that changes in serum copper concentration were due mainly to hemoconcentration and liberation, but partly also to diffusion, and that the net result of changes was a significant increase in serum copper. We observed no correlation between serum copper levels and RBC, Hct, Hb, and serum iron levels.