Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.     

Clinical correlates of splenic histopathology and splenic karyotype in myelofibrosis with myeloid metaplasia

Splenic extramedullary hematopoiesis is an integral component of myelofibrosis with myeloid metaplasia (MMM) and may be classified into 3 distinct histologic patterns of infiltration by myeloid precursors: diffuse, nodular, and a predominance of immature granulocytes. These 3 histologic patterns occurred in 121 (56.8%), 75 (35.2%), and 17 (8%), respectively, of 213 patients with MMM who underwent splenectomy at a single institution. In general, karyotypic findings in splenic tissue (n = 92) were similar to those seen in the bone marrow. The histologic pattern of immature granulocyte predominance, the presence of microscopic splenic infarcts (26 patients), or the detection of an abnormal splenic karyotype (52 patients) was significantly associated with decreased postsplenectomy survival. These adverse features were also associated with characteristics of advanced disease. These observations support the bone marrow origin of the myeloid progenitor pool in the spleen of patients with MMM and suggest a prognostic value for splenic histopathology and karyotype. (Blood. 2001;97:3665-3667)     

A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia

The anti-fibrotic and cytokine modulatory properties of pirfenidone suggest its usefulness in the treatment of myelofibrosis with myeloid metaplasia (MMM). In a prospective study, 28 patients with MMM were treated with oral pirfenidone. Twelve patients completed 1 year of therapy; 13 were withdrawn because of disease progression and three because of drug intolerance. Only one patient experienced a clinically relevant benefit with respect to anaemia and splenomegaly. The overall lack of clinical benefit correlated with no significant improvement in the bone marrow morphological features of the disease. We conclude that pirfenidone has no significant clinical or biological activity in MMM.     

What are the primary concerns of recently graduated surgeons and how do they differ from those of the residency training years?

HYPOTHESIS: Graduated surgeons have differences in concerns when comparisons are made between fellows and practicing surgeons, practicing surgeons and residents, and male and female surgeons. DESIGN AND SETTING: A survey was distributed to surgeons who graduated from 17 New England residency programs from 1993 to 1996, consisting of 9 demographic questions and 33 items coded on a Likert-type scale (with scores from 1 [least concerning] to 5 [most concerning]). PARTICIPANTS: Surgical fellows and practicing surgeons recently graduated from general surgical residency programs in New England who had participated in a previous study as residents. INTERVENTION: Distribution and completion of the survey. MAIN OUTCOME MEASURE: Personal and career-oriented concerns of recently graduated surgical residents. RESULTS: Personal issues continue to rank high for graduated residents, but the areas of greatest concern became more financially and career oriented. The top concerns of fellows were personal finances (mean score, 3.2), child rearing (mean score, 3.1), salary (mean score, 3.1), postponing family plans (mean score, 3.0), availability of role models (mean score, 2.9), and number of work hours (mean score, 2.8). The top concerns of practicing surgeons were salary (mean score, 3.2), personal finances (mean score, 3.1), number of referrals (mean score, 3.0), support for research (mean score, 2.7), child rearing (mean score, 2.7), and availability of role models (mean score, 2.7). Differences existed between men and women for child rearing, initiating personal relationships, maintaining personal relationships, maternity leave, and promotional advancement. Women were more concerned than men. CONCLUSIONS: Assistance with career planning and job selection during the residency years should be enhanced to diminish the concerns about financial issues and the availability of role models after graduation. Many of the concerns among male and female graduates are still reflective of larger societal expectations, but some, such as promotional advancement, may be attenuated through guidance and mentoring of residents before job selection.     

Peripheral vascular surgery and magnetic resonance arteriography--a review.

OBJECTIVES: to review the current status of lower limb MRA. DESIGN: a literature review based predominantly on a MEDLINE database search of English-language publications from January 1991 to October 2000. MATERIALS AND METHODS: twenty-eight articles, concerning non-enhanced MRA (13), gadolinium-enhanced MRA (14) or both (1), met the predefined requirement for quality. Results gadolinium-enhanced MRA (CE-MRA) seems to be more accurate, quicker and associated with fewer problems than non-enhanced (TOF) MRA. TOF-MRA has a sensitivity and specificity of 93% (range 64-100%) and 88% (range 57-100%) respectively, and CE-MRA presents values of 96% (range 71-100%) and 96% (63-100%), respectively, using conventional arteriography as the gold standard. Some articles report a substantial incidence of runoff vessels suitable for distal bypass visible on MRA but invisible on conventional arteriography. Gadolinium contrast is given intravenously and is generally well tolerated and has no known nephrotoxicity. CONCLUSION: CE-MRA is accurate compared to conventional arteriography, has the potential to increase the limb salvage rate for selected patients, is non-invasive and well tolerated.     

Hyaluronsäure und Hyaluronidase Zwei neue Blasenkarzinommarker

The heterogeneity of bladder cancer concerning progress of recurrence is an essential characteristic of this disease. Hyaluronic acid (HA) and its degrading enzyme hyaluronidase (HAase) are intricately associated with bladder cancer angiogenesis and metastasis. Tumor-associated HA and HAase are secreted in urine. In 513 urine specimens (261 bladder cancer patients, 252 patients without bladder cancer) and 83 bladder tissue specimens (71 bladder tumors, 12 normal bladder tissues), the accuracy of HA and HAase as tumor markers was studied. Elevated urinary HA levels (> or = 500 ng/ml), indicating a positive HA test, suggest the presence of bladder cancer regardless of tumor grade. Elevated urinary HAase levels (> or = 10 mU/mg) indicate high-grade (G2/G3) bladder cancer. The combined HA-HAase urine test showed 91% sensitivity and 84% specificity to detect bladder cancer. The HA-HAase test is equally sensitive for monitoring tumor recurrence. Immunohistochemistry (IHC) staining of HA and HAase in the G1 and G2/G3 bladder cancer specimens was significantly (p < 0.001) higher than in normal bladder tissue. HA and HAase appear to be useful markers in the diagnosis of bladder cancer. When compared with other noninvasive tests, the HA-HAase urine test may be less expensive and more accurate.     

The dorsal aponeurosis, intrinsic, hypothenar, and thenar musculature of the hand

The intrinsic muscles of the hand consist of seven interossei and four lumbrical muscles. With the extrinsic long extensors, the intrinsic muscles act via the dorsal aponeurosis to control finger motion. The interossei also control finger abduction and adduction, and flexion of the metacarpophalangeal joints. The lumbricals are the main extensors of the interphalangeal joints. The complex structure of the dorsal aponeurosis allows coordination and individual joint motion. The muscles of the hypothenar and thenar eminences also insert into the dorsal aponeurosis and the skeleton of the small finger and thumb, respectively, and are responsible for the specialized motion. Knowledge of the anatomy is necessary for understanding the function in treating abnormalities and trauma to the intricate structures of the hand.     

Increased susceptibility to apoptosis in circulating lymphocytes of critically ill patients

BACKGROUND AND AIMS: Lymphocyte apoptosis may influence immune responsiveness in systemic inflammation. Therefore, we investigated whether early signs of apoptosis (i.e., annexin-V binding and cell shrinkage) in peripheral lymphocytes were different among patients with severe sepsis, critically ill, nonseptic patients after major surgery, and healthy individuals. PATIENTS/METHODS: Ten patients with severe sepsis and ten critically ill, nonseptic patients after major surgery admitted to a surgical intensive care unit in a university hospital were included in the study. In addition, ten healthy blood donors were included for comparison. We investigated early signs of apoptosis using flow cytometric measurement of annexin-V binding to the cell surface and cell shrinkage of peripheral lymphocytes. RESULTS: The percentage of apoptotic lymphocytes determined as annexin-V positive and propidium iodide negative cells was increased in freshly prepared cells of patients with severe sepsis (11.4 +/- 0.5%) and critically ill, nonseptic patients after major surgery (18.5 +/- 2.0%) relative to healthy blood donors (4.4 +/- 0.5%) (P < 0.05). No significant difference between patients with severe sepsis and patients after major surgery were found. Annexin-V binding increased significantly after OKT-3 stimulation of lymphocytes in patients with severe sepsis (34.4 +/- 1.6%), patients after major surgery (33.8 +/- 3.4%), and healthy blood donors (21.1 +/- 2.8%). No significant difference among groups was detected following OKT-3 stimulation. Furthermore, freshly isolated peripheral lymphocytes of patients with severe sepsis and critically ill, nonseptic patients after major surgery revealed a significantly higher proportion of cell shrinkage than in healthy blood donors (55.0 +/- 2.2%, 21.5 +/- 2.4% vs 3.6 +/- 0.7%; P < 0.05). CONCLUSION: Circulating lymphocytes of critically ill patients show a high degree of early signs of cellular apoptosis. This may contribute to hyporesponsiveness of immune cells in systemic inflammation.     

Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography

BACKGROUND: The ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. METHODS AND RESULTS: Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (< 1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 microg/mL of the beta3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 microM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 +/- 8% inhibition of fibrinogen binding at 12.5 microg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab. CONCLUSIONS: These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.