Cognitive disorder and dementia in type 2 diabetes mellitus

Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer’s disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.     

三种供体阴茎灌注方法的特点比较

目的:比较供体阴茎腹主动脉灌注、髂总动脉灌注和髂内动脉灌注法的临床观察指标,试图寻找最佳的尸体阴茎灌注方法。方法:广州军区广州总医院于2004-03/2005-09采用腹主动脉灌注法、髂总动脉灌注法和髂内动脉灌注法取得供体阴茎各15例,共获取供体阴茎45个。①腹主动脉灌注法:于腹主动脉分叉上方6cm处做切口,切口近端插管灌注肝、肾,切口远端套入一粗线,插入20F气囊导尿管,深约5cm。②髂总动脉灌注法:分别于腹主动脉与髂总分叉处套入一粗线,上提粗线,剪开髂总动脉前壁,插入自制12F硅胶管,深约4cm。③髂内动脉灌注法:分别于髂总动脉与髂内动脉分叉处套入一粗线,上提粗线,剪开髂内动脉前壁,插入自制10F硅胶管,深约3cm。分析45例供体阴茎灌注临床资料,比较3种灌注方法切取供体阴茎的手术时间、热缺血时间、灌注液用量和灌注不良率。结果:①手术时间方面,腹主动脉灌注法短于髂总动脉灌注法[(3.28±1.02,4.96±1.84)min(P<0.05)],髂总动脉灌注法短于髂内动脉灌注法(6.02±2.25)min(P<0.05)。②热缺血时间方面,腹主动脉灌注法热缺血时间短于髂总动脉灌注法[(1.08±0.85,3.08±1.12)min(P<0.05)],髂总动脉灌注法热缺血时间短于髂内动脉灌注法(4.14±1.81)min(P<0.05)。③灌注不良率方面,腹主动脉灌注法明显低于髂总动脉灌注法[0,10.25%(P<0.05)],髂总动脉灌注法低于髂内动脉灌注法(15.23%)(P<0.05)。④3组灌注方法的灌注液用量差异无显著性意义(P>0.05)。结论:腹主动脉灌注法切取供体阴茎操作简单,手术时间和热缺血时间均较短,灌注不良发生率低,优于髂总动脉和髂内动脉灌注法。     

Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation

We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.     

Enhanced in vivo homing of uncultured and selectively amplified cord blood CD34+ cells by cotransplantation with cord blood-derived unrestricted somatic stem cells

Mesenchymal stem cells have been implicated as playing an important role in stem cell engraftment. Recently, a new pluripotent population of umbilical cord blood (UCB) cells, unrestricted somatic stem cells (USSCs), with intrinsic and directable potential to develop into mesodermal, endodermal, and ectodermal fates, has been identified. In this study, we evaluated the capacity of ex vivo expanded USSCs to influence the homing of UCB-derived CD34(+) cells into the marrow and spleen of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. USSCs induced a significant enhancement of CD34(+) cell homing to both bone marrow and spleen (2.2 +/- 0.3- and 2.4 +/- 0.6-fold, respectively; p < .05), with a magnitude similar to that induced by USSCs that had been thawed prior to transplantation. The effect of USSCs was dose-dependent and detectable at USSC:CD34(+) ratios of 1:1 and above. Enhanced marrow homing by USSCs was unaltered by extensive culture passaging of the cells, as similar enhancement was observed for both early-passage (passage 5 [p5]) and late-passage (p10) USSCs. The homing effect of USSCs was also reflected in an increased proportion of NOD/SCID mice exhibiting significant human cell engraftment 6 weeks after transplantation, with a similar distribution of myeloid and lymphoid components. USSCs enhanced the homing of cellular products of ex vivo expanded UCB lineage-negative (lin(-)) cells, generated in 14-day cultures by Selective Amplification. The relative proportion of homing CD34(+) cells within the culture-expanded cell population was unaltered by USSC cotransplantation. Production of stromal-derived factor-1 (SDF-1) by USSCs was detected by both gene expression and protein released into culture media of these cells. Knockdown of SDF-1 production by USSCs using lentiviral-SiRNA led to a significant (p < .05) reduction in USSC-mediated enhancement of CD34(+) homing. Our findings thus suggest a clinical potential for using USSCs in facilitating homing and engraftment for cord blood transplant recipients.     

Changing epidemiology of invasive pneumococcal disease in central Australia prior to conjugate vaccine: a 16-year study

This study reports a 16-year prospective surveillance of invasive disease isolates in central Australian Aborigines. There were 621 (89.6% of total) isolates recovered from Aborigines. The mortality in children less than 5 years of age was 4% but rose to 34.5% in those over 49 years of age. The study documented continuing high rates of disease overall, but with significant reductions in incidence rates for children. In children under 2 years of age, the incidence fell by 32% from 2053 per 100,000 in the period 1985-1990 to 1184 per 100,000 in the period 1996-2000. Rates of disease in adults showed no reduction despite an adult immunisation programme with 23 valent vaccine which occurred in the 1990s. Epidemics of serotypes 1, 5 and 12F were documented during the study period.     

Acute depletion of plasma glutamine increases leucine oxidation in prednisone-treated humans

BACKGROUND, AIMS & METHODS: To determine whether depletion in plasma glutamine worsens the catabolic response to corticosteroids, seven healthy volunteers received oral prednisone for 6 days on two separate occasions, at least 2 weeks apart, and in random order. On the sixth day of each treatment course, they received 5 h intravenous infusions of L-[1-(14)C]-leucine and L-[1-(13)C]-glutamine in the postabsorptive state (1) under baseline conditions (prednisone only day) and (2) after 24h of treatment with phenylbutyrate (prednisone+phenylbutyrate day), a glutamine chelating agent. RESULTS: Phenylbutyrate treatment was associated with (1) an approximately 15% decline in plasma glutamine concentration (627+/-39 vs. 530+/-31 micromol l(-1); P<0.05), (2) no change in leucine appearance rate, an index of protein breakdown (124+/-9 vs. 128+/-9 micromol kg(-1) h(-1); NS) nor in non-oxidative leucine disposal, an index of whole body protein synthesis (94+/-9 vs. 91+/-7 micromol kg(-1) h(-1); NS), and (3) a approximately 25% rise in leucine oxidation (30+/-1 vs. 38+/-2 micromol kg(-1) h(-1), P<0.05), despite an approximately 25% decline (P<0.05) in leucine concentration. CONCLUSIONS: In a model of mild, stress-induced protein catabolism, depletion of plasma glutamine per se may worsen branched chain amino acid and protein wasting.     

Ultrasensitive flow-based immunoassays using single-molecule counting

BACKGROUND: Immunoassay (IA) technology has expanded the clinical utility of protein biomarkers, but demands for increased sensitivity, dynamic reporting ranges, and small sample volumes have limited the potential clinical usefulness of many biomarkers. We assessed the performance, including limits of detection (LODs) and the dynamic reporting range, of an IA-based technology, Erenna Immunoassay System, for a series of biomarkers, including cardiac troponin I (cTnI). METHODS: Erenna IAs were used with 10 different and clinically important biomarkers to ascertain the LOD with various sample sizes (10 microL to 200 microL). RESULTS: The Erenna Immunoassay System generated LODs of 10-100 pg/L using 100 microL of sample. For cTnI, the LOD was 0.2 ng/L and a 10% CV was seen between 0.78 and 1.6 ng/L. CONCLUSIONS: The Erenna IA-based technology reproducibly measures protein biomarkers with detection limits of 10-100 pg/L, with a dynamic range of >4.5 logs in sample volumes of 50-150 microL.     

Stress experienced by mothers of Malaysian children with mental retardation

OBJECTIVE: To compare parenting stress among Malaysian mothers of children with mental retardation and a control group, and to determine factors associated with stress. METHODOLOGY: Seventy-five mothers of children with mental retardation aged 4-12 years and 75 controls (those without disabilities who attended the walk-in paediatric clinic) participated in the Parenting Stress Index (PSI). Intelligence quotient (IQ) and Child Behaviour Checklist (CBCL) scores, together with sociodemographic data, were entered into a multiple stepwise regression analysis, using the PSI as the criterion. RESULTS: Mothers of children with mental retardation scored significantly higher than control subjects in both the child-related domain (difference between means 26.1, 95% confidence interval 19.6-32.5) and parent-related domain (difference between means 15.0, 95% confidence interval 7.9-22.1) of the PSI. The total child behaviour scores from the CBCL (P < 0.01), IQ scores (P < 0. 01) and sibship size (P < 0.01) were associated with child-related domain scores. For the parent-related domain, CBCL (P < 0.01) and IQ scores (P = 0.01) remained important factors but Chinese ethnicity (P < 0.01) and maternal unemployment (P < 0.01) were also significant predictors of stress. CONCLUSION: A large proportion of mothers of children with mental retardation experienced substantial parenting stress, especially Chinese and unemployed mothers, and this warrants appropriate intervention.     

BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast

BAG-1 (bcl-2-associated athanogene) enhances oestrogen receptor (ER) function and may influence outcome and response to endocrine therapy in breast cancer. We determined relationships between BAG-1 expression, molecular phenotype, response to tamoxifen therapy and outcome in a cohort of breast cancer patients and its influence on tamoxifen sensitivity in MCF-7 breast cancer cells in vitro. Publically available gene expression data sets were analysed to identify relationships between BAG-1 mRNA expression and patient outcome. BAG-1 protein expression was assessed using immunohistochemistry in 292 patients with invasive ductal carcinoma and correlated with clinicopathological variables, therapeutic response and disease outcome. BAG-1-overexpressing MCF-7 cells were treated with antioestrogens to assess its effects on cell proliferation. Gene expression data demonstrated a consistent association between high BAG-1 mRNA and improved survival. In ER+ cancer (n=189), a high nuclear BAG-1 expression independently predicted improved outcome for local recurrence (P=0.0464), distant metastases (P=0.0435), death from breast cancer (P=0.009, hazards ratio 0.29, 95% CI: 0.114–0.735) and improved outcome in tamoxifen-treated patients (n=107; P=0.0191). BAG-1 overexpression in MCF-7 cells augmented antioestrogen-induced growth arrest. A high BAG-1 expression predicts improved patient outcome in ER+ breast carcinoma. This may reflect both a better definition of the hormone-responsive phenotype and a concurrent increased sensitivity to tamoxifen.     

Multimodality therapy of an acquired factor V inhibitor

Acquired inhibitors of factor V are rare causes of clinical bleeding, whose severity ranges from mild to life-threatening. Optimal treatment of patients with factor V inhibitors is uncertain. We report on our successful treatment approach in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient deteriorated after initial treatment with fresh-frozen plasma and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, which led to complete recovery. Our experience suggests that plasma exchange may be life-saving in cases of severe bleeding caused by factor V inhibitors. The use of plasmapheresis in conjunction with chemotherapy is an efficacious and well-tolerated treatment and should be considered in patients with factor V inhibitors. © 1996 Wiley-Liss, Inc.