Seasonal exacerbation of rheumatoid arthritis detected by big claims data analysis: A retrospective population study.

OBJECTIVES: The objective of the study was to determine the seasonal changes in the initiation of biological disease-modifying antirheumatic drugs (bDMARDs) and methotrexate (MTX) using big claims data. METHODS: We counted the monthly number of initial administrations of each bDMARD and MTX in patients with rheumatoid arthritis (RA) between April 2010 and March 2017. Data were collected from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. This database covers more than 95% of Japanese citizens. Seasonal changes in the number of initiations were determined. Patient claims were also classified according to drugs, districts, gender, and ages. RESULTS: The initiation of bDMARDs and MTX administration varied according to the season in a sine curve shape, with the highest numbers in May to July and the lowest numbers in November to January. The same changing pattern was observed among each bDMARD, district, gender, and age groups particularly when the number was on the higher side. CONCLUSION: We noted an apparent seasonal change in the number of bDMARDs initiated, with a peak during spring, suggesting an exacerbation of RA in the spring in Japan. These changes are overlooked in daily practice and are only visible using big data.

Trend in prescription and treatment retention of molecular-targeted drugs in 121,131 Japanese patients with rheumatoid arthritis: A population-based real-world study.

OBJECTIVES: To describe the real-world prescription and treatment retention of molecular-targeted drugs for rheumatoid arthritis (RA) in Japan. METHODS: A total of 204,416 patients with RA were prescribed at least one of the eight molecular-targeted drugs in 7 years from the National Database of Health Insurance Claims and Specific Health Checkups of Japan covering 98.3% of the Japanese population. The retention rates of each drug as well as head-to-head comparisons were estimated by Kaplan-Meier method. RESULTS: A total of 121,131 RA patients were prescribed any molecular-targeted drug for the first time, while 36,633 uses of molecular-targeted drug were switched from another (switch use). The overall retention rates of molecular-targeted drugs at 12, 36, and 60 months were 0.64, 0.42, and 0.32 for the naïve use and 0.59, 0.40, and 0.31 for the switch use, respectively. Non-tumour necrosis factor (TNF)-inhibitor molecular-targeted drugs, particularly tocilizumab and tofacitinib, had higher retention rates than TNF inhibitors for both naïve and switch uses regardless of the previous drug and showed higher retention rates in head-to-head comparisons between eight molecular-targeted drugs. CONCLUSIONS: Our data reveal that the real-world drug retention is overall lower than previously reported and higher with non-TNF inhibitors than with TNF inhibitors.

The distance and chance of lifetime geographical movement of physicians in Japan: an analysis using the age-period-cohort model.

BACKGROUND: The uneven geographical distribution of physicians in Japan is a result of those physicians electing to work in certain locations. In order to understand this phenomenon, it is necessary to analyze the geographic movement of physicians across the Japanese landscape. METHODS: We obtained individual data on physicians from 1978 to 2012 detailing their attributes, work institutions, and locations. The data are from Japanese governmental sources (the Survey of Physicians, Dentists, and Pharmacists). The total sample size was 122 150 physicians, with 77.5% being male and 22.5% female. After obtaining the data, we calculated the geographical distance of each physician's movement by using geographic information systems software (GIS; ArcGIS, ESRI, Inc., CA, USA). Geographical distance was then converted into time distance. We compared the resulting median values through nonparametric testing and then conducted a multivariate analysis. Our next step involved the use of an age-period-cohort (APC) model to measure the degree of impact three points of data, experience (experience years), the historical and environmental context of the data (survey year), and physician cohort (registration year) had on the movement of each physician. RESULTS: The ratio of female physicians who selected an urban area as their first working location was higher than that of male physicians. However, the selection of an urban area was becoming more popular as a first working location for both males and females as the year of data increased. The overall distance of geographical movement for female physicians was less than it was for male physicians. Physicians moved the greatest distance between their second and fourth years following license acquisition, at which point the time distance became shorter. The median time distance was 46 min in 2000 and 22 min in 2008. The physicians in our study did not move far from their first working location, and the overall distance of movement lessened in the more recent years of study. The median distance of movement after 20 years was 25.9 km for male physicians, and 19.1 km for female physicians. The results of the APC model indicated that the effects of experience years (age) gradually declined, that the survey year (period) effects increased, and that the registration year (cohort) effects increased initially before leveling off. CONCLUSIONS: The trends following the introduction of the new mandatory training system in 2004 may imply that the concentration of physicians in Japan's urban areas is expected to increase. After 2000, the effect of that period on physicians explains their geographical movements more so than the factor of their age.

A boy with IgA nephropathy complicated by tubulointerstitial nephritis and uveitis (TINU) syndrome.

BACKGROUND: Abnormal cellular and humoral immunity underlie both immunoglobulin A (IgA) nephropathy and tubulointerstitial nephritis and uveitis (TINU) syndrome. We encountered a teenage boy who developed TINU syndrome during the course of IgA nephropathy. CASE REPORT: 1 year after onset of IgA nephropathy following acute enteritis, a 14-year-old boy again experienced acute enteritis caused by Campylobacter jejuni, which was followed by TINU syndrome with prominent low-molecular-weight proteinuria. Renal histologic examination showed T-cell-dominant tubulointerstitial infiltration of marked immune cells including CD54-positive cells. Steroid therapy improved renal function, reversing aggravation of IgA nephropathy by TINU syndrome. CONCLUSIONS: The boy's human leukocyte antigen profile suggested predisposition to these two diseases, triggered by which were intestinal infections. The enteritis probably induced abnormalities in cellular and humoral immunity. Low-molecular-weight proteinuria, which reflected our patient's tubulointerstitial lesions, should call for consideration of TINU syndrome, including ophthalmologic assessment for possible uveitis.

Cyclosporin A may cause injury to undifferentiated glomeruli persisting in patients with Alport syndrome.

BACKGROUND/AIMS: Alport syndrome (AS) is a renal disorder caused by a genetic abnormality of type IV collagen α3 and α4, or α5 genes and shows a poor prognosis. Since the defect of type IV collagen synthesis disturbs the maturation process of the glomerular capillary loop, residual immature glomeruli persist after birth. The therapeutic efficacy of cyclosporin A (CyA) for AS patients seems to be controversial. We recently noted that renal specimens obtained from a child with AS who was treated with CyA and then developed CyA nephropathy included an increased number of undifferentiated embryonic-type glomeruli. METHODS: We analyzed renal histologic and immunohistologic findings in children with AS who did (n = 3) or did not (n = 2) develop CyA-induced nephropathy despite appropriately low serum CyA concentrations (<100 ng/mL) being maintained over a period of 2 years. To discriminate embryonic-type from mature glomeruli, staining for type IV collagen α1, laminin ß1, and laminin ß2 accompanied by light microscopic observation were employed. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). RESULTS: In initial biopsy specimens, residual embryonic-type glomeruli were observed in each patient. Patients with early-onset CyA nephropathy had a high GII (median value 2.91 vs 1.23 ± 0.62 normal kidney tissues). In the follow-up biopsy after CyA treatment, surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli that had failed to differentiate were observed. Taken together, the number of these glomeruli essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. CONCLUSIONS: Our findings indicate a need for caution in CyA therapy for patients with AS, even for a relatively short course of administration, because some patients may have an unexpected number of embryonic-type glomeruli that predispose to CyA nephropathy.

A novel OCRL1 mutation in a patient with the mild phenotype of Lowe syndrome.

Oculocerebrorenal syndrome of Lowe (OCRL, OMIM 309000), also known as Lowe syndrome, is a rare X-linked multisystem disorder characterized by congenital cataracts, mental retardation, and Fanconi syndrome of the kidney proximal tubules. Lowe syndrome is caused by mutations in the gene encoding a member of the inositol polyphosphate-5-phosphatase protein family (OCRL1) on chromosome Xq26.1. OCRL1 contains 24 exons and encodes a 105-kDa phosphatidylinositol (4,5) bisphosphate 5-phosphatase. An OCRL1 isoform generated by alternative splicing is predominantly expressed in brain, and localizes to the trans-Golgi network, lysosomes, and endosomes. Impaired inositol polyphosphate-5-phosphatase activity elevates phosphatidylinositol (4,5) bisphosphate levels that are required for vesicle trafficking within the Golgi apparatus, actin cytoskeleton remodeling closely associated with Golgi, and endosomal membrane trafficking. Accordingly, abnormalities in the actin cytoskeleton may influence the function of renal epithelial cells in patients with Lowe syndrome. OCRL1 mutations exist in about 95% of patients with Lowe syndrome, and new mutations occur in 32% affected males. We here describe a Japanese male with the mild phenotype of Lowe syndrome. Physical examination revealed mild congenital bilateral cataracts, mild mental disability, and short stature. Proteinuria was also mild with a high ß2-microglobulinuria level. Nucleotide sequence analysis identified a hemizygous mutation (T-to-C transition) at nucleotide 2039 in exon 18 that substitutes Ser (TCT) for Phe (TTT) at amino acid position 680. This missense mutation is located outside the known catalytic domain that is encoded by exons 4 through 15. The present patient carries a novel OCRL1 mutation that is helpful for genetic counseling.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and IgA nephropathy.

BACKGROUND: A syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA), as well as immunoglobulin A nephropathy (IgAN), may be caused by autoimmune reactivity nephropathy. CASE-DIAGNOSIS/TREATMENT: A 10-year-old boy presented with periodic fever, exudative tonsillitis, oral aphthous ulcer, and cervical lymph node inflammation. These conditions had occurred at intervals of about 2-6 weeks since the age of 3 years. Microscopic hematuria, first detected at age 8 years, worsened during episodes of PFAPA-related fever; since 10 years of age, the hematuria was accompanied by sustained proteinuria. Examination of a kidney biopsy specimen led to a diagnosis of IgAN. In the kidney specimen, fractalkine immunoreactivity and heavy macrophage infiltration were prominent. Multi-drug cocktail therapy improved the urinalysis findings, and subsequent tonsillectomy succeeded in controlling recurrences of PFAPA and IgAN. In a post-treatment renal biopsy specimen, mesangial proliferation was decreased, and fractalkine immunoreactivity was absent. CONCLUSION: Immunologic reactions against certain antigens in local mucosa, including tonsils, may be impaired in PFAPA and IgAN, as evidenced by the suppression of both diseases in our patient by tonsillectomy. Accordingly, the concurrence of PFAPA and IgAN in our patient appeared to be a consequence of shared autoimmune mechanisms and systemic and local increases in cytokine concentrations, rather than coincidence.

Cure of relapsing nephrosis by an allogeneic marrow graft for chronic myelogenous leukemia.

BACKGROUND: Minimal-change nephrotic syndrome has recently been attributed to an immature, dysfunctional T-cell population. CASE-DIAGNOSIS/TREATMENT: A woman, now 23 years old, developed nephrotic syndrome when she was 6 years old. Despite treatment with steroids and immunosuppressants such as cyclosporine, mizoribine, mycophenolate mofetil, and tacrolimus, the patient relapsed 14 times. At the age of 19 years, she developed chronic myelogenous leukemia, against which imatinib achieved cytogenetic remission. The patient received an allogeneic bone marrow graft transplantation from an unrelated marrow bank donor, with an uncomplicated recovery and molecular genetic remission. Immunosuppressants were withdrawn within 6 months. The patient is now without drug treatment. Complete remission of nephrotic syndrome has also been maintained for over 4 years without any drug administration. CONCLUSIONS: The patient's course supports suggestions that immunological dysfunction in nephrosis is associated with abnormality of immature, relatively unclassified T cells (CD34(+)) representing hematopoietic stem cells, as opposed to mature T cells (CD34(-)).

Multiple electron injection dynamics in linearly-linked two dye co-sensitized nanocrystalline metal oxide electrodes for dye-sensitized solar cells.

Understanding the electron transfer dynamics at the interface between dye sensitizer and semiconductor nanoparticle is very important for both a fundamental study and development of dye-sensitized solar cells (DSCs), which are a potential candidate for next generation solar cells. In this study, we have characterized the ultrafast photoexcited electron dynamics in a newly produced linearly-linked two dye co-sensitized solar cell using both a transient absorption (TA) and an improved transient grating (TG) technique, in which tin(IV) 2,11,20,29-tetra-tert-butyl-2,3-naphthalocyanine (NcSn) and cis-diisothiocyanato-bis(2,2'-bipyridyl-4,4'-dicarboxylato)ruthenium(II) bis(tetrabutylammonium) (N719) are molecularly and linearly linked and are bonded to the surface of a nanocrystalline tin dioxide (SnO(2)) electrode by a metal-O-metal linkage (i.e. SnO(2)-NcSn-N719). By comparing the TA and TG kinetics of NcSn, N719, and hybrid NcSn-N719 molecules adsorbed onto both of the SnO(2) and zirconium dioxide (ZrO(2)) nanocrystalline films, the forward and backward electron transfer dynamics in SnO(2)-NcSn-N719 were clarified. We found that there are two pathways for electron injection from the linearly-linked two dye molecules (NcSn-N719) to SnO(2). The first is a stepwise electron injection, in which photoexcited electrons first transfer from N719 to NcSn with a transfer time of 0.95 ps and then transfer from NcSn to the conduction band (CB) of SnO(2) with two timescales of 1.6 ps and 4.2 ps. The second is direct photoexcited electron transfer from N719 to the CB of SnO(2) with a timescale of 20-30 ps. On the other hand, back electron transfer from SnO(2) to NcSn is on a timescale of about 2 ns, which is about three orders of magnitude slower compared to the forward electron transfer from NcSn to SnO(2). The back electron transfer from NcSn to N719 is on a timescale of about 40 ps, which is about one order slower compared to the forward electron transfer from N719 to NcSn. These results demonstrate that photoexcited electrons can be effectively injected into SnO(2) from both of the N719 and NcSn dyes.

Pediatric left renal vein entrapment syndrome diagnosed by 99mTc-albumin-conjugate scintigraphy.

BACKGROUND/AIMS: Procedures for diagnosis of left renal vein entrapment syndrome (LRVES) in children have been either invasive or limited in accuracy. We examined scintigraphy with (99m)Tc-diethylene triamine pentaacetic acid-conjugated human serum albumin ((99m)Tc-HSA-D) scintigraphy in childhood LRVES, demonstrating selective left renal nuclides excretion. We also measured peak velocity using pulse Doppler ultrasonography, calculating pressure differences between inferior vena cava and left renal vein using a simplified Bernoulli equation. METHODS: Thirteen patients provisionally diagnosed with LRVES by ultrasonography combined with other imaging such as magnetic resonance angiography and three-dimensional computer tomography (CT) were examined. RESULTS: Four children showing repeated gross hematuria all showed pressure differences exceeding 3.0 mm Hg. Selective left renal albumin excretion was demonstrated by (99m)Tc-HSA-D scintigraphy. Single-photon emission CT also showed accumulation in a site consistent with the left renal pelvis. Among 9 children manifesting mainly orthostatic proteinuria, selective left renal albumin excretion examined by (99m)Tc-HSA-D scintigraphy was demonstrated only in those with proteinuria exceeding 1 g/g Cr after standing in a lordotic position. Pressure differences in patients with orthostatic proteinuria were unrelated to proteinuria severity. CONCLUSIONS: Combining pulse Doppler ultrasonography with (99m)Tc-HSA-D scintigraphy, both noninvasive and safe in children, may suffice for diagnosis of LRVES, especially with gross hematuria.

GSTT1 gene abnormality in minimal change nephrotic syndrome with elevated serum immunoglobulin E.

INTRODUCTION: Imbalance between T-helper 1 (Th1) and 2 (Th2) lymphocytes and effects of reactive oxygen species (ROS) upon glomerular capillary walls have been implicated in minimal change nephrotic syndrome (MCNS). METHODS: By polymerase chain reaction and comparative genomic hybridization, we evaluated mutations of the GSTT1 gene (GSTT1), a member of the glutathione S-transferase (GST) supergene family associated with both protection of cells from ROS and control of allergic reactions and serum immunoglobulin (Ig) E. RESULTS: Among 15 children with MCNS, IgE elevation (over 2,000 IU/l) and GSTT1 deletion was found in 2 who showed severe allergic symptoms. Serum ROS concentrations in these 2 patients were significantly higher than in healthy controls or other MCNS patients. In addition, a Th2 shift caused by increased serum interleukin (IL)- 4 was observed. CONCLUSION: These results suggest presence of a GSTT1 abnormality in some children with MCNS having marked serum IgE elevations and various allergic complications. Defective ROS degradation and Th1/Th2 imbalance caused by GSTT1 abnormality could initiate proteinuria leading to MCNS.

Nonfunction of the ECT2 gene may cause renal tubulointerstitial injury leading to focal segmental glomerulosclerosis.

BACKGROUND: Secondary focal segmental glomerulosclerosis (FSGS) follows congenital or acquired tubulointerstitial alterations such as in Dent's disease, Lowe syndrome, and reflux nephropathy. Failure of adequate regeneration after tubulointerstitial injury, or abnormal tubulogenesis, can disturb intrarenal blood circulation, causing excessive glomerular filtration. The epithelial cell-transforming sequence 2 gene (ECT2) contributes to tight junction function in epithelial cells. METHODS: We encountered two patients with a nonfunctioning ECT2 genotype who later developed FSGS. Both developed proteinuria associated with acute renal failure in early childhood. RESULTS: Renal biopsy specimens showed marked tubulointerstitial nephritis at the onset of proteinuria, later progressing to FSGS consequent to tubulointerstitial injury. The patients did not respond to corticosteroids and attained only incomplete remission upon cyclosporine A administration. One patient received a maternal renal transplant with good function and no rejection. CONCLUSIONS: ECT2 is important for tight junction function and maintenance of cell polarity. Nonfunction of this gene may cause renal tubulointerstitial injury, progressing to glomerular sclerosis.

Effect and therapeutic mechanisms of tonsillectomy for childhood IgA nephropathy.

AIM: We investigated efficacy and therapeutic mechanisms of tonsillectomy for intractable childhood IgA nephropathy. Five patients refused tonsillectomy. Among 25 patients, 19 patients were able to evaluate histological findings before and after surgery. Patients with poor (n = 7) or relatively poor (n = 18) histologically determined prognosis and an age of at least 7 years, together with proteinuria of at least 0.3 g/day or severe persisting despite ongoing drug treatment, are candidates for surgery. Patients were grouped by interval between diagnosis of IgA nephropathy and tonsillectomy (within 3 years; early group vs 3 years or later; later group). Patients underwent kidney biopsy shortly before and 1 to 2 years after tonsillectomy. RESULTS: Proteinuria was reduced after tonsillectomy over 2 years of follow-up in both early and later groups compared with proteinuria in the 6 months preceding surgery. Complete remission was achieved in 10 patients, most often among those having surgery within 3 years, while patients refusing surgery failed to attain complete remission of urinary findings. Histological activity decreased in both groups, significantly when surgery was early. Complement component C3 deposition and activated macrophages in glomeruli decreased after tonsillectomy, especially with early surgery. CONCLUSION: Tonsillectomy improved clinicopathological features in relatively severe paediatric IgA nephropathy, especially with the early-surgery group. Therapeutic mechanisms may include inhibition of complement activity in glomeruli and glomerular infiltration by activated macrophages.

Nephrotic syndrome complicated by renal and cerebral infarctions in a 14-year-old girl.

Venous thrombosis is a well-known complication of nephrotic syndrome (NS), while arterial thrombosis is rare. We know of no reports of children with this complication. Here we report a case of 14-year-old girl with NS, who complicated with renal and cerebral infarctions resulting from arterial thrombosis. Urinary examination showed heavy proteinuria. She had intravascular dehydration. Serum albumin was 0.9 g/dL. Contrast-enhanced computed tomography (CT) showed a low-attenuation area in the right kidney. Decreased blood flow in the right middle cerebral artery was observed on MRA and also on multi-detector-row head CT. Urokinase and heparin were given. Cerebral infarction was treated neuroprotectively by i.v. infusion of edaravone. Comprehensive assessment of intravascular dehydration and the coagulation-fibrinolysis system is needed to guide decisions concerning prophylactic anticoagulation therapy. Better understanding of NS and its risks, as well as the necessity of drug therapy, may help teenagers to accept and cooperate with treatment.

C3 glomerulonephritis associated with a missense mutation in the factor H gene.

The complement system, the major component of the innate immune functions resisting microbial infection, includes the classical complement pathway, the alternate pathway, and the mannose-binding lectin pathway. All of these merge at the level of complement component (C) 3. Complement factor H (CFH), a soluble complement mediator in blood, regulates alternate pathway activation; a conformational change of C3 molecules by C3 convertases leads to an enzyme complex formation resulting in opsonization and cell lysis. Clinical manifestations arising from CFH gene (CFH) abnormalities include hemolytic uremic syndrome and membranoproliferative glomerulonephritis. We encountered a 24-year-old woman initially diagnosed with C3 glomerulonephritis associated with persistently low circulating C3. Definitive diagnosis of C3 glomerulonephritis was made from immunohistologic demonstration of isolated mesangial C3 deposits. The biopsy specimen showed moderately increased mesangial proliferation, without thickening of the glomerular capillary walls. Genetic analysis disclosed a homozygous CFH missense mutation, a G-to-T transversion at nucleotide 3,048 in exon 18, resulting in substitution of Asp for Glu at position 936. A low serum CFH concentration (110 µg/mL) might reflect the consequences of this CFH mutation. C3 glomerulonephritis is associated with a CFH mutation, the mutation of which results in the unexpected activation of alternate pathway complement with clinical laboratory fluctuations, such as varying reduction of serum CFH and C3. The finding of a patient with a CFH mutation associated with C3 glomerulonephritis represents an opportunity to expand the phenotypic spectrum of the CFH mutations.

[A new attempt to promote home medical care in Kashiwa city-usefulness of information and communication technology with seamless multidisciplinary cooperation].

Due to the rapidly increasing super-aging society, medical policy in Japan should be redefined. Therefore, the medical and nursing home care system should now be revised greatly. We need to change the current principle that is based on cure only. The patients should receive hospitable care closely connected with their life in their home-town(region)throughout their lifetime. This is termed as "home medical care system". Here, we promote patient-centered medical home care, which implements the chronic and/or End-Of-Life care models, in Kashiwa city, Chiba prefecture. This system is a promising framework for primary care transformation. There is a need for a multidisciplinary team-based care system using information and communication technology(ICT)with smooth and seamless cooperation. However, increased awareness among the workers engaged in home medical care is first required.

[Development of a home care educational program for community physicians and other professionals-a trial in Kashiwa City].

From May to October 2011, we conducted an 8-day homecare educational program for physicians, dentists, pharmacists, visiting nurses, long-term care managers, and hospital staff in Kashiwa city, Chiba, which was primarily intended to increase home visits by physicians. The characteristics of the program were as follows: 1) active and busy community physician participation, 2) attendance of practical training by physicians, 3) interprofessional discussion, 4) recruitment of participants from the same city, 5) recommendation of participant recruitment by a community-level professional association such as Kashiwa City Medical Association. By comparison of the pre- and post-program questionnaires completed by participants, the motivation for homecare practice, knowledge about homecare, and interactions with other professionals have increased. We will further standardize and generalize this program in order to contribute to homecare promotion in Japan.

Renal tubular dysgenesis and tubulointerstitial nephritis antigen in juvenile nephronophthisis.

AIM: The relationship between abnormalities of tubular architecture and tubulointerstitial nephritis antigen (TIN-ag) in juvenile nephronophthisis (J-NPH) was evaluated. METHODS: Sixteen J-NPH patients were examined. Nephrocystin-1, TIN-ag, type IV collagen, Fas antigen and the C5b-9 complement complex were stained by immunohistochemical methods. RESULTS: Renal tubules of patients with J-NPH showed morphological abnormalities of tubular basement membranes (TBM) and frequent apoptosis of tubular epithelial cells. Additionally, the C5b-9 complement complex was deposited within the TBM in the absence of immunoglobulin deposition, suggesting complement-dependent TBM injury. Localization of TIN-ag in the TBM of J-NPH patients disclosed a partial defect or discontinuity in 14 of the 16 patients, while type IV collagen immunoreactivity was relatively preserved. These findings suggest that tubulogenesis is disturbed during nephronogenesis in J-NPH patients because of a defect in nephrocystin, an NPHP gene product. TBM defects induce further morphological abnormalities such as cystic dilation of tubules; as tubular function impairment advances, the incomplete tubules may be injured by C5b-9 complement complexes, followed by apoptotic cell death. CONCLUSION: TIN-ag, which is important in early nephrogenesis, lacks normal activity, and vulnerable and incomplete tubules with deficient TIN-ag expression are formed. Removal of these defective tubules by apoptosis combined with the C5b-9 complement complex could be the primary reason for progression to end-stage renal disease in J-NPH patients.

Pathogenesis of focal segmental glomerular sclerosis in a girl with the partial deletion of chromosome 6p.

Focal segmental glomerular sclerosis (FSGS) is a leading cause of the nephrotic syndrome and characterized by the sclerosing lesions that affect one or more segments of some glomeruli. We encountered a female patient with a partial deletion of chromosome 6p, who presented proteinuria at age 3 years. Detailed chromosomal analysis disclosed an interstitial deletion of 6p: del(6)(p22.1p22.3). No abnormality such as hydronephrosis or renal agenesis was disclosed by imaging, but FSGS was present in a renal biopsy specimen. The patient is currently 11 years old and shows mental retardation with mild deterioration in the renal function. To address the defective genes in the present patient, we carried out comparative genomic hybridization (CGH), showing that E2F3 on chromosome 6p is absent in this patient. E2F3, a member of the E2F family transcription factors, inhibits expression of vascular endothelial growth factor (VEGF) and induces apoptosis during vascular development. The deletion of E2F3 was also detected by employing a PCR method, suggesting that glomerular architecture had been compromised in this patient. Serum VEGF concentrations were elevated to 177 ± 21.4 pg/mL (upper limit of 33.3 pg/mL), when she was 6 years old, associated with the enhanced expression of VEGF in glomeruli. These findings suggest that the dysregulation of VEGF synthesis caused by the deletion of E2F3 may be associated with development of FSGS. In conclusion, among patients with idiopathic FSGS, an abnormality of E2F3 may exist on chromosome 6p. Therefore, one might consider chromosomal analyses in children with FSGS who have mental retardation.

[Home medical care center project for an aging society].

We have to create a new paradigm for home medical care system towards a historical increase of elderly population in Japan. Tokyo University and Chiba University have been collaborating to erect a home medical care support center in Kashiwa, Chiba prefecture. We have been constructing a support center as well as a home care doctor system, and also created a teaching course for GPs to learn a home care doctor activity. We have also been constructing a regional network system called IT Net in Chiba, which connects all the entire medical and care staff. We will expand this model in many places and to instruct medical students and residents there in the near future.