Citations

Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo , transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.

Background and Purpose— The aim of this study was to analyze the distribution patterns of delayed cerebral ischemia after subarachnoid hemorrhage (SAH) and the factors that determine their occurrence. Methods— We analyzed clinical and radiological data of 143 consecutive patients with aneurysmal SAH. Computed tomography scan revision was blinded to clinical information. Superficial infarctions were defined as territorial lesions with cortical involvement. Perioperative infarctions were excluded. Results— Fifty-six patients (39%) had cerebral infarctions. They were unilateral in 34 patients (61%) and involved a single territory in 29 (52%). Location was cortical in 34 patients (61%), deep in 10 (18%), and combined cortical and deep in 12 (21%). Single infarctions were cortical in 23 of 28 cases (79%). Deep territory ischemia was more common with multiple lesions (16/28, 57% versus 6/29 with single lesions, 21%; P <0.01). Single infarctions occurred frequently in the territory of the ruptured aneurysm (22/28 patients; 79%), whereas multiple infarctions were often distant to the site of rupture (21/28 cases, 75%). History of diabetes ( P =0.05), early hydrocephalus ( P =0.05), and requirement of external ventricular drainage ( P =0.02) were associated with the occurrence of multiple infarctions on univariate analysis. On multivariable analysis, this association only remained significant for the requirement of external ventricular drainage. Conclusion— The 2 most common patterns of delayed cerebral ischemia after aneurysmal SAH are single cortical infarction, typically near the ruptured aneurysm, and multiple widespread lesions including subcortical locations and often unrelated to the site of aneurysm rupture. These 2 patterns may represent different pathophysiological mechanisms or different degrees of severity of the same vascular process.

Abstract The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P &lt; 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P &lt; 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.

There are theoretical and practical advantages to modular rather than monoblock designs of prostheses for shoulder arthroplasty, but there are no reported studies which specifically compare the clinical and radiological results of their use. We have compared the results of unconstrained total shoulder arthroplasty for osteoarthritis using both types of implant. The monoblock design was used between 1992 and 1995 and the modular design after 1995. Both had cemented all-polyethylene glenoids, the monoblock with matched and the modular with mismatched radii of curvature. There were 34 consecutive shoulders in each group with a mean follow-up of 6.1 years in the first and 5.2 years in the second. There were no significant differences in improvement of pain scores, active elevation, external rotation, internal rotation, patient satisfaction, or the Neer ratings between the two groups. Two of 28 glenoid components in the first group and six of 30 in the second met the criteria for being radiologically at risk for loosening (p = 0.25). There were no significant differences in clinical outcome or radiological changes between the first- and second-generation designs of implant for shoulder arthroplasty.

Abstract Background: The quantitative assay for free light chains (FLCs) is a recently introduced commercial test reported to be sensitive and specific for detecting FLC diseases such as primary systemic amyloidosis (AL), light chain deposition disease (LCDD), nonsecretory multiple myeloma (NSMM), and light chain multiple myeloma. We evaluated its diagnostic performance in clinical practice. Methods: All FLC clinical test results generated in 2003 were abstracted from the Laboratory Information System. Diagnoses were obtained from the Dysproteinemia database and the patient medical history. Results: In 2003, we received samples for FLC assays from 1020 Mayo Clinic patients. The majority of these patients (88%) had bone marrow-derived monoclonal plasma cell disorders (PCDs). The 121 patients who did not have monoclonal gammopathy all had FLC κ/λ ratios within the range of values obtained for a reference population in our laboratory. Among the patients with monoclonal gammopathies were patients with multiple myeloma (330), AL (269), monoclonal gammopathy of undetermined significance (114), smoldering multiple myeloma (72), plasmacytoma (22), NSMM (20), macroglobulinemia (9), LCDD (7), and a variety of other PCDs. Among the 110 AL patients who had not been previously treated and who had a FLC assay performed within 120 days of diagnosis, the FLC κ/λ ratio was positive in 91% compared with 69% for serum immunofixation electrophoresis (IFE) and 83% for urine IFE. The combination of serum IFE and serum FLC assay detected an abnormal result in 99% (109 of 110) of patients with AL. Conclusion: The performance of the FLC assay in this analysis of clinical laboratory data is consistent with results from published retrospective validation studies.

Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.