Correlation of growth factor receptor expression with clinical growth in vestibular schwannomas.

OBJECTIVE: To examine the relationship between growth rate of vestibular schwannomas and the expression of various growth factor receptors. STUDY DESIGN: Retrospective case review of clinical growth rate in conjunction with a histopathologic and immunohistochemical reexamination of archival specimens. SETTING: A tertiary referral neurotologic center. PATIENTS: Three groups: a historical group to act as controls, consisting of 30 patients with sporadic vestibular schwannomas removed before the unit adopted an initial interval scan policy; a group of 14 patients with sporadic vestibular schwannomas who had undergone an initial interval scan policy, showed radiologic evidence of growth, and therefore had their schwannoma removed; and a group of 16 schwannomas removed from 11 neurofibromatosis Type 2 patients. MAIN OUTCOME MEASURES: A comparison between the three clinical groups using immunohistochemical studies to determine the level of expression of the proliferation factor Ki-67, c-erbB-2, and c-erbB-3 receptors and fibroblastic growth factor receptors 1 and 4. RESULTS: The level of expression of the proliferation factor Ki-67 was very low and similar in all three groups. C-erbB-2 and c-erbB-3 receptors were not expressed in any of the groups. fibroblastic growth factor receptor 4 expression was not significantly different, but there was a variation in the expression of fibroblastic growth factor receptor 1 between the three groups that correlated well with the differing incidence of growth in the groups. The increase in expression of fibroblastic growth factor receptor 1 in the neurofibromatosis Type 2 group was not statistically significant, but the increase in expression of fibroblastic growth factor receptor 1 in the growing sporadic group was statistically significant when compared with the historical controls. The level of fibroblastic growth factor receptor 1 expression correlates significantly with the rate of growth as measured on interval magnetic resonance imaging. CONCLUSIONS: Overexpression of fibroblastic growth factor receptor 1 has a positive correlation with the incidence and the rate of growth of sporadic vestibular schwannomas.     

A randomized trial of two types of adjuvant chemotherapy in radiotherapy-treated patients with clinical stages I and II high-grade non-Hodgkin's lymphoma

Summary This paper reports the 8-year results of comparing the use of two types of adjuvant chemotherapy following involved field radiotherapy for clinical stages I and II high-grade non-Hodgkin's lymphoma. Twenty-four patients received 6 weeks of VAP plus 2 years of oral maintenance chemotherapy, and 30 had six cycles of CMOPP. Four patients were not in complete remission at completion of i. v. chemotherapy (CR rate 91%). Ten patients (18.5%) have relapsed (VAP/M=5; CMOPP=5), with only two of these remaining alive, both of them being disease free. There have been three deaths from intercurrent causes, one from malignant melanoma and the other two from myocardial infarction. The relapse-free survivals at 2, 5 and 8 years were 80%, 76% & 76% respectively. The overall survivals at the same time points were 86%, 72% & 68%. There were no significant differences in either relapse-free or overall survival for either of the two treatment groups. The shorter period of weekly intravenous chemotherapy (VAP/M) was better tolerated than 36 weeks of CMOPP, and the former appears to produce equivalent results.     

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors

One hundred sixty-two patients with Stages III and IV non-Hodgkin's lymphoma of low-grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow-up alone or "maintenance" chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow-up, 74 months). Multivariate analysis revealed stage (P less than 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P less than 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse-free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.     

Molecular approach to the epidemiology of swine vesicular disease: correlation of variation in the virus structural polypeptides with serological properties.

Variation has been observed in the structural polypeptides of swine vesicular disease viruses isolated from the United Kingdom and Hong Kong. Despite the limited number of isolates examined, several distinct polypeptide patterns were obtained when the virus structural proteins were examined by polyacrylamide gel electrophoresis. Isolates from outbreaks in the United Kingdom which were known to be connected gave the same polypeptide pattern, whereas viruses with different polypeptide patterns could not be traced to a common source. The different polypeptide patterns were obtained consistently and were not altered by passage of the virus in tissue culture. In general, isolates with identical polypeptide patterns could not be distinguished by neutralization or antibody blocking tests or by competition radioimmunoassays. However, isolates with different polypeptide patterns could be differentiated by antibody blocking tests or radioimmunoassay. The correlation between the serological tests and the polyacrylamide gel electrophoresis analyses illustrates the value of analyzing structural polypeptides in the epidemiological study of swine vesicular disease.     

The detection of antibodies against foot-and-mouth disease virus (FMDV) in filter paper eluates from pig sera or whole blood by ELISA.

The use of pig blood samples dried on paper discs for the detection of antibodies against FMDV by the liquid phase blocking ELISA has been evaluated. The average volume of whole heparinised blood required to fully saturate 6.0 mm discs was 7.65 microliters (range 7.2 to 8.1; variation = 0.24, P = 0.05). When 200 clinically healthy animals were assessed by virus neutralisation (VN) titres up to 1/22 were recorded against types O, A and C, 97% being 1/11 or less. Using ELISA, results were more skewed. Overall, 91% showed titres of 1/32 or less, and there were occasional high non-specific reactors with types O and A. Using small groups of sera from experimental animals, a VN titre of 1/16 was found to be equivalent to an ELISA titre of approximately 1/100 (log10 2.0 +/- 0.2) with type O and 1/56 (log10 1.75 +/- 0.1) for type A. Although some loss in sensitivity from disc dried sera was found in selected negatives on testing at a single dilution of 1/32, sera from vaccinated animals with VN titres of 1/16 to 1/708 all gave strong positive results. A monoclonal antibody (Mab) assay was successfully developed to detect different swine anti-FMDV antibody isotypes.     

Approach to knee problems in primary care

Evaluation of knee problems is common in primary care. A basic understanding of relevant anatomy as well as clinical and diagnostic tests can assist the primary care practitioner (PCP) in determining the correct diagnosis, deciding whether to refer, and ordering appropriate treatment. Specific clinical tests, common causes of knee pain, and appropriate workup are reviewed, along with initial primary care treatment.     

Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption

BACKGROUND AND PURPOSE: Acute disruption of atherosclerotic plaques precedes the onset of clinical syndromes, and studies have implicated a role for matrix metalloproteinases (MMPs) in this process. The aim of this study was to establish the character, level, and expression of MMPs in carotid plaques and to correlate this with clinical status, cerebral embolization, and histology. METHODS: Plaques were obtained from 75 consecutive patients undergoing carotid endarterectomy and divided into 4 groups according to symptomatology (group 1, asymptomatic; group 2, symptomatic >6 months before surgery; group 3, symptomatic within 1 to 6 months; group 4, symptomatic within 1 month). All patients underwent preoperative and intraoperative transcranial Doppler monitoring. Plaques were subjected to histological examination and quantification of MMPs by zymography and ELISA. RESULTS: The level of MMP-9 was significantly higher in group 4 (median 125.7 ng/mL for group 4, median <32 ng/mL for all other groups; P=0.003), with no difference in the levels of MMPs 1, 2, or 3. Furthermore, the MMP-9 concentration was significantly higher in plaques undergoing spontaneous embolization (P=0.019) and those with histological evidence of plaque instability (P<0.03). In situ hybridization demonstrated increased MMP-9 expression in highly symptomatic plaques in areas of intense inflammatory infiltrate. CONCLUSIONS: The concentration, production, and expression of MMP-9 is significantly higher in unstable carotid plaques. If this proves to be a causal relationship, MMP-9 may be a strong candidate for pharmacotherapy aimed at stabilizing plaques and preventing stroke.     

New Anticoagulants

Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran).