Aberrantly Glycosylated IgA1 as a Factor in the Pathogenesis of IgA Nephropathy

Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN

Insulin Resistance, Obesity, Hypertension, and Renal Sodium Transport

Sodium transport through various nephron segments is quite important in regulating sodium reabsorption and blood pressure. Among several regulators of this process, insulin acts on almost all the nephron segments and is a strong enhancer of sodium reabsorption. Sodium-proton exchanger type 3 (NHE3) is a main regulator of sodium reabsorption in the luminal side of proximal tubule. In the basolateral side of the proximal tubule, sodium-bicarbonate cotransporter (NBCe1) mediates sodium and bicarbonate exit from tubular cells. In the distal nephron and the connecting tubule, epithelial sodium channel (ENaC) is of great importance to sodium reabsorption. NHE3, NBCe1, and ENaC are all regulated by insulin. Recently with-no-lysine (WNK) kinases, responsible for familial hypertension, stimulating sodium reabsorption in the distal nephron, have been found to be also regulated by insulin. We will discuss the regulation of renal sodium transport by insulin and its roles in the pathogenesis of hypertension in insulin resistance

Epidemiology of potentially inappropriate medication use in elderly patients in Japanese acute care hospitals.

[Purpose]The elderly receive many medications which may have adverse effects. Little evidence is available about the epidemiology of potentially inappropriate medications being prescribed to the elderly in Japan as defined by the Beers criteria, or whether or not these medications result in harm when used in this population. [Methods]We conducted a prospective cohort study of patients aged ≥65 years who were admitted to three acute care hospitals in Japan. Trained research nurses followed up patients from randomly selected wards and collected data about their medications and all potential adverse drug events (ADEs). Two independent reviewers evaluated all the data. The use of potentially inappropriate medications and their effects on patients were identified using the updated Beers criteria. [Results]A total of 2155 elderly patients were eligible; 56.1% received at least one drug listed in the Beers criteria (BL drug). The rates of BL drug prescriptions were 103.8 per 100 admissions and 53.7 per 1000 patient-days, and the incidence rate of ADEs related to BL drugs was 1.7 per 100 BL drug prescriptions. Among patients aged ≥65 years, relatively younger patients (p = 0.0002) and those with less complications (p = 0.04) were likely to be prescribed BL drugs. [Conclusions]Although BL drugs were frequently prescribed to elderly Japanese inpatients, the incidence of related ADEs appeared infrequent. These data suggest that re-evaluation of the appropriateness of the Beers criteria is needed before they are used in Japan and other nations to assess quality or for decision support

A Case of Corticotroph Carcinoma that Caused Multiple Cranial Nerve Palsies, Destructive Petrosal Bone Invasion, and Liver Metastasis

A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 μg/dl) levels. The patient underwent transsphenoidal surgery followed by γ-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed

乳腺神経内分泌癌の一例

稀な癌である乳腺神経内分泌癌(neuroendocrine carcinoma:以下NEC)を経験したので報告する.患者は35歳の女性で,右乳頭直下に腫瘤を自覚し当科を受診した.画像診断で乳癌を疑い,細胞診では乳頭腺管癌あるいは硬癌が推定された.針生検で浸潤性乳管癌と診断し,乳房温存術とセンチネルリンパ節生検を施行した.腫瘍は乳腺原発であり,組織像は,小細胞癌などの神経内分泌癌に類似していた.免疫組織化学的検査では,chromogranin A, synaptophysin, neuronspecific enolase陽性細胞が大部分を占めていたためWHO分類に従い神経内分泌癌の診断に至った.リンパ節転移は認めなかった.乳腺NECは稀な癌であり,臨床病理学的な特徴,予後,治療法についての定まった見解はない.本症例では,通常の乳癌同様に臨床病理学的予後因子に基づき術後補助化学療法を行った.術後8年5カ月の時点で無再発生存中である.We are reporting a rare case of breast neuroendocrine carcinoma (NEC). A 35-year- old woman noticed a breast lump underneath her right nipple, and she consulted our hospital. The mass was suspected of being breast cancer by mammography, ultrasonography and MRI. Cytological diagnosis was papillotubular or scirrhous carcinoma. Finally, it was diagnosed as invasive ductal carcinoma by a core needle biopsy. We performed breastconserving surgery and sentinel lymph node biopsy. There was no metastasis in the sentinel lymph node. Pathological findings suggested that it was a small cell carcinoma or a neuroendocrine carcinoma. Chromogranin A, synaptophysin, neuron-specific enolase were positively stained in most of the cancer cells by immunohistochemistry. Therefore, it was diagnosed as breast NEC according to the WHO classification. Because breast NEC is a relatively rare cancer, its clinicopathological significance, prognosis and appropriate treatment has not been evaluated. We chose the adjuvant systemic therapy based on recommendations from the St.Gallen Consensus Conference in this case. 101 months after the operation, she has no recurrence and is alive

Mechanical properties of a new thermally deformable mitral valve annuloplasty ring and its effects on the mitral valve

Ideally, an annuloplasty ring's shape should be changed intraoperatively if mitral valve repair is unsuccessful because of a short coaptation length or systolic anterior motion. Several post-implantation adjustable rings have been developed, but they are not freely deformable and are unsuitable for asymmetric repair of the valvular annulus. We developed a novel thermally deformable mitral annuloplasty ring to address these problems and assessed the ring's mechanical properties and its effect on the mitral valve anatomy. This ring was made of polycaprolactone. Tensile and bending tests were performed to evaluate the ring's mechanical properties. The ratio of the transverse and septal-lateral length was determined as 4:3. Using 10 pig hearts, we measured the post-deformation coaptation length and minimum distance from the coaptation to the ventricular septum, which is a factor of abnormal systolic anterior motion of the mitral valve. In the mechanical tests, the ring's yield point was greater than the deformation force of the annulus in humans. In pigs with deformation from 4:3 to 4:2, the coaptation length was significantly increased in each mitral valve part. In pigs with deformation from 4:3 to 4:4, the minimum distance from the coaptation to the ventricular septum was significantly increased. Asymmetrical ring deformation increased the coaptation length only at the deformed area. In conclusion, this new thermally deformable mitral annuloplasty ring could be order-made to effectively change the coaptation length in all parts of the mitral valve and the distance from the coaptation to septum post-deformation via intraoperative heating

Glucocorticoid Receptor Antagonist Administration Prevents Adrenal Gland Atrophy in an ACTH-Independent Cushing’s Syndrome Rat Model

ACTH-independent Cushing’s syndrome (CS) is mainly caused by cortisol-secreting adrenocortical tumours. It is well known that secondary adrenal insufficiency occurs after surgical resection of these tumours. In this regard, impaired adrenocortical function is likely induced by atrophy of the residual adrenal tissue as a result of chronic suppression by the low ACTH levels of the hypercortisolism state. Therefore, we considered the prevention of adrenal atrophy as a method for preventing postoperative adrenal insufficiency. On the basis of these findings, we hypothesized that the use of a glucocorticoid receptor (GR) antagonist before surgery in ACTH-independent CS would rapidly activate the hypothalamic-pituitary-adrenal (HPA) axis and residual adrenal function. We thus examined adrenal function in a dexamethasone- (DEX-) induced CS rat model with or without mifepristone (MIF). In this study, MIF-treated rats had elevated plasma ACTH levels and increased adrenal weights. In addition, we confirmed that there were fewer atrophic changes, as measured by the pathological findings and mRNA expression levels of corticosterone synthase CYP11B1 in the adrenal glands, in MIF-treated rats. These results indicate that MIF treatment prevents the suppression of the HPA axis and the atrophy of the residual adrenal tissue. Therefore, our study suggests that preoperative GR antagonist administration may improve residual adrenal function and prevent postoperative adrenal insufficiency in ACTH-independent CS