Regional lymph node and pulmonary metastases after local hyperthermia of melanomas in C57BL/6 mice

The effects of local tumor hyperthermia on regional lymph node metastases are inconclusive. We studied the effects of hyperthermia on the incidence of popliteal, femoral, and abdominal lymph node metastases in C57BL/6 mice with primary B16 melanomas (F10 variant) growing subcutaneously in the left foot. Tumors were heated to 42.3, 43.5, and 44.2 degrees C for 90 minutes either 7 days after inoculation of 5 X 10(4) viable cells (microscopic tumor = mic) or when the tumors were approximately 3 mm in diameter (macroscopic tumor = mac). Femoral lymph node metastases occurred in 0/21 control animals and in 8/22 (36%), 11/19 (58%), and 11/17 (65%) animals whose primary tumors were heated to 42.3, 43.5, and 44.2 degrees C, respectively. For all three treatments, the increase in metastases as compared to controls was statistically significant (p less than 0.004, Fisher's exact test). The incidence of abdominal lymph node metastasis was slightly higher in the treated groups than controls. Twenty of 21 (95%) control mice developed popliteal lymph node metastases and hyperthermia-induced increases could not be demonstrated. Fifteen of 21 control mice killed 3 weeks after amputation of tumor-containing leg had pulmonary metastases with an average of 6 +/- 4 (standard deviation) lesions per affected mouse. Pulmonary metastases occurred in 22/22 (100%), 17/19 (89%), and 13/17 (76%) of mice whose tumors were heated to 42.3, 43.5, and 44.2 degrees C, respectively. The numbers of metastases for affected mice were significantly increased compared to controls for tumors heated to 43.5 and 44.2 degrees C (28 +/- 43, 43 +/- 52, 119 +/- 121, p greater than 0.02, p less than 0.006, p less than 0.002, for two sample T-test). While 0/8 mic tumors were cured 5/9 mac tumors heated to 44.2 degrees C disappeared (p less than 0.03, Fisher's exact test) and there was a growth delay in the remaining mice. Mic tumors, heated to 43.5 degrees C, had an accelerated onset of growth while mac tumors heated to this temperature had a slight growth delay. Growth of both mic and mac primary tumors heated to 42.3 degrees C was similar to controls. These results show that therapeutic and subtherapeutic local hyperthermia increases metastases to regional lymph nodes and to lungs even when primary tumor growth rate is partially or totally controlled.     

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.     

Hypertrophic cardiomyopathy in the dog.

Clinical and necropsy findings in 10 dogs with a spontaneous primary hypertrophic cardiomyopathy are described. Each dog had marked cardiac hypertrophy, and 8 dogs had disproportionate thickening of the ventricular septum with respect to the left ventricular free wall (compared with dogs with normal hearts or with cardiac hypertrophy due to acquired or congenital heart disease). Septal:free wall thickness ratios in the 10 dogs ranged from 1.1 to 1.5; 6 had ratios greater than or equal to 1.3. However, marked cardiac muscle cell disorganization in the ventricular septum, characteristic of patients with hypertrophic cardiomyopathy, was present in only 2 of the 10 dogs. Death occurred most commonly while the dogs were under anesthesia during the course of operative procedures (5 dogs) or suddenly and unexpectedly in animals without previous symptomatic manifestations of cardiac disease (3 dogs). Four dogs had clinical signs of congestive heart failure, including 2 with marked cardiac decompensation. In addition, 2 of these 4 dogs with heart failure and 1 dog without previous symptoms (that died during a noncardiac operation) manifested complete heart block. It is conceivable that dogs with spontaneous hypertrophic cardiomyopathy may prove useful in the future investigations of the clinical, hemodynamic, and pathologic features of this disease in humans.     

Primary myocardial disease in the cat. A model for human cardiomyopathy.

Thirty-four cats with primary myocardial disease were studied. The cats were divided into two groups, depending on the clinical, hemodynamic, angiocardiographic, and pathologic findings. Group A consisted of those cats with hypertrophic cardiomyopathy and Group B consisted of those cats with congestive cardiomyopathy. Similarity in the characteristics of cardiomyopathy in the human cat was found. Both Group A and Group B consisted predominantly of mature adult male cats. The most common presenting signs were dyspnea and/or thromboembolism, systolic murmurs with gallop rhythms on auscultation, cardiomegaly with (Group A) or without (Group B) pulmonary edema, abnormal electrocardiograms, elevated left ventricular end diastolic pressures, and angiocardiographic evidence of mitral regurgitation with left ventricular concentric hypertrophy (Group A) or left ventricular dilatation (Group B). Some cats in Group A also had evidence of left ventricular outflow obstruction. The principal pathologic findings in these cats were left atrial dilatation, symmetric hypertrophy or asymmetric septal hypertrophy of the left ventricle (Group A), and dilatation of the four cardiac chambers (Group B). Aortic thromboembolism was commonly observed in both groups. These clinical and pathologic findings indicate that cardiomyopathy in the cat is similar to the two most common forms of cardiomyopathy in the human (hypertrophic cardiomyopathy, with and without obstruction, and congestive cardiomyopathy).     

The ring-infected erythrocyte surface antigen of Plasmodium falciparum associates with spectrin in the erythrocyte membrane.

The malaria parasite Plasmodium falciparum synthesises a protein, RESA, which associates with the membrane of newly invaded erythrocytes. Using spent supernatants from P. falciparum growing in culture as a source of soluble RESA we have developed an assay to examine the characteristics of RESA binding to the erythrocyte membrane in vitro. RESA associated with the Triton X-100 insoluble proteins on the inner face of the host erythrocyte membrane but did not bind to the outer surface of intact erythrocytes. Other proteins present in culture supernatants did not bind to the erythrocyte membrane. RESA was co-sedimented with the ternary complex formed between actin, spectrin and band 4.1 and co-precipitated with spectrin precipitated with anti-spectrin antibodies. The extent of association between RESA and the inner face of the erythrocyte membrane was reduced by the inclusion of excess purified spectrin in the assay. Thus, RESA appears to be associated with spectrin in the erythrocyte membrane skeleton.     

Feline hypertrophic cardiomyopathy: gross anatomic and quantitative histologic features.

Gross anatomic features and the pattern and extent of cardiac muscle cell disorganization were studied in the hearts of 51 with spontaneously occurring hypertrophic cardiomyopathy. Each cat had a hypertrophied, but nondilated, left ventricle. Ventricular septal disorganization was extensive, involving 5% or more of the relevant areas of the tissue section, in 14 (27%) of the 51 cats. Marked septal disorganization occurred only in those cats with asymmetric septal hypertrophy (ventricular septal to left ventricular free wall thickness ratio of greater than or equal to 1.1) Disorganization of cardiac muscle cells was uncommon and less extensive in the left ventricular free wall of the cats with hypertrophic cardiomyopathy. Disorganization involved the free wall of only 7 cats, each with asymmetric septal hypertrophy, and occupied greater than 5% of the free wall tissue sections in just 3. Hence, about one fourth of this population of cats had hypertrophic cardiomyopathy resembling the human form of this disease, with asymmetric left ventricular hypertrophy and marked disorganization of cardiac muscle cells in the ventricular septum. The majority of cats (about 75%), however, demonstrated a form of hypertrophic cardiomyopathy characterized by symmetric ventricular hypertrophy and normal arrangement of cardiac muscle cells.     

Correct promoter control is needed for trafficking of the ring-infected erythrocyte surface antigen to the host cytosol in transfected malaria parasites

Following invasion of human erythrocytes, the malaria parasite, Plasmodium falciparum, exports proteins beyond the confines of its own plasma membrane to modify the properties of the host red cell membrane. These modifications are critical to the pathogenesis of malaria. Analysis of the P. falciparum genome sequence has identified a large number of molecules with putative atypical signal sequences. The signals remain poorly characterized; however, a number of molecules with these motifs localize to the host erythrocyte. To examine the role of these atypical signal sequences in the export of parasite proteins, we have generated transfected parasites expressing a chimeric protein comprising the N-terminal region of the P. falciparum ring-infected erythrocyte surface antigen (RESA) appended to green fluorescent protein (GFP). This N-terminal region contains a hydrophobic stretch of amino acids that is presumed to act as a noncanonical secretory signal sequence. Modulation of the timing of transgene expression demonstrates that trafficking of malaria proteins into the host erythrocyte is dependent on both the presence of an appropriate transport signal and the timing of expression. Transgene expression under the control of a trophozoite-specific promoter mistargets the chimeric molecule to the parasitophorous vacuole surrounding the parasite. However, expression of RESA-GFP in schizont stages, under the control of the RESA promoter, enables correct trafficking of a population of the chimeric protein to the host erythrocyte.     

Differences in reasons for smoking between younger and older smokers

The reasons why older people smoke have not been examined in the literature. This paper attempted to examine the differences in motivation and maintenance factors of elderly and young smokers using the Horn-Waingrow Why do you smoke questionnaire. One hundred and thirteen clinical patients and 112 non-patient controls were used in this study. The clinical group was divided into an elderly group (n = 58) and a younger group (n = 55). The results of a discriminant analysis showed that patients significantly differed from non-patients on 'automatic habit and stimulation', and 'crutch/tension reduction' factors. Elderly patients were found to be significantly differentiated from both younger patients and the control group on the 'pleasurable relaxation' factor. These findings offer support for the US Surgeon Generals' report that elderly smokers do have different motivating factors for their smoking behaviours from younger smokers.