Development of a novel artificial intelligence algorithm to detect pulmonary nodules on chest radiography.

BACKGROUND: In this study, we aimed to develop a novel artificial intelligence (AI) algorithm to support pulmonary nodule detection, which will enable physicians to efficiently interpret chest radiographs for lung cancer diagnosis. METHODS: We analyzed chest X-ray images obtained from a health examination center in Fukushima and the National Institutes of Health (NIH) Chest X-ray 14 dataset. We categorized these data into two types: type A included both Fukushima and NIH datasets, and type B included only the Fukushima dataset. We also demonstrated pulmonary nodules in the form of a heatmap display on each chest radiograph and calculated the positive probability score as an index value. RESULTS: Our novel AI algorithms had a receiver operating characteristic (ROC) area under the curve (AUC) of 0.74, a sensitivity of 0.75, and a specificity of 0.60 for the type A dataset. For the type B dataset, the respective values were 0.79, 0.72, and 0.74. The algorithms in both the type A and B datasets were superior to the accuracy of radiologists and similar to previous studies. CONCLUSIONS: The proprietary AI algorithms had a similar accuracy for interpreting chest radiographs when compared with previous studies and radiologists. Especially, we could train a high quality AI algorithm, even with our small type B data set. However, further studies are needed to improve and further validate the accuracy of our AI algorithm.

Henoch-Schönlein purpura nephritis in childhood: pathogenesis, prognostic factors and treatment.

Henoch-Schönlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis involving the capillaries and the deposition of IgA immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. Thus, it is important to clarify the onset mechanism as well as the prognostic factors of Henoch-Schönlein purpura nephritis (HSPN) and to identify the most appropriate treatment. We herein review the pathogenesis, the prognostic factors and treatment of HSPN. As to the pathogenesis, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, thereby inducing renal injury. With regard to the prognostic factors, a number of factors have been suggested including nephrotic syndrome, decreased factor XIII activity, hypertension, severe renal injury, high renal accumulation of activated macrophage, alpha-smooth muscle actin, and high serum myeloid-related protein levels. For the treatment of severe HSPN, aggressive therapies including multiple drug combination therapy and plasmapheresis have been shown to be effective in ameliorating proteinuria and histological severity. Nevertheless, detailed investigation into the pathogenesis of HSPN and double-blind randomized control studies on children with HSPN are still necessary.

Role of vascular endothelial growth factor and angiopoietin 1 in renal injury in hemolytic uremic syndrome.

BACKGROUND/AIMS: The recovery process from renal injury in hemolytic uremic syndrome (HUS) remains obscure. In order to clarify the role of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang-1) in the renal recovery from HUS, we produced a model of mild HUS and examined the renal recovery process. METHODS: We investigated three groups of mice. Group 1 consisted of mice that received an injection of Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS); group 2 consisted of mice that received an injection of low dose of Stx2 and LPS, and group 3 consisted of control mice. RESULTS: Serum Cr levels in group 1 were greater than those in group 2, and all mice in group 1 died, whereas all mice in group 2 remained alive. Endothelial injury at 24 h in group 1 was higher than in group 2. Electron-microscopic findings demonstrated that the endothelial cells formed immature capillary-like lumina from 7 to 28 days with increases in the expression of CD31-positive cells. Glomerular VEGF expression decreased at 72 h in group 1, but gradually increased in group 2. Glomerular Ang-1 expression peaked from 72 h to 28 days. Ang-1 expression was frequently found in the endothelial cell region of vesicle walls simultaneous with increased CD31-positive staining. CONCLUSION: Our findings suggest that VEGF and Ang-1 play important roles in the recovery process, particularly in the regeneration of endothelial injury.

[Actual state of understanding and utilization of "home pharmacy" in residents and their regional differences].

To know the actual states of understanding and utilization of "home pharmacy" in regional residents and their regional differences, we performed questionnaire survey for the residents in Ueda-shi in Nagano and the Kita-tama area in Tokyo, where it was found in the past survey that the medical activities as "home pharmacy" in Ueda-shi was remarkably higher than those in the Kita-tama area. By the present survey it was confirmed that the percentages of the person who keeps "home pharmacy" and of the person who fixes a pharmacy to get a filled prescription were remarkably higher in the residents of Ueda-shi than those of the Kita-tama area. The level of understanding of "home pharmacy" was also higher in the residents of Ueda-shi. These results suggested that the spread of "home pharmacy" is influenced by the extent of activity of regional pharmacy and the regional society of pharmacists.

Mizoribine attenuates renal injury and macrophage infiltration in patients with severe lupus nephritis.

The purine synthesis inhibitor mizoribine (MZR) has been successfully used without serious adverse effects in the treatment of several renal diseases including lupus nephritis. Besides its immunosuppressive effects, MZR has recently been reported to ameliorate tubulointerstitial fibrosis in rats via suppression of macrophage infiltration. However, there has been little information regarding the beneficial effects of MZR from the histologic standpoint in human lupus nephritis. Pre- and posttreatment renal biopsy specimens obtained from nine patients with diffuse proliferative lupus nephritis (DPLN) were divided into two groups (group A, five patients who received immunosuppressive treatment with MZR and group B, four patients who received immunosuppressive treatment without MZR) and histologically evaluated. Grading was done according to the 2003 classification system for lupus nephritis developed by the International Society of Nephrology/Renal Pathology Society, which considers the activity and chronicity indices, an immunohistologic study to assess intraglomerular and interstitial infiltration by macrophages, and the expression of osteopontin. Although in all the patients the posttreatment renal biopsy showed improvement of histologic grading and activity indices, group A patients showed a significant decrease of the chronicity indices and of intraglomerular infiltration by macrophages when compared to group B patients (2.6 +/- 0.5 vs 4.0 +/- 1.4 and 0.5 +/- 0.2 vs 2.4 +/- 1.9 cells per glomerulus, respectively; p < 0.05). Although this was a preliminary study in a small number of subjects, these histological observations may further confirm the beneficial effects of MZR for selected patients with DPLN.

[Actual state of medical activities as "home pharmacy" including preventive medicine in community pharmacy and their regional differences].

To determine the "home pharmacy" activities including preventive medicine in community pharmacies and their regional differences, we conducted two questionnaire surveys of pharmacies belonging to the pharmacists' association in four areas, two metropolitan areas (Kita-tama area and Minato-ku in Tokyo) and two rural areas (Ueda-shi in Nagano and Aira-gun in Kagoshima) in 1998 and 2007. The questionnaire consisted of 42 questions including the scale and characteristics of the pharmacy, the offering of information to patients and information collection from patients, and activities related to home care medicine, environmental sanitation, and healthcare. Based on 14 factors in the questionnaire, an index of "Community Medicine Contributed by Home Pharmacies" was evaluated to represent the extent of activity including preventive medicine in pharmacy. The median of the indexes in the four areas rose in 2007, and was the highest in Ueda-shi. However, the increase in the index was found to result from increases in activity related to clinical medicine such as the use of "Medication Notebooks" and the circulation of "Pharmaceutical Instructions" and did not result from increased activity related to preventive medicine. Factors to promote preventive medicine activity are discussed based on the data from Aira-gun where the greatest home care medicine activity occurred and from Ueda-shi where the greatest environmental sanitation and healthcare activities occurred.

Mizoribine treatment of young patients with severe lupus nephritis: a clinicopathologic study by the tohoku pediatric study group.

BACKGROUND: A novel purine synthesis inhibitor, mizoribine (MZR), with a similar activity to that of mycophenolate mofetil, was developed in Japan. We suspected that long-term oral MZR intermittent pulse therapy (MZR-P) might be more effective than the conventional daily MZR regimen due to the higher peak serum MZR levels that are achieved. Here, we examined the clinicopathologic efficacy of MZR-P treatment in 10 young patients with diffuse proliferative lupus nephritis (DPLN), including 3 patients who received MZR-P as their primary cytotoxic therapy. METHODS: After their most recent renal flare-ups, all the patients were treated using MZR-P combined with oral prednisolone (PDN). MZR was administered as a single daily dose of 6-10 mg/kg per day (maximum dose of 500 mg) on 2 days of the week (Monday and Thursday) for at least 12 months or longer. The concomitantly administered PDN dose was gradually reduced. RESULTS: The baseline characteristics of the patients were as follows: mean age 15 years; urinary protein/creatinine (Up/cr) ratio 1.57 +/- 1.05 mg/mg; serum C3 level 50.3 +/- 19.7 mg/dl; serum complement hemolytic activity (CH50) 18.1 +/- 9.9 U/ml; serum anti-dsDNA antibody titer 177.5 +/- 152.7 IU/ml; serum creatinine 0.6 +/- 0.1 mg/dl, and European Consensus Lupus Activity Measurement (ECLAM) index 4.9 +/- 2.6. Despite the gradual tapering of the PDN dose, marked improvements compared with the baseline values were observed at the last observation, mean interval of 29 months after the start of treatment: Up/cr ratio 0.19 +/- 0.14; ECLAM index 1.3 +/- 0.7 (p < 0.01); serum C3 level 76.5 +/- 22.1 mg/dl; serum CH50 value 31.9 +/- 8.7 U/ml, and anti-dsDNA antibody titer 34.2 +/- 20.5 IU/ml (p < 0.05). The serum creatinine level remained within the normal range in all study participants. Post-treatment renal biopsies were performed in 5 of the patients; histology showed a marked attenuation of lesion progression. No serious adverse effects were observed. CONCLUSION: We believe that long-term MZR-P may prove to be a treatment of choice for young patients with DPLN. However, confirmation is needed as this preliminary study is limited by the small number of subjects, lack of controls, and its retrospective nature.

Efficacy of single dose of oral mizoribine pulse therapy two times per week for frequently relapsing nephrotic syndrome.

We assessed the efficacy of a single dose of oral mizoribine (MZB) pulse therapy two times per week for children with frequently relapsing nephrotic syndrome (FRNS). Eleven children with FRNS in remission were treated with oral MZB pulse therapy (daily dose 6 mg/kg; maximum total dose 300 mg). We compared their clinical manifestations before and after oral MZB pulse therapy and examined the changes in serum MZB concentration in each patient on the days when MZB was administered. Eight patients had no subsequent relapses (responders), and prednisolone could be discontinued. Although 2 of the other 3 patients (nonresponders) had one relapse and the remaining patient had two relapses, both the dosages of prednisolone and frequency of relapse after oral MZB pulse therapy were significantly lower than before oral MZB pulse therapy. The peak blood concentration and AUC0-4 of MZB in the responders were higher than in the nonresponders. None of patients had severe adverse effects, such as uricacidemia, leukopenia, liver dysfunction or alopecia. Oral mizoribine pulse therapy consisting of a single dose two days a week may be effective and safe in some FRNS patients.

Efficacy of tonsillectomy plus methylprednisolone pulse therapy for a child with Henoch-Schoenlein purpura nephritis.

Henoch-Schoenlein purpura (HSP) is a systemic disorder characterized by a leukocytoplastic vasculitis involving small vessels with the deposition of immunoglobulin A (IgA) immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. We report here an 11-year-old boy with Henoch-Schoenlein purpura nephritis (HSPN) accompanied by recurrent purpura and persistent nephropathy despite conventional therapy such as prednisolone, methylprednisolone pulse therapy and immunosuppressive agent (Mizoribine). The patient was treated with tonsillectomy plus methylprednisolone pulse therapy. This treatment decreased proteinuria, induced disappearance of microscopic hematuria, and improved renal pathological findings. Tonsillectomy plus methylprednisolone pulse is effective and useful therapy for some children with recurrent purpura and persistent nephropathy.

Long-term efficacy of low-density lipoprotein apheresis for focal and segmental glomerulosclerosis.

Recently, there have been reports on the efficacy of low-density lipoprotein (LDL) apheresis (LDL-A) for focal and segmental glomerulosclerosis (FSGS) in pediatric patients. However, there have been few reports on the long-term efficacy of LDL-A for FSGS in such patients. We report here a case of long-term efficacy of LDL-A for FSGS. The patient was a 13-year-old boy with FSGS who presented with steroid-resistant and cyclosporine-resistant nephrotic syndrome and hyperlipidemia. LDL-A was performed 24 times on one year. Following LDL-A, serum concentrations of LDL, very low-density lipoprotein (VLDL), apoprotein B, and vascular endothelial growth factor significantly decreased, and urinary excretion of protein also decreased. In addition, 3 years after LDL-A, the pathology findings on a second renal biopsy had improved. The patient has been in remission from FSGS for 12 years since LDL-A. These findings suggest that LDL-A may be useful in maintaining long-term remission from pediatric FSGS.

Agmatine suppresses mesangial cell proliferation by modulating polyamine metabolism.

Polyamines play an essential role in the growth and differentiation of mammalian cells. The depletion of intracellular polyamines results in the suppression of growth. Proliferation of glomerular mesangial cells (MC) is the most common pathologic change in many forms of glomerulonephritis. Agmatine is a metabolite of arginine via arginine decarboxylase (ADC), highly expressed in the kidney, and unique in its capacity to suppress intracellular polyamine levels required for proliferation. As agmatine enters mammalian cells via the polyamine transport system, its antiproliferative effects may preferentially target cells with increased proliferative kinetics. In the present study, we evaluated the antiproliferative effects of agmatine on human MC in vitro. MC proliferation was stimulated with 20% fetal bovine serum (FBS) or platelet-derived growth factor (PDGF-BB, 20 ng/ml). Cell proliferation was measured using the (4.3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (MTT) proliferation assay. Intracellular polyamine levels were assayed by high performance liquid chromatography, and cell death was assessed by cellular DNA fragmentation enzyme-linked immunosorbent assay. The MTT proliferation assay showed that agmatine significantly suppressed proliferation of human MC treated with 20% FBS or 5% FBS + PDGF as compared to human MC treated with 5% FBS. Polyamine levels were markedly lower in cells treated with agmatine, and proliferation was rescued by administration of putrescine. The fragmented DNA was hardly detected in agmatine-treated human MC. In summary, human MC stimulated to increase their proliferative kinetics are significantly more sensitive to the antiproliferative effects of agmatine than normally cultured cells. Suppressed proliferation of the agmatine-treated human MC is not due to increased cell death. These results suggest that agmatine is a promising drug candidate for the treatment of human mesangial proliferative glomerulonephritis.

Detection of enteroviruses in renal biopsies from patients with immunoglobulin A nephropathy.

Viruses have been suspected to be one of the causes of IgA nephropathy (IgAN). Recent studies have detected viruses in renal tissues of patients with IgAN. Enteroviruses have been reported as pathogenic agents in some renal diseases. We previously reported that group B coxsackieviruses cause pathological changes in experimentally infected mouse kidney. The aim of the present study was to examine the participation of enteroviruses in the pathogenesis of renal diseases including IgAN. Renal biopsies of ten patients with IgAN (group 1) and of 19 patients with non-IgAN renal disease (group 2) were analyzed by polymerase chain reaction (PCR) for the presence of enteroviral RNA. Positive PCR results were obtained for three patients (30%) of group 1. We confirmed by sequencing that the positive PCR products were derived from strains of enteroviruses. One of these three patients also had a positive result for lymphocytes from peripheral blood. In contrast, enteroviral RNA was detected in none of the 19 patients of group 2. The incidence of enteroviral RNA detection in patients of group 1 was higher than that in group 2 (P<0.05). Our findings suggest that enteroviral infection may have the possibility of becoming one of the factors involved in the mechanism of onset or evolution of IgAN.

IgA deficiency and membranous glomerulonephritis presenting as nephrotic syndrome.

Selective IgA deficiency associated with glomerulonephritis is rare and no previous reports in childhood have been made of the association of IgA deficiency and membranous glomerulonephritis (MGN). We report a 5-year-old boy with selective IgA deficiency and MGN. He presented with nephrotic syndrome. Percutaneous renal needle biopsy showed diffuse global thickening on light microscopy and heavy IgG and moderate C3 deposits were found on immunofluorescence. Electron microscopy detected extensive global subepithelial deposition of electron-dense material with frequent intramembranous extension and spike formation. The pathological diagnosis was diffuse MGN stage 1. Oral prednisolone (1 mg kg(-1) day(-1)), angiotensin-converting enzyme inhibitors (ACEI), and angiotensin II receptor blocker (ARB) were given resulting in reduction of proteinuria. The prednisolone dose was gradually tapered and discontinued after 2 months. At present the patient has been in complete remission for 10 months despite the discontinuance of prednisolone. In conclusion, our treatment with corticosteroid, ACEI and ARB reduced proteinuria and was effective for our case with selective IgA deficiency and MGN.

Uninephrectomy induces progressive glomerulosclerosis and apoptosis in anti-Thy1 glomerulonephritis.

Administration of the anti-Thy1 antibody in rats induces reversible glomerulonephritis resembling human mesangiolytic and mesangioproliferative diseases. The purpose of the present study was to design a model of irreversible glomerulosclerosis, using the anti-Thy1 antibody injection after uninephrectomy, and examine it, focusing on apoptosis in the process of progressive sclerotic changes. Wistar rats were divided into three groups: one-kidney groups (group I and III) and a two-kidney group (group II). All groups were injected with the anti-Thy1 antibody (OX-7) at day 0, and group I and III were uninephrectomized at day -6. Only group III rats were given a half dose of OX-7 as compared with group I and II. Rats were killed for histological examinations at days 7, 14 and 30. In group I, progressive glomerular lesions, such as glomerular adhesion to Bowman's capsule, crescent formation, and collapse of capillary tufts were observed at days 14 and 30. No significant differences were observed in the pathological findings between group I and III. There was a significantly higher number of glomerular terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells in group I as compared to group II at days 7 and 14. Moreover, the glomerular expression of transforming growth factor-beta, heparan sulfate proteoglycan and chondroitin sulfate proteoglycan significantly increased in group I as compared to group II at days 7 and 14. Progressive glomerulosclerosis can be induced in the rat by a single injection of the anti-Thy1 antibody after unilateral nephrectomy. It is suggested that apoptosis and extracellular matrix accumulation play an important role in the development of glomerulosclerosis.

Mizoribine oral pulse therapy for steroid-dependent nephrotic syndrome.

There have been reports of the use of mizoribine (MZB) oral pulse therapy for the treatment of systemic lupus erythematosus. We report its efficacy in a 9-year-old girl with steroid- and cyclosporine-dependent nephrotic syndrome (NS). The patient experienced relapses of NS when prednisolone was tapered to 20 mg/day after discontinuing cyclosporine due to biopsy proven toxicity. When methylprednisolone pulse therapy combined with prednisolone therapy (40 mg/day) failed to result in a complete remission after 3 weeks, oral MZB pulse therapy (total dose of 500 mg, 10 mg/kg per day in three divided daily doses twice a week) was given. This therapy was continued for 9 months and resulted in complete remission of the NS for 6 months despite the discontinuation of prednisolone. The serum concentration of MZB was above 2.5 microg/ml for about 10 h (from 3 h after the first dose of MZB to 2 h after the final dose). Thus, our results suggest that this regimen may be effective for patients with steroid-dependent NS.

Epstein-Barr virus-associated hemophagocytic syndrome in a patient with lupus nephritis.

Hemophagocytic syndrome (HPS) is an unusual but severe illness associated with a variety of infections, as well as genetic, malignant tumors, and autoimmune diseases. We report an 11-year-old girl with systemic lupus erythematosus and nephritis who developed HPS associated with Epstein-Barr virus reactivation. In our patient, the onset of reactive HPS might be related to immunosuppressive treatment during the course of lupus nephritis.

Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy.

AIM: To evaluate the efficacy of prednisolone, warfarin, and dipyridamole therapy combined with mizoribine (PWDM) in the treatment of diffuse immunoglobulin A (IgA) nephropathy in comparison with prednisolone, warfarin, and dipyridamole therapy without mizoribine (PWD) and with methylprednisolone pulse therapy (PWD pulse). METHODS: We collected data on 61 patients diagnosed with diffuse IgA nephropathy, and these patients were retrospectively divided into three groups without randomization. Group A included 21 patients before 1987 who were treated with PWD for 24 months, group B included 20 patients from 1987 to 1989 who were treated with PWD pulse therapy for 24 months, and group C included 20 patients after 1990 who were treated with PWDM for 24 months. Clinical features and pathological findings in each group were analyzed retrospectively. RESULTS: The time from initiation of therapy in group A, group B, and group C was 8.9 +/- 5.2, 8.1 +/- 3.9, and 7.7 +/- 3.8 years, respectively. At the latest follow-up examination, the mean urinary protein excretion (mg/m2/h) was 17 +/- 10 in group A, 22 +/- 20 in group B, and 6 +/- 6 in group C and had decreased significantly in group C as compared with the other groups. The activity index in all three groups was lower at the second biopsy than that at the first biopsy (5.1 +/- 0.8 vs. 6.5 +/- 2.1 in group A, p < 0.05; 5.6 +/- 0.9 vs. 6.6 +/- 1.7 in group B, p < 0.01, and 4.5 +/- 1.0 vs. 6.8 +/- 1.9 in group C, p < 0.01). The chronicity index in groups A and B at second biopsy was higher than at first biopsy (7.3 +/- 1.4 vs. 4.8 +/- 1.0 in group A, p < 0.01, and 8.1 +/- 2.0 vs. 5.3 +/- 0.9 in group B, p < 0.01), but was unchanged in group C. At the latest follow-up examination, 1 patient (4.8%) in group A, 3 patients (15%) in group B, and none (0%) in group C had renal insufficiency. CONCLUSION: These results suggest that PWDM appears to be more effective than PWD or PWD pulse in ameliorating proteinuria and histological severity of patients with IgA nephropathy.

Axial radiographic evaluation in hallux valgus: evaluation of the transverse arch in the forefoot.

To quantitatively evaluate the shape of the transverse arch in the forefoot with hallux valgus, a method for axial imaging and analysis of the forefoot has been developed. A foot was imaged at 30 degrees of flexion. A two-dimensional coordinate system was established by drawing a vertical line on the X-ray image through the lowest point of the head of the second metatarsal. The origin was set at the intersection between the plane of the base of the foot and this vertical line. A control group of 51 feet from 29 normal subjects and a test group of 59 feet from 34 subjects with hallux valgus were examined. Compared with the normal group, the heads of the first, second, and third metatarsal bones were lower in the hallux valgus group, and their sesamoids were shifted outward with a rotational deviation. There was a statistical correlation between the degree of outward dislocation of the fibular sesamoid bone and the hallux valgus angle. The position of the fibular sesamoid bone become higher than the head of the first metatarsal when the angle of the hallux valgus exceeded 25 degrees.