Efficacy of granulocytapheresis and leukocytapheresis for the treatment of microscopic polyangiitis

We evaluated the efficacy of granulocytaperesis and leukocytapheresis for the treatment of rapidly progressive glomerulonephritis (RPGN) and lung hemorrhage caused by microscopic polyangiitis. Three patients with RPGN were treated by granulocytapheresis (GCAP) and five patients with RPGN were treated by leukocytapheresis (LCAP). The prednisolone dose was 0.4 +/- 0.2 g/kg/day (mean +/- SD; range 0.2-0.8 g/kg/day). Pre-treatment serum creatinine was 3.2 +/- 1.4 mg/dL (1.4-5.1 mg/dL). The patients were followed for a mean period of 15 +/- 6 months (6-23 months). Renal function improved in five of the eight RPGN patients. Three lung hemorrhage episodes in two different patients were treated with GCAP and one lung hemorrhage episode was treated with LCAP combined with various doses of corticosteroids. All four lung hemorrhage episodes were ameliorated. We concluded that combined therapy of GCAP or LCAP and corticosteroids is effective for the treatment of RPGN and lung hemorrhage due to microscopic polyangiitis.     

Acute Basophilic Leukemia Lacking Basophil-Specific Antigens: The Importance of Cytokine Receptor Expression in Differential Diagnosis

De novo acute basophilic leukemia (ABL) is a rare form of myeloid leukemia. The low prevalence of ABL makes it difficult to define its clinical characteristics and to establish an effective therapeutic protocol. We present here a case of de novo ABL in a 64-year-old Japanese man. The diagnosis of ABL depended on the following: (1) metachromasia with toluidine blue stain, (2) intracytoplasmic theta granules identified by electron microscopy, and (3) findings obtained from extensive immunophenotypic analysis. Although blast cells lacked basophil-specific antigens such as CDw17, CD88, and FcepsilonRI, an expression profile of cytokine receptors including CD116 (GM-CSF receptor), CD117 (c-kit), and CD123 (IL-3 receptor alpha) helped to define the cellular lineage in our case. The patient achieved complete remission with intensive chemotherapy composed of idarubicin and cytosine arabinoside and was disease free during the following 30 months. We propose that immunophenotyping, especially focusing on cytokine receptors, is useful in diagnosing ABL.     

Elevated concentrations of alpha-defensins in gastric juice of patients with Helicobacter pylori infection

OBJECTIVE: Defensins (alpha- and beta-defensins) are endogenous antimicrobial peptides. Little is known about alpha-defensins during Helicobacter pylori infection. METHODS: The concentrations of human neutrophil peptides (HNP-1, -2, and -3), the major components of neutrophils-derived alpha-defensins, were measured by radioimmunoassay (RIA) in plasma and gastric juice of 61 H. pylori-infected and 33 uninfected subjects, and before and after anti-H. pylori treatment in 12 patients with H. pylori-associated gastritis. Interleukin (IL)-8 concentrations in gastric juice were measured by enzyme-linked immunosorbent assay. Histological grades of gastritis and neutrophil counts (/mm(2)) infiltrating in the gastric mucosa were determined using two biopsy specimens taken from the antrum and corpus. Immunohistochemistry and reverse-phase high performance liquid chromatography (RP-HPLC) were used to identify HNPs 1-3. RESULTS: HNP 1-3 concentrations in gastric juice were significantly higher in H. pylori-positive than in H. pylori-negative patients and significantly decreased after cure. HNP 1-3 concentrations in gastric juice correlated with IL-8 levels and neutrophil densities in the gastric mucosa and were associated with histological degree of gastritis, especially the grades of activity. Intense immunoreactivity for anti-HNPs 1-3 antiserum was noted in infiltrating neutrophils in H. pylori-infected mucosa. In RP-HPLC analysis, all of the HNP 1-3 molecules were identified as their mature forms. Plasma HNP 1-3 concentrations were similar in H. pylori-infected and non-infected groups and showed no correlations with other parameters. CONCLUSIONS: We demonstrated significantly elevated levels of HNPs 1-3 in gastric juice during H. pylori infection. The elevation of HNPs is presumably secondary to H.pylori-associated gastric inflammation involving neutrophil infiltration.     

Pharmacokinetic analysis based on dynamic contrast-enhanced MRI for evaluating tumor response to preoperative therapy for oral cancer

Purpose:

To evaluate whether a pharmacokinetic analysis is useful for monitoring the response of oral cancer to chemoradiotherapy (CRT).

Materials and Methods:

Twenty‐nine patients were included. They underwent dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) before and after CRT. The DCE‐MRI data were analyzed using a Tofts and Kermode (TK) model. The histological evaluation of the effects of CRT was performed according to Ohboshi and Shimosato's classification.

Results:

None of the pre‐CRT parameters were significantly different between the responders and nonresponders. The post‐CRT volume of the extravascular extracellular space (EES) per unit volume of tissue (v_e) of responders (0.397 ± 0.080) was higher than that of nonresponders (0.281 ± 0.076) (P = 0.01). The change of the v_e between the pre‐ and post‐CRT of the responders (0.154 ± 0.093) was larger than that of the nonresponders (0.033 ± 0.073) (P = 0.001). Therefore, the increase in the v_e strongly suggested a good tumor response to CRT, which reflected an increase of the EES secondary to the destruction of the cancer nest. The changes in the volume transfer constant (K^trans) were significantly different between the responders and nonresponders (P = 0.018).

Conclusion:

Both the increase of the v_e and the elevation of permeability (K^trans) were indicative of a good tumor response to CRT. The pharmacokinetic analysis had potential for monitoring the histopathological response to CRT. J. Magn. Reson. Imaging 2012;36:589–597. © 2012 Wiley Periodicals, Inc.     

Safety and efficacy of oral rehydration therapy until 2?h before surgery: a multicenter randomized controlled trial

Purpose

In many countries, patients are generally allowed to have clear fluids until 2?C3?h before surgery. In Japan, long preoperative fasting is still common practice. To shorten the preoperative fasting period in Japan, we tested the safety and efficacy of oral rehydration therapy until 2?h before surgery.

Methods

Three hundred low-risk patients scheduled for morning surgery in six university-affiliated hospitals were randomly assigned to an oral rehydration solution (ORS) group or to a fasting group. Patients in the ORS group consumed up to 1,000?ml of ORS containing balanced glucose and electrolytes: 500?ml between 2100 the night before surgery and the time they woke up the next morning and 500?ml during the morning of surgery until 2?h before surgery. Patients in the fasting group started fasting at 2100 the night before surgery. Primary endpoints were gastric fluid volume and pH immediately after anesthesia induction. Several physiological measures of hydration and electrolytes including the fractional excretion of sodium (FENa) and the fractional excretion of urea nitrogen (FEUN) were also evaluated.

Results

Mean (SD) gastric fluid volume immediately after anesthesia induction was 15.1 (14.0) ml in the ORS group and 17.5 (23.2) ml in the fasting group (P?=?0.30). The mean difference between the ORS group and fasting group was ?2.5?ml. The 95% confidence interval ranged from ?7.1 to +2.2?ml and did not include the noninferior limit of +8?ml. Mean (SD) gastric fluid pH was 2.1 (1.9) in the ORS group and 2.2 (2.0) in the fasting group (P?=?0.59). In the ORS group, mean FENa and FEUN immediately after anesthesia induction were both significantly greater than those in the fasting group (P?P?Conclusions Oral rehydration therapy until 2?h before surgery is safe and feasible in the low-risk Japanese surgical population. Physicians are encouraged to use this practice to maintain the amount of water in the body and electrolytes and to improve the patient??s comfort.     

Ovarian morphology and prevalence of polycystic ovary syndrome in Japanese women with type 1 diabetes mellitus

Aims/Introduction

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder including polycystic ovary morphology (PCOM), ovulatory dysfunction and hyperandrogenism. PCOS is frequently associated with type 2 diabetes mellitus; however, it is unknown whether PCOM and PCOS are prevalent in Japanese patients with type 1 diabetes mellitus. The purpose of our study was to determine the frequency of PCOM and PCOS in women with type 1 diabetes mellitus.

Materials and Methods

We evaluated clinical, hormonal and ovarian ultrasound data from 21 type 1 diabetes mellitus patients whose average glycated hemoglobin levels were 7.9 ± 1.5%.

Results

Ultrasound identified PCOM in 11 patients (52.4%) and these patients also had higher levels of the androgen dehydroepiandrosterone sulfate (DHEA‐S) than those without PCOM (P < 0.05). Of the patients with PCOM, five presented menstrual irregularities (45.5%) and three met the Japanese criteria for PCOS (27.2%); whereas all patients without PCOM had a normal menstrual cycle (P < 0.05).

Conclusions

Japanese premenopausal women with type 1 diabetes mellitus had a high frequency of PCOM as well as PCOS. This is the first research of this area carried out in an Asian population.     

β‐catenin regulates parathyroid hormone/parathyroid hormone–related protein receptor signals and chondrocyte hypertrophy through binding to the intracellular C‐terminal region of the receptor

Objective

To investigate the underlying mechanisms of action and functional relevance of β‐catenin in chondrocytes, by examining the role of β‐catenin as a novel protein that interacts with the intracellular C‐terminal portion of the parathyroid hormone (PTH)/PTH‐related protein (PTHrP) receptor type 1 (PTHR‐1).

Methods

The β‐catenin–PTHR‐1 binding region was determined with deletion and mutagenesis analyses of the PTHR1 C‐terminus, using a mammalian two‐hybrid assay. Physical interactions between these 2 molecules were examined with an in situ proximity ligation assay and immunostaining. To assess the effects of gain‐ and loss‐of‐function of β‐catenin, transfection experiments were performed to induce overexpression of the constitutively active form of β‐catenin (ca‐β‐catenin) and to block β‐catenin activity with small interfering RNA, in cells cotransfected with either wild‐type PTHR1 or mutant forms (lacking binding to β‐catenin). Activation of the G protein α subunits G_αs and G_αq in the cells was determined by measurement of the intracellular cAMP accumulation and intracellular Ca²⁺ concentration, while activation of canonical Wnt pathways was assessed using a TOPflash reporter assay.

Results

In differentiated chondrocytes, β‐catenin physically interacted and colocalized with the cell membrane–specific region of PTHR‐1 (584–589). Binding of β‐catenin to PTHR‐1 caused suppression of the G_αs/cAMP pathway and enhancement of the G_αq/Ca²⁺ pathway, without affecting the canonical Wnt pathway. Inhibition of Col10a1 messenger RNA (mRNA) expression by PTH was restored by overexpression of ca‐β‐catenin, even after blockade of the canonical Wnt pathway, and Col10a1 mRNA expression was further decreased by knockout of β‐catenin (via the Cre recombinase) in chondrocytes from β‐catenin–floxed mice. Mutagenesis analyses to block the binding of β‐catenin to PTHR1 caused an inhibition of chondrocyte hypertrophy markers.

Conclusion

β‐catenin binds to the PTHR‐1 C‐tail and switches the downstream signaling pathway from G_αs/cAMP to G_αq/Ca²⁺, which is a possible mechanism by which chondrocyte hypertrophy may be regulated through the PTH/PTHrP signal independent of the canonical Wnt pathway.