Vitamin D supplementation is effective for olanzapine-induced dyslipidemia.

Olanzapine is an atypical antipsychotic drug that is clinically applied in patients with schizophrenia. It increases the risk of dyslipidemia, a disturbance of lipid metabolic homeostasis, usually characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides, and accompanied by decreased high-density lipoprotein (HDL) in the serum. In this study, analyzing the FDA Adverse Event Reporting System, JMDC insurance claims, and electronic medical records from Nihon University School of Medicine revealed that a co-treated drug, vitamin D, can reduce the incidence of olanzapine-induced dyslipidemia. In the following experimental validations of this hypothesis, short-term oral olanzapine administration in mice caused a simultaneous increase and decrease in the levels of LDL and HDL cholesterol, respectively, while the triglyceride level remained unaffected. Cholecalciferol supplementation attenuated these deteriorations in blood lipid profiles. RNA-seq analysis was conducted on three cell types that are closely related to maintaining cholesterol metabolic balance (hepatocytes, adipocytes, and C2C12) to verify the direct effects of olanzapine and the functional metabolites of cholecalciferol (calcifediol and calcitriol). Consequently, the expression of cholesterol-biosynthesis-related genes was reduced in calcifediol- and calcitriol-treated C2C12 cells, which was likely to be mediated by activating the vitamin D receptor that subsequently inhibited the cholesterol biosynthesis process via insulin-induced gene 2 regulation. This clinical big-data-based drug repurposing approach is effective in finding a novel treatment with high clinical predictability and a well-defined molecular mechanism.

Lisinopril prevents bullous pemphigoid induced by dipeptidyl peptidase 4 inhibitors via the Mas receptor pathway.

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.

Vascular Response Occurring at 3 Months After Everolimus-Eluting Cobalt-Chromium Stent Implantation in Patients With ST-Segment Elevation Myocardial Infarction vs. Stable Coronary Artery Disease.

BACKGROUND: Second-generation drug-eluting stents (DES) reduce the incidence of stent thrombosis, even in patients with ST-segment elevated myocardial infarction (STEMI). However, the early local vascular healing after DES implantation in STEMI lesions, which mainly concerns stent thrombosis, is still unclear.Methods and Results:We attempted to determine early local vascular healing 3 months after cobalt-chromium everolimus-eluting stent (CoCr-EES) implantation in STEMI lesions relative to stable coronary artery disease (CAD) lesions. This prospective, multicenter study analyzed 96 total lesions (STEMI=49, stable CAD=51) by frequency domain-optical coherence tomography (FD-OCT) performed post-procedure and at the 3-month follow-up. Although CoCr-EES implanted in STEMI were almost entirely covered at 3 months, they had a relatively high incidence of uncovered struts compared with stable CAD (5.5% vs. 1.6%, P<0.001). Intrastent thrombus in the 2 groups was primarily resolved at the 3-month follow-up (STEMI: 91.7%→26.5%, stable CAD: 74.5%→11.8%). Regarding irregular protrusion, complete resolution was observed in stable CAD (21.6%→0%), while a few stents remained in STEMI (79.2%→8.2%). Although there were almost no changes for the serial change of average lumen area in STEMI, there were slight but significant decreases in stable CAD [STEMI 0.08 (-0.44, 0.55) mm2, stable CAD -0.35 (-0.55, 0.11) mm2; P=0.009]. CONCLUSIONS: Although strut coverage after CoCr-EES implantation for STEMI lesions was slightly delayed, the healing process appeared to be acceptable in both STEMI and stable CAD.

Early vascular responses to everolimus-eluting cobalt-chromium stent in the culprit lesions of st-elevation myocardial infarction: results from a multicenter prospective optical coherence tomography study (MECHANISM-AMI 2-week follow-up study).

The use of cobalt-chromium everolimus-eluting stents (CoCr-EES) for ST-segment elevation myocardial infarction (STEMI) reduces the incidence of stent thrombosis compared with bare metal stents, and a substantial difference is apparent in the initial 2 weeks. However, vascular behavior during this early period remains unclear. This was a prospective study (MECHANISM-AMI-2W) to investigate early vascular responses in STEMI patients immediately after CoCr-EES implantation and at 2-week follow-up using frequency domain-optical coherence tomography (FD-OCT). The study enrolled 52 patients (age 63.7 ± 11.7 years, male 85.0%), of whom 44 patients were available for complete serial FD-OCT analyses. Both % uncovered struts and % malapposed struts were improved at 2-week follow-up (63 ± 20 vs. 21 ± 14%, p < 0.0001 and 7.3 ± 9.0 vs. 4.7 ± 5.9%, p = 0.005, respectively). Thrombus was decreased, with significant changes in longitudinal length to stent (28.8 ± 27.7 vs. 18.1 ± 20.2%, p = 0.0001) and maximal area (0.93 ± 0.84 vs. 0.65 ± 0.63 mm2, p = 0.034). As a result, the average lumen area was significantly larger at 2 weeks (6.49 ± 1.82 vs. 6.71 ± 1.89 mm2, p = 0.048, respectively). The number of dissection flaps was lower (0.86 ± 1.11 vs. 0.52 ± 0.90%, p = 0.024). In conclusion, this study showed early vascular responses to CoCr-EES for STEMI lesions-including a significant reduction of thrombus-that resulted in lumen enlargement, earlier progression of strut coverage, and improvements in strut apposition and dissection. The combination of these factors may therefore be responsible for the safety of CoCr-EES within the initial 2 weeks.

Rapid Staphylococcus aureus Detection From Clinical Mastitis Milk by Colloidal Gold Nanoparticle-Based Immunochromatographic Strips.

Rapid diagnostic technologies for bovine mastitis caused by Staphylococcus aureus (S. aureus) are urgently needed. In the current study, we generated an anti-ribosomal protein-L7/L12 antibody to detect S. aureus and an anti-ribosomal protein-L7/L12 antibody-coated immune-chromatographic strip (ICS) test. Moreover, we determined the ability of the ICS test to detect S. aureus from milk samples collected from cows with clinical mastitis. The developed ICS reacted to S. aureus in a bacteria load-dependent manner with a detection limit of ~104 CFU/mL. In the evaluation of possible cross-reactivity of the ICS test, six strains of coagulase-negative Staphylococci showed slightly positive reactions, although at a lower level; however, other bacteria were completely negative. Next, we investigated the sensitivity and specificity of the ICS test compared with the bacteriological culture method using milk samples from clinical bovine mastitis. The results of the experiments demonstrated that the ICS test had high sensitivity [100%, 95% confidence interval (CI): 91.3-100%] and specificity (91.9%, CI: 90.5-91.9%) compared with culture tests. In addition, the kappa statistic demonstrated that ICS tests showed substantial agreement (k = 0.77, CI: 0.66-0.87) with culture tests. Positive correlations were observed for the statistical analysis between S. aureus (nuc gene) copy numbers and ICS test scores in mastitic milk infected by S. aureus. Therefore, we assume that this new detection method using ICS may be useful as a highly sensitive S. aureus-screening method for the diagnosis of bovine mastitis. Our findings support the ongoing effort to develop an ICS method for bovine S. aureus-induced mastitis, which can contribute to the rapid diagnosis of this disease.

The bacterial load in milk is associated with clinical severity in cases of bovine coliform mastitis.

We evaluated the relationship between the severity of coliform mastitis and bacterial load in 106 quarter milk samples. We found no significant relationship between somatic cell count and coliform bacterial load in milk in bovine clinical coliform mastitis. Results of the Cochran-Armitage test for trend in milk bacterial load proportions indicated a significant decreasing low group (P<0.001), increasing medium group (P<0.002) and increasing high group (P<0.02) with increasing clinical grade. The present study indicates that the coliform bacterial load in milk is significantly associated with clinical severity states in cases of bovine coliform mastitis, and can be a useful indicator for optimal management of this disease.

Complete healing of spontaneous coronary artery dissection extending from the left main trunk to the left anterior descending and the left circumflex artery.

Spontaneous coronary artery dissection (SCAD) is defined as a spontaneous separation of the coronary artery wall that is not iatrogenic or related to trauma and usually affects young women. We describe a 65-year-old woman who presented with SCAD extending from the left main trunk involving the left anterior descending artery and the left circumflex artery, and coronary artery bypass graft surgery was performed to treat the dissection. Coronary angiography performed 3 months later, showed complete angiographic healing. A conservative management strategy is known to be associated with spontaneous angiographic healing in patients with SCAD who are hemodynamically stable. Healthcare providers should consider SCAD among the differential diagnoses in patients presenting with acute coronary syndrome, particularly in women. Further studies are needed to establish an optimal management strategy for SCAD. .

Particle-Induced X-ray Emission Analysis of Zierum Trace and Major Elements in Cattle with Acute Coliform Mastitis.

The aim of the present study was to examine the applicability of the direct determination of trace and major element concentrations in serum samples collected from Holstein dairy cattle with acute coliform mastitis (n = 53) compared with a healthy control group (n = 39). Twenty-eight elements (Na, Mg, Al, Si, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Ce, Ni, Cu, Zn, Ga, As, Se, Br, Rb, Sr, Y, Zr, Nb, Mo, and Pb) were detected by particle-induced X-ray emission (PIXE). Significant differences were observed in serum K, Fe, Zn, and Br concentrations, but not in those of the remaining twenty-four elements. Furthermore, serum Fe concentrations (0.751 ± 0.583 µg/ml, n = 18) were significantly lower in dairy cattle with a poor prognosis than in those with a good prognosis (0.945 ± 0.393 µg/ml, n = 35, P < 0.05) and healthy controls (1.458 ± 0.391 µg/ml, n = 39, P < 0.01). We proposed a diagnostic cut-off point for serum Fe concentrations of <0.82 µg/ml based on receiver operating characteristic (ROC) curves in order to identify cattle with a poor prognosis. The results of the present study indicated that assessing the elemental composition of serum, particularly iron, is a promising prognostic tool for determining the outcomes of cattle with severe acute coliform mastitis.

A novel exon 17 deletion mutation of RPGRIP1 gene in two siblings with Leber congenital amaurosis.

PURPOSE: To investigate mutations of causal genes in two affected male siblings of a Japanese family with suspected Leber congenital amaurosis (LCA) and to characterize the related clinical features. METHODS: After obtaining informed consent, genomic DNA was extracted from peripheral blood of the proband and his family members. Mutation screening was initially performed with microarrays. The PCR and direct sequencing were successively done for confirmation of mutation detected by microarray, and the two patients who are the subjects of this study were also clinically examined. RESULTS: Results of the microarray suggested deletion of exon 17 of RPGRIP1. Confirmation by PCR and direct sequencing following microarray analysis revealed that both siblings had homozygous deletion of exon 17 of the RPGRIP1 gene, while their unaffected parents were heterozygous carriers. Length of the deletion was 1339 bp including exon 17 at the position of c.2710+372_2895+76del1339. Clinical features of the two siblings showed nystagmus, poor visual acuity, hyperopia, and photophobia since early childhood; but there was no oculo-digital sign, vessel attenuation or RPE mottling from the mid-retina to the periphery. Full-field single flash ERG was recordable but 30 Hz flicker ERG was not detectable. CONCLUSIONS: Although the present patients did not show sufficient clinical findings as LCA, PCR findings and direct sequencing following microarray analysis confirmed that they were LCA. Genetic analyses are helpful for confirmation of clinical diagnosis.

A case of slowly progressive scleroderma kidney.

A rapidly progressive renal deterioration accompanied by acute-onset/uncontrolled hypertension characterizes scleroderma renal crisis (SRC), a life-threatening complication that occurs in patients with systemic sclerosis (SSc). To date, however, SSc with advanced renal failure has only rarely been reported in the absence of SRC. We report here an atypical case of diffuse cutaneous SSc where renal insufficiency progressed slowly to end-stage renal failure over a 14-year follow-up period after the diagnosis of SSc. In the renal biopsy, which was obtained at a relatively early stage of renal impairment, we found histological findings consistent with those of scleroderma kidneys. Unlike typical SRC, however, the larger renal arteries seemed to be unaffected. These histological findings were probably responsible for the "slowly progressive" renal impairment over the years without causing typical SRC.

A predictive clinical grading system for immunoglobulin A nephropathy by combining proteinuria and estimated glomerular filtration rate.

BACKGROUND: There is no clinical classification of immunoglobulin A nephropathy (IgAN) in clinical practice. In this study, we used receiver-operating characteristic (ROC) analysis to create accurate clinical grades based on clinical parameters associated with the development of end-stage renal disease (ESRD) in IgAN patients. METHODS: We performed a retrospective analysis of 116 patients with IgAN. The association between clinical variables and progression to ESRD was examined. RESULTS: Logistic regression analysis indicated that 24-hour urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) at the time of renal biopsy (RBx) were independently associated with the development of ESRD. When combining UPE and eGFR, the areas under the curve were superior to those for UPE or eGFR alone. Moreover, two-graph ROC analysis indicated that the threshold values for UPE and eGFR in predicting future ESRD were 1.0 g/day and 64.0 ml/min/1.73 m(2), respectively. Of note, the patients were classified into 4 grades by levels of UPE and/or eGFR, and the OR for risk of ESRD rose significantly from grade I to grade IV. CONCLUSION: The combination of UPE and eGFR at the time of RBx can improve the predictive accuracy of risk for subsequent ESRD in IgAN patients.

A case of glomerulopathy showing podocytic infolding in association with Sjögren's syndrome and primary biliary cirrhosis.

A 49-year-old man was admitted to our hospital with mild proteinuria. Prior to admission, he had been diagnosed as having Sjögren's syndrome in association with primary biliary cirrhosis. Examination of a renal biopsy under light microscopy revealed diffuse and global mesangial cell proliferation and a spike and/or bubbling formation of the glomerular basement membrane (GBM), resembling membranoproliferative glomerulonephritis. In contrast, immunofluorescent studies showed marked immunoglobulin and complement depositions in the mesangial areas; however, only faint granular IgG and IgA deposition was observed along the GBM. Interestingly, electron microscopy revealed that a microtubular structure, derived from podocytes, was present in the GBM. We present a case of glomerulopathy showing podocytic infolding in association with Sjögren's syndrome and primary biliary cirrhosis.

A case of alternating bundle branch block in combination with intra-Hisian block.

We describe a 66-year-old woman who had an alternating bundle branch block consisting of coexisting occurrence of right bundle branch block (RBBB) and left bundle branch block (LBBB) combined with Mobitz type II atrioventricular block (AVB). A prolonged PQ interval was associated with the RBBB pattern whereas it was not apparent in the LBBB pattern. Electrophysiologic study revealed that the LBBB pattern was combined with a double His bundle potential. On the other hand, the RBBB pattern was combined with a markedly prolonged HV interval with a low voltage monophasic His bundle potential, which we speculated was the former part of the split His bundle potential seen during the LBBB pattern. A combination of the longitudinal dissociation in the His bundle and the gap phenomenon at the intra-Hisian block portion may account for this observation.

Gene delivery using human cord blood-derived CD34+cells into inflamed glomeruli in NOD/SCID mice.

BACKGROUND: Bone marrow reconstitution using genetically-modified hematopoietic stem cells has been reported to confer resistance to inflammation and prevent renal injury in glomerulonephritis. Although this strategy has potentials for clinical use, taking hematopoietic stem cells from bone marrow is highly stressful for patients. In this regard, umbilical cord blood may be a useful alternative and, therefore, we focused on their suitability as a source of hematopoietic stem cells for transplantation-based therapy for glomerulonephritis. METHODS: CD34+ cells were obtained from human umbilical cord blood, retrovirally transduced with human beta-glucuronidase (HBG) gene, and transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After confirming the successful chimerism, these mice were treated with lipopolysaccharide (LPS), and local HBG expression in glomeruli was examined using immunohistochemical analysis, HBG bioassay, and Western blot analysis. RESULTS: Clonogenic assay showed that 88.4 +/- 5.9% burst-forming unit-erythroid (BFU-E), 79.7 +/- 11.4% in colony-forming unit-macrophage (CFU-M), and 81.1 +/- 14.1% in colony-forming unit-granulocyte (CFU-G), respectively, possessed the transgene after transfection, suggesting that precommited cells were susceptible to retroviral infection. Flow cytometric analysis revealed that 24.1 +/- 14.5% of bone marrow cells in these chimera mice expressed human lymphocyte antigen (HLA) 8 weeks after transplantation. Also, clonogenic assay showed that a sustained engraftment of human hematopoietic cells expressed HBG. CD14-positive cells were recruited into the glomeruli upon LPS treatment and they secreted bioactive HBG, suggesting that cord blood-derived CD34+cells may differentiate into monocyte lineage while maintaining the expression of the transgene. CONCLUSION: These data indicate that umbilical cord blood cells can be utilized as a source of hematopoietic stem cells for the transplantation-based therapy of glomerulonephritis.

[A case of allopurinol-induced muscular damage in a chronic renal failure patient].

A 73-year-old woman with chronic renal failure developed generalized muscular weakness and pain 6 days after the start of allopurinol treatment(200 mg/day). Routine laboratory tests revealed elevated levels of serum creatine kinase, and the patient was clinically diagnosed as rhabdomyolysis, due probably to severe myositis. A high level of serum oxipurinol, the chief active metabolite of allopurinol, was also revealed. The muscular weakness was relieved in seven weeks with intermittent hemodiafiltration.