Removal of Subfoveal Massive Hard Exudates through an Intentional Macular Hole in Patients with Diabetic Maculopathy: A Report of Three Cases.

Recently, good postoperative visual acuity has been reported using surgical removal of hard exudates (HEs) through an intentional macular hole (iMH). We report 3 cases of subfoveal HE secondary to diabetic maculopathy (DM) treated with HE removal via an iMH. Pars plana vitrectomy (PPV) was performed in three eyes of 3 patients with subfoveal HE secondary to DM. In all eyes, after PPV, internal limiting membrane (ILM) peeling of the lower half was performed within the range of papilla diameter 2 centered on the fovea, leaving the upper half for subsequent inverted ILM flap technique. Then, by grabbing the inner layer of the fovea using ILM forceps, an iMH was created. The HE was then flushed from the iMH with a balanced salt solution as much as possible. Finally, the inverted ILM flap technique was performed using the upper half of the ILM that was left during the previous maneuver. At the end of the surgery, the eyes were flushed with 50 mL of 20% sulfur hexafluoride (SF6) after the fluid-air exchange of the vitreous cavity. After surgery, HE was adequately removed, iMH was completely closed, and visual acuity improved in all eyes. This surgical procedure did not cause a central scotoma but rather improved the central sensitivity of the visual field in all eyes. No serious surgery-related complications occurred. In conclusion, HE removal via an iMH hole can be one of the treatment options for patients with subfoveal HE secondary to DM.

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66 years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

[Atezolizumab-induced Guillain-Barré syndrome-like acute demyelinating polyneuropathy responsive to steroid therapy: a case report].

A 76-year-old man, who received atezolizumab for the treatment for small cell lung cancer, acutely developed limb weakness with sensory disturbance after the third course of the treatment. Nerve conduction studies were consistent with demyelinating polyneuropathy and acute demyelinating polyneuropathy caused by atezolizumab was suggested. Atezolizumab was immediately withdrawn, and intravenous immunoglobulin (IVIg) and methylprednisolone pulse therapies with subsequent oral administration of prednisolone were initiated, after which neurological deficits steadily improved. Although Guillain-Barré syndrome-like neuropathy caused by immune checkpoint inhibitor (ICI) was occasionally reported, this is the first case of acute demyelinating polyneuropathy triggered by atezolizumab, monoclonal antibody targeting programmed death-ligand 1. This case suggests that combined treatments with IVIg and corticosteroids are effective for neuropathy induced by atezolizumab as same as those by other ICI.

[A 81-year old man of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody-positive myopathy associated with lung adenocarcinoma cancer].

An 81-year-old man, who had no history of taking statins, developed progressive muscle weakness of the limbs and dysphagia. Laboratory tests showed a high level of CK and positivity for serum 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Tests for other autoantibodies to ARS and SRP were negative. A pathological analysis of the left biceps muscle revealed numerous necrotic and regenerated fibers with macrophage infiltration and deposition of C5b-9 complement in and around the myofibers. Chest CT showed a nodular shadow, which was suspected to be lung cancer, in the upper left lobe. A pathological analysis of a transbronchial lung biopsy specimen revealed lung adenocarcinoma with high level of HMGCR. He was diagnosed with HMGCR necrotizing myopathy associated with lung cancer, and both his muscle strength and dysphagia improved after three treatments with intravenous immunoglobulin (IVIg). He did not undergo surgery or radiation therapy because of interstitial pneumonia. This case suggests that a paraneoplastic mechanism caused the production of HMGCR antibodies, leading to myositis in this patient. Treatment with IVIg can be effective for patients with HMGCR antibody-positive paraneoplastic necrotizing myopathy that is refractory to corticosteroid therapy.

Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis.

INTRODUCTION: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. METHODS: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. RESULTS: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-µm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. CONCLUSIONS: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.

Autologous Transplantation of the Internal Limiting Membrane for Refractory Macular Hole following Ruptured Retinal Arterial Macroaneurysm: A Case Report.

PURPOSE: To report a case of macular hole (MH) secondary to a retinal arterial macroaneurysm (RAMA) which was successfully treated with an autologous transplantation of internal limiting membrane (ILM). CASE REPORT: An 87-year-old female presented with a sudden decrease in central vision in the right eye. A fundus examination revealed a RAMA in the superonasal macular region, a subretinal hemorrhage (SRH), involving the macula, and a sub-ILM hemorrhage. A pars plana vitrectomy (PPV) was performed. Intraoperatively, an MH filled with coagulum was detected. We tried to blow off and drain the SRH with a current of BSS and a gentle suction with a 27-gauge vitreous cutter from the MH, but some amount of SRH at the bottom of the MH remained. The ILM was peeled off for 2 disc diameters around the MH. The vitreous cavity was filled with air at the end of the operation. Two weeks after the surgery, the MH was not closed. One month following the initial PPV, a second PPV was performed to achieve closure of the MH. RESULTS: An autologous transplantation of ILM was performed as second PPV. Six months after the final surgery, the MH was successfully closed and the best-corrected decimal visual acuity was 0.6. CONCLUSIONS: Autologous ILM transplantation can be an effective treatment option for MH closure following RAMA rupture.

Comparison of cystatin C- and creatinine-based estimated glomerular filtration rate to predict coronary heart disease risk in Japanese patients with obesity and diabetes.

The aim of this study is to determine which indicator of chronic kidney disease most closely correlates with 10-year Framingham coronary heart disease (CHD) risk among serum creatinine, serum cystatin C (S-CysC), urine albumin-creatinine ratio (UACR), estimated creatinine-based GFRs (eGFRcre), and estimated CysC-based GFRs (eGFRcys) in patients with obesity and diabetes. Serum creatinine, S-CysC, UACR, and cardio-ankle vascular index (CAVI) were examined in 468 outpatients with obesity and type 2 diabetes, free of severe renal dysfunction or previous history of cardiovascular disease, as a cross-sectional survey using baseline data from the multi-centered Japan Diabetes and Obesity Study. S-CysC and eGFRcys had significantly stronger correlations with the 10-year Framingham CHD risk than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.318; S-CysC, ρ = 0.497; UACR, ρ = 0.174; eGFRcre, ρ = -0.291; eGFRcys, ρ = -0.521; P < 0.01 by Fisher's z-test). S-CysC and eGFRcys had significantly stronger correlations with CAVI than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.198; S-CysC, ρ = 0.383; UACR, ρ = 0.183; eGFRcre, ρ = -0.302; eGFRcys, ρ = -0.444; P < 0.05 by Fisher's z-test). The receiver operating characteristic curves to distinguish the high-risk patients for CHD revealed significantly larger areas under the curve of S-CysC and eGFRcys than those of serum creatinine, UACR, and eGFRcre (serum creatinine, 0.64; S-CysC, 0.75; UACR, 0.56; eGFRcre, 0.63; eGFRcys, 0.76; P < 0.01). The data suggested that eGFRcys can be more predictive of the 10-year CHD risk than eGFRcre in Japanese patients with obesity and diabetes.

NMO sera down-regulate AQP4 in human astrocyte and induce cytotoxicity independent of complement.

Autoantibodies against astrocyte water channel aquaporin-4 (AQP4) are highly specific for neuromyelitis optica (NMO). However, the molecular mechanism of NMO still remains unclear. The purpose of this study was to identify the possible humoral mechanisms responsible for the occurrence of astrocytic damage. Human primary astrocytes (AST) were immortalized by retroviral vectors harboring temperature-sensitive SV40 T antigen gene and AQP4 cDNA (M23), designated as hAST-AQP4. The effects of NMO sera on the content and localization of AQP4, including cytotoxicity and astrocytic morphology, were evaluated. In addition, this study examined whether the amount and localization of AQP4 protein in astrocytes were influenced by direct contact with the immortalized human brain microvascular endothelial cell line, TY09. NMO sera alone induced cytotoxicity and addition of complement had a more harmful effect on hAST-AQP4. NMO sera also decreased AQP4 mRNA and protein. NMO sera alone up-regulated TNFα and IL-6 in astrocytes and co-incubation with anti-TNFα and anti-IL-6 neutralizing antibodies blocked both the cytotoxicity and reduction of AQP4 in astrocytes. In the experiment using the in vitro BBB models, AQP4 protein mainly localized at the astrocytic membrane after co-culture with TY09, in contact with TY09. The future elucidation of factors that up-regulate AQP4 in astrocytes presumably released by blood brain barrier forming endothelial cells and that block the production of inflammatory cytokines may therefore lead to the development of a novel therapeutic strategy.

Remnant-like particle cholesterol and serum amyloid A-low-density lipoprotein levels in obese subjects with metabolic syndrome.

BACKGROUND: Although the circulating levels of remnant-like particle cholesterol (RLP-C) or serum amyloid A-low-density lipoprotein (SAA-LDL) can individually be increased in subjects with metabolic syndrome (MetS), the correlation between the two markers has not yet been previously studied. In the present study, we aimed to investigate the correlation between RLP-C and SAA-LDL in obese subjects with MetS in comparison to those without MetS. METHODS: A total of 436 obese subjects were divided into groups with MetS and without MetS (male/female 75/143, mean age 49 years, current smokers 16% in both groups) by applying the age-, gender-, and smoking habit-matching method based on the database in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The data, including RLP-C and SAA-LDL, were compared in each group. RESULTS: Significantly greater levels of RLP-C or SAA-LDL were observed in subjects with MetS in comparison with those without MetS. There was a significantly positive correlation between RLP-C and SAA-LDL, with a relatively greater correlation in subjects with MetS (coefficient = 0.290, P < .01) in comparison with those without MetS (coefficient = 0.181, P < .01). Multivariate-adjusted correlation analyses showed a greater correlation between RLP-C and SAA-LDL in subjects with MetS, relative to those without MetS, although the significant correlation decreased in both groups when the hypertriglyceridemic states were taken into account. CONCLUSIONS: A relatively greater and positive correlation between greater levels of RLP-C and SAA-LDL in obese subjects with MetS, in comparison with those without MetS, may be linked to the development of MetS-related cardiovascular disease.

Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome.

BACKGROUND AND OBJECTIVES: Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study. RESULTS: UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P<0.05). Interestingly, diet- and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P<0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. CONCLUSIONS: This study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that U-CysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

Prevalence of albuminuria and renal insufficiency and associated clinical factors in type 2 diabetes: the Japan Diabetes Clinical Data Management study (JDDM15).

BACKGROUND: Microalbuminuria is widely accepted as the first clinical sign of diabetic nephropathy. However, normoalbuminuric type 2 diabetic patients who have renal insufficiency (RI), i.e. low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), exist. We explored the prevalence of such patients and associated clinical factors. METHODS: We investigated the distribution of patients when stratified by albuminuria stages and chronic kidney disease (CKD) stages in a large-scale population of Japanese type 2 diabetic patients (N = 3297), and the common and independent factors for albuminuria and low eGFR. RESULTS: The proportion of subjects with low eGFR was 15.3% (506/3297), which was 11.4% among those with normoalbuminuria (NA) (262/2298), 14.9% among those with microalbuminuria (105/705) and 47.3% among those with macroalbuminuria (139/294). There were 262 patients with NA and low eGFR, and 63.4% of them had neither diabetic retinopathy nor neuropathy. They were older and included a higher proportion of women and patients with hypertension, hyperlipidaemia and cardiovascular disease (CVD), and fewer smokers compared with those with NA and preserved eGFR. Multiple logistic regression analysis revealed that factors commonly associated with RI and albuminuria were hypertension, CVD and proliferative retinopathy. Factors independently associated with RI were age, duration of diabetes, A1C (negative), hyperlipidaemia, smoking (negative) and macroalbuminuria, whereas those associated with albuminuria were male sex, BMI, A1C, simple retinopathy and RI. CONCLUSIONS: A significant proportion of type 2 diabetic patients have normoalbuminuric RI. Renal disease in type 2 diabetes could be heterogeneous, implying the possibility of involvement of renal atherosclerosis and lipid toxicity.

Edutainment tools for initial education of type-1 diabetes mellitus: initial diabetes education with fun.

PURPOSE: Appropriate initial education for type-1 diabetes mellitus patients is important to prevent late complications. However, type-1 diabetic children have not appreciated traditional learning methods since they rarely contain the elements of fun and interactivity. In this study, we developed, implemented and evaluated a preliminary version of edutainment tools for initial education for type-1 diabetic children. METHODS: Three games running on either personal computer (PC) and GameBoy Advance were developed. All games were designed to educate patients about relationships among food (carbohydrate), plasma glucose level, exercise, and insulin dose. A total of 58 testers evaluated degree of entertainment, usability and clinical usefulness of the games. RESULTS: Generally, testers felt all games were intuitive and fun and the usability of games was highly scored. More than 90% of testers showed an interest in the edutainment approach, and approximately 60% agreed that these games could provide attractive educational environment compared to traditional education, especially for children. CONCLUSIONS: Our edutainment systems were accepted as attractive learning tools for type-1 diabetic children who need initial education.