Concomitant pyoderma gangrenosum and erythema nodosum in a patient with ulcerative colitis / Pioderma gangrenoso concomitante y eritema nudoso en paciente con colitis ulcerosa

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IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer.

BACKGROUND: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. METHODS: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed. RESULTS: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01). CONCLUSIONS: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

Arthroscopy of the distal radioulnar joint.

Wrist arthroscopy is now widely indicated for diagnosis and treatment of acute or chronic wrist pain, especially for triangular fibrocartilage complex (TFCC) lesions, as a gold standard. In most cases radiocarpal and midcarpal arthroscopy was performed, while DRUJ arthroscopy has been rarely performed because of its difficulties. Recent anatomic and biomechanical studies demonstrated that the radioulnar ligament (RUL), which is the proximal component of the TFCC facing to the DRUJ, is the primary stabilizer of the distal radioulnar joint (DRUJ). Rupture of the radioulnar ligament (RUL) at the fovea area, where it is the main attaching portion to the ulna and is the isometric point during forearm rotation as the rotation axis passes, is responsible for DRUJ instability. Although physical examination and imaging diagnosis may indicate a foveal detachment of the TFCC, DRUJ arthroscopy is potential for visualizing the RUL at the fovea. Role of DRUJ arthroscopy should be more important not only for diagnosis of rupture of the RUL but also for decision making of treatment option for RUL tear. DRUJ arthroscopy also demonstrates the joint surface of both the sigmoid notch and ulnar head, and the proximal surface of the TFCC.

An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530).

The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.

Caffeine and uric acid mediate glutathione synthesis for neuroprotection.

Several lines of epidemiological studies have indicated that caffeine consumption and plasma uric acid (UA) level were negatively correlated with the incidence of some neurodegenerative diseases. We report here a novel mechanism by which these purine derivatives increase neuronal glutathione (GSH) synthesis. Intraperitoneal injection of caffeine or UA into male C57BL/6 mice significantly increased total GSH levels in the hippocampus. Neither SCH58261, an adenosine A2A receptor antagonist, nor rolipram, a phosphodiesterase-4 inhibitor, increased GSH levels. Pretreatment with allopurinol, a drug to inhibit UA production, did not change the GSH level in the caffeine-treated mice. Hippocampal CA1 pyramidal neurons treated with caffeine or UA were resistant to oxidant exposure in the slice culture experiments. In experiments with the SH-SY5Y cell line, cysteine uptake was sodium-dependent and pretreatment with caffeine or UA increased cysteine uptake significantly as compared with the control conditions. Slice culture experiments using the hippocampus also showed increased cysteine and GSH contents after the treatment with caffeine or UA. Immunohistochemical analysis showed increased GSH levels in the hippocampal excitatory amino acid carrier-1 (EAAC1)-positive neurons of mice treated with caffeine or UA. These findings suggest that purine derivatives caffeine and UA induce neuronal GSH synthesis by promoting cysteine uptake, leading to neuroprotection.

Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes.

Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1beta (HNF-1beta) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1beta and VCAN in OCCC cell lines. This genome-wide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes.

MHC class I and II expression in juvenile dermatomyositis skeletal muscle.

OBJECTIVE: To assess MHC I and II expressions in muscle fibres of juvenile dermatomyositis (JDM) and compare with the expression in polymyositis (PM), dermatomyositis (DM) and dystrophy. PATIENTS AND METHODS: Forty-eight JDM patients and 17 controls (8 PM, 5 DM and 4 dystrophy) were studied. The mean age at disease onset was 7.1+/-3.0 years and the mean duration of weakness before biopsy was 9.4+/-12.9 months. Routinehistochemistry and immunohistochemistry (StreptABComplex/HRP) for MHC I and II (Dakopatts) were performed on serial frozen muscle sections in all patients. Mann-Whitney, Kruskal Wallis, chi-square and Fisher's exact statistical methods were used. RESULTS: MHC I expression was positive in 47 (97.9%) JDM cases. This expression was observed independent of time of disease, corticotherapy previous to muscle biopsy and to the grading of inflammation observed in clinical, laboratorial and histological parameters. The expression of MHC I was similar on JDM, PM and DM, and lower in dystrophy. On the other hand, MHC II expression was positive in just 28.2% of JDM cases and was correlated to histological features as inflammatory infiltrate, increased connective tissue and VAS for global degree of abnormality (p<0.05). MHC II expression was similar in DM/PM and lower in JDM and dystrophy, and it was based on the frequency of positive staining rather than to the degree of the MCH II expression. CONCLUSIONS: MHC I expression in muscle fibres is a premature and late marker of JDM patient independent to corticotherapy, and MHC II expression was lower in JDM than in PM and DM.

Anchorage-independent cell growth signature identifies tumors with metastatic potential.

The oncogenic phenotype is complex, resulting from the accumulation of multiple somatic mutations that lead to the deregulation of growth regulatory and cell fate controlling activities and pathways. The ability to dissect this complexity, so as to reveal discrete aspects of the biology underlying the oncogenic phenotype, is critical to understanding the various mechanisms of disease as well as to reveal opportunities for novel therapeutic strategies. Previous work has characterized the process of anchorage-independent growth of cancer cells in vitro as a key aspect of the tumor phenotype, particularly with respect to metastatic potential. Nevertheless, it remains a major challenge to translate these cell biology findings into the context of human tumors. We previously used DNA microarray assays to develop expression signatures, which have the capacity to identify subtle distinctions in biological states and can be used to connect in vitro and in vivo states. Here we describe the development of a signature of anchorage-independent growth, show that the signature exhibits characteristics of deregulated mitochondrial function and then demonstrate that the signature identifies human tumors with the potential for metastasis.

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells.

The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133- daughter cells, whereas CD133- cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133- progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133- ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133- progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

Increased cyclooxygenase-2 expression is correlated with suppressed antitumor immunity in cervical adenocarcinomas.

Cyclooxygenase-2 (COX-2) inhibition suppressed the growth of various tumors. The augmentation of antitumor immunity by increasing cytotoxic lymphocytes may be an important mechanism for COX-2 inhibition. Among cervical cancers, adenocarcinomas present more aggressive behavior and overexpressed COX-2. The expression of COX-2 and the CD8+ lymphocyte infiltrations were evaluated in this study by immunohistochemistry. We studied COX-2 expression and CD8+ lymphocyte infiltration in 55 women with cervical adenocarcinomas. COX-2 expression and tumor stromal CD8+ lymphocytes were evaluated by semiquantified methods. Tumor intraepithelial lymphocytes were counted under microscopic field of x200. Correlations between these data and other clinicopathologic features were investigated. Thirty-seven out of 55 (67.3%) cervical adenocarcinomas significantly expressed COX-2. Patients who died within 5 years showed higher percentage of COX-2 expression than survivors (100% vs 58.1%, P < 0.05). Victims also showed lesser intraepithelial CD8+ lymphocyte counts than survived patients (3.4 vs 26.4, P < 0.05). COX-2 expression and tumor intraepithelial lymphocyte count were reversely correlated with each other (correlation index: -0.38, P < 0.01). Up-regulated COX-2 expression and lesser tumor intraepithelial CD8+ lymphocyte count are poor prognostic indicators for cervical adenocarcinoma patients. COX-2 may play an important role in the suppression of host antitumor immunity in cervical adenocarcinomas.

Impact of neuronavigation and image-guided extensive resection for adult patients with supratentorial malignant astrocytomas: a single-institution retrospective study.

Neuronavigation has become an effective therapeutic modality and is used routinely for intra-axial tumor removal. This retrospective study was conducted to evaluate the clinical impact of neuronavigation and image-guided extensive resection for adult patients with supratentorial malignant astrocytomas. Between 1990 and 2002, 76 adult patients with pathologically confirmed malignant astrocytomas underwent craniotomy and removal of the tumors at the Toyama Medical and Pharmaceutical University Hospital. Of these 76 patients, 42 were treated using neuronavigation with conventional microneurosurgery and the other 34 were treated with conventional microneurosurgery alone. Postoperative early MRI with contrast enhancement was done, and gross total resection was defined as the complete absence of residual tumor. Survival time was analyzed with the Kaplan-Meier method. Prognostic factors were obtained from the Cox proportional hazards model. In univariate analysis, age (< 65), grade 3, preoperative KPS (>/= 80), use of neuronavigation, and gross total resection were significantly associated with longer survival. However, when the data were submitted to multivariate analysis, grade 3, preoperative KPS (>/= 80), and gross total resection were independent prognostic factors. The median survival periods of patients receiving gross total resection (vs. partial resection) and neuronavigation (vs. no neuronavigation) were 16 (vs. 9) months and 16 (vs. 10) months, respectively. The percentage of a gross total resection was significantly higher in the neuronavigation group compared to that in the no-navigation group (64.3 % vs. 38.2 %, p < 0.05). Neurological deterioration occurred in 4 of 42 (9.5 %) and in 6 of 34 (17.6 %) patients after surgery with neuronavigation and surgery without neuronavigation, respectively, although this difference was not statistically significant. Our results showed that neuronavigation increases the radicality in the resection of malignant astrocytomas and is objectively useful for improving survival time.

Regulation of Chk2 gene expression in lymphoid malignancies: involvement of epigenetic mechanisms in Hodgkin's lymphoma cell lines.

The tumor suppressor Chk2 kinase plays crucial roles in regulating cell-cycle checkpoints and apoptosis following DNA damage. We investigated the expression levels of the genes encoding Chk2 and several cell-cycle regulators in nine cell lines from lymphoid malignancies, including three Hodgkin's lymphoma (HL) lines. We found that all HL cell lines exhibited a drastic reduction in Chk2 expression without any apparent mutation of the Chk2 gene. However, expression of Chk2 in HL cells was restored following treatment with the histone deacetylase inhibitors trichostatin A (TsA) and sodium butyrate (SB), or with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC). Chromatin-immunoprecipitation (Chip) assays revealed that treatment of HL cells with TsA, SB or 5Aza-dC resulted in increased levels of acetylated histones H3 and H4, and decreased levels of dimethylated H3 lysine 9 at the Chk2 promoter. These results indicate that expression of the Chk2 gene is downregulated in HL cells via epigenetic mechanisms.

Livaditis' circular myotomy does not decrease anastomotic leak rates and induces deleterious changes in anastomotic healing.

Considering that Livaditis' myotomy is still accepted as a good method for lengthening the esophagus to allow primary repair of long-gap esophageal atresia, the aim of this experimental study was to verify if this procedure decreases the incidence of leaks in anastomoses performed under severe tension. In addition, it was verified whether the myotomy promotes any morphological or biochemical change in the healing esophageal anastomosis. Sixty small dogs were submitted to a cervicotomy and resection of an esophageal segment (8.0 - 10.0 cm) resulting in an anastomosis under severe tension. The animals were divided into two groups (control group: only anastomosis; experimental group: anastomosis plus circular myotomy in the proximal esophageal segment). The animals were sacrificed on the 14th postoperative day, submitted to autopsy, and were evaluated as to the presence of leaks. Twelve scars of each group were collected for histological, histomorphometric (evaluation of scar thickness), electrophoretic and immunoblotting studies of collagen (total collagen and types of collagen determinations). Leak rates were the same in both groups. Histologic examination showed that the scar at the anastomosis was formed by fibrous tissue, without mucosa or muscular tissue. In the myotomy animals, a decreased number of newly formed small vessels was noted in comparison to control animals, and morphometric analysis showed that in the myotomy animals the anastomotic scar was thinner than in the control animals. Biochemical analysis of scars demonstrated that myotomy promoted a decrease in the soluble collagen content in comparison with the control animals and no alteration in the content of insoluble collagen. The electrophoretic separation of the types of collagen and characterization by immunoblotting demonstrated the presence of collagen types I, III, and V, and the quantification by densitometry of the bands showed a reduction in collagen type V (present in the blood vessels) in the myotomy animals in comparison to controls. This result is in accordance with the histological observation of a decrease in newly formed blood vessels. Circular myotomy does not decrease the possibility of anastomotic leaks, in addition to promoting deleterious changes in anastomotic healing.

Asymptomatic pyuria in diabetic women.

The aim of the present study was to determine the prevalence of and the host factors for asymptomatic pyuria (ASP) in women with type 2 diabetes. The study included 179 type 2 diabetic women and consecutive 455 non-diabetic women attending as out-patients in 1996. Patients with symptoms of a urinary tract infection were excluded. ASP was defined as the presence of more than 10 leukocytes/high-power field in a random urine sample. Diabetic women more often had ASP than non-diabetic women (27.9 vs. 15.8%, P<0.001). The prevalence of ASP was significantly increased in patients with a duration of diabetes exceeding 15 years (0 approximately 4 years; 20.3%, 5 approximately 9 years; 24.3%, 10 approximately 14 years; 23.8%, and > or =15 years; 46.3%). No differences were evident in HbA(1C) between diabetic patients without ASP and those with ASP. Diabetic women with ASP more often had diabetic retinopathy, neuropathy, nephropathy, cerebrovascular disease, ischemic heart disease, and hyperlipidemia than those without ASP. However, no statistically significant differences were evident in the prevalence of hypertension, constipation, or dementia. As the degree of neuropathy increases, it is accompanied by an increasing prevalence of ASP (none, 21.4%; blunt tendon reflexes, 24.5%; symptomatic, 50.0%; and gangrene, 66.6%). The prevalence of ASP was significantly increased in the patients with proliferative diabetic retinopathy (none, 23.2%; background, 29.4%; pre-proliferative, 18.2%; and proliferative, 50.0%). As the degree of nephropathy increases, it is accompanied by an increasing prevalence of ASP (none, 20.0%; microalbuminuria, 31.9%; macroalbuminuria, 37.0%; and renal failure, 60.0%). Thus, the prevalence of ASP is increased in women with diabetes and increased with longer duration of diabetes but was not affected by glucose control. The incidence of ASP increases significantly as diabetic microangiopathy becomes severer.

Right sylvian fissure subarachnoid hemorrhage has electrocardiographic consequences.

BACKGROUND AND PURPOSE: Abnormal ECG changes are frequently observed in patients with subarachnoid hemorrhage (SAH). Recently, evidence has been obtained that right insular cortex mediates sympathetic cardiovascular effects. We therefore assessed the laterality and location of SAH dominance in inducing cardiovascular changes as measured by ECG, blood pressure, and heart rate. METHODS: After exclusion of 11 SAH patients who died within 1 month after onset, we studied 118 consecutive patients. Data were obtained from records of blood pressure and pulse on admission. Abnormal ECG changes were determined from ECGs on admission and almost 1 month later. From brain CT scans performed immediately after admission, the amount of SAH in each of the 8 cisterns and fissures was measured semiquantitatively. RESULTS: Twenty-six patients had abnormal changes on admission ECG, while 92 patients did not. Systolic blood pressure, diastolic blood pressure, and the amounts of blood in the left ambient cistern, left suprasellar cistern, quadrigeminal cistern, right ambient cistern, right suprasellar cistern, right sylvian fissure, and the set of all cisterns were significantly greater in the group with ECG change than in the group without ECG change. Multivariate logistic regression analysis with stepwise method indicated that systolic blood pressure >160 mm Hg (P=0.0006) and the amounts of SAH in the quadrigeminal cistern (P=0.022) and right sylvian fissure (P=0.0019) were independently associated with abnormal ECG change. CONCLUSIONS: Cardiac consequences are possible in patients with massive right sylvian fissure SAH or when systolic blood pressure is >160 mm Hg.

Helicobacter pylori infection and the development of gastric cancer.

BACKGROUND: Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain. METHODS: We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests. RESULTS: Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers. CONCLUSIONS: Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.

[A four-year prospective study on the influence of serum elevated lipoprotein (a) concentration on ischemic heart disease and cerebral infarction in elderly patients with type 2 diabetes].

To clarify the influence of elevated serum lipoprotein (a) (Lp(a)) concentration on ischemic heart disease (IHD) and the perforating artery occlusion type of cerebral infarction (CI) in elderly patients with type 2 diabetes, we measured the serum levels of Lp(a) of type 2 diabetic patients (n = 158, 81 men and 77 women). The group was followed up prospectively for 4 years and the incidence of IHD or CI was monitored. The diagnosis of CI was confirmed by computed tomography and that of IHD, which includes myocardial infarction and angina pectoris, was diagnosed by electrocardiogram and blood chemistry examination, Lp(a) concentrations of 20 mg/dl or more were identified as elevated Lp(a) levels and Lp(a) concentrations of less than 20 mg/dl were identified as normal Lp(a) levels. A Kaplan-Meier survival analysis (log-rank test) assessed the time to event rate stratified by an Lp(a) cutoff point of 20 mg/dl. The predictive value for CI or IHD events was assessed by multiple logistic regression analysis. The probability of IHD events was significantly higher in the elevated Lp(a) group than in the normal Lp(a) group without a history of IHD but was similar in the two groups for those patients with a history of IHD. There was no significant difference between the elevated Lp(a) group and the normal Lp(a) group with regard to CI events in patients without a history of CI and with a history of CI. On multiple logistic regression analysis, Lp(a), hyperlipidemia and a history of IHD were significant predictors of IHD and hypertension, hyperlipidemia and a history of CI were significant predictors of CI. These results show that elevated serum Lp(a) concentrations is an independent risk factor for IHD, but not for the perforating artery occlusion type of CI in type 2 elderly diabetic patients.