Synergism between tissue-type plasminogen activator and a genetically engineered variant lacking the finger domain, the growth factor domain and the first kringle domain.

A modified variant of human tissue-type plasminogen activator (t-PA) lacking the finger domain (F), the growth factor domain (G) and the first kringle domain (K1), has an extended plasma half-life in vivo, compared to that of t-PA. When the variant (denoted K2P) was tested in vitro for its ability to lyse human plasma clots we found that the activity was characterized by a time lag phase and a sigmoidal dose-response curve. However, an attenuation of the lag phase in vitro was observed both when K2P was mixed with t-PA in a w/w ratio of 4:1 and when K2P was allowed to lyse a clot that had been pre-exposed to t-PA i.e. submitted to a limited plasmic digestion. Dosis that in vitro caused 50% lysis within 6 h were calculated from individual dose-response curves and were for K2P, t-PA and K2P/t-PA (4:1 w/w) 540 ng/ml, 360 ng/ml and 310 ng/ml, respectively. These results indicated a synergistic effect between K2P and t-PA. However, the data from individual dose-response curves showed that the effect of the K2P/t-PA mixture never was better than that of t-PA alone, and the synergistic effect in vitro is therefore considered to be of limited use. The thrombolytic activity in vivo was evaluated in a rabbit jugular vein thrombus model. Despite the lag phase observed in vitro, K2P was approximately 3 times as effective as t-PA in vivo (bolus injection). The thrombolytic effect of K2P was further potentiated when it was administered together with a small amount of t-PA (4:1 w/w).(ABSTRACT TRUNCATED AT 250 WORDS)     

Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation.

The characteristic of malignant pleural mesothelioma is a tumor that grows by plate-like extension over the pleura, and invades adjacent tissues and organs. Radical surgical removal of the tumor is generally not possible, and most treatment regimens involve combined chemotherapy and radiotherapy, as well as debulking surgery. We have prospectively evaluated five locally-aggressive multi-modality treatment programs, using different hemithorax irradiation schedules and chemotherapy regimens. One hundred patients with confirmed malignant pleural mesothelioma entered the study between 1977 and 1989. The treatment programs, which can consecutively, were: I, 20 Gy (10 x 2 Gy) to the hemithorax + CYVADIC (cyclophosphamide 500 mg/m2 d 1, vincristine 1 mg/m2 d 1 and 5, adriamycin 40 mg/m2 d 1 and dacarbazine 200 mg/m2 d 1 and 5, several cycles before and after irradiation); II, 55 Gy (25 x 2.2 Gy) to the hemithorax + 15 Gy (6 x 2.5 Gy) to the tumor + CYVADIC (2 cycles before, 1 cycle during, and 2 cycles after irradiation); III, Mitoxantrone (14 mg/m2 q 28 d, < or = 6 cycles) followed by 70 Gy (56 x 1.25 Gy, twice a day); IV, 4-Epirubicin (110-130 mg/m2 q 28 d, < or = 6 cycles) followed by 35 Gy (28 x 1.25 Gy twice a day) to the hemithorax + 36 Gy (9 x 4 Gy every 2 days) to the tumor; V, Etoposide (150 mg/m2 1, 3, 5 q 28 d) followed by 38.5 Gy (11 x 3.5 Gy) to the hemithorax. A new system for evaluating tumor response in pleural mesothelioma was applied. None of the combined treatment programs prevented local invasive growth or the spread of mesothelioma outside the hemithorax. The median survival time was slightly increased from 8 to 12 months for those patients who completed the protocol treatments, but progressive disease was the invariable outcome. Radiation pneumonitis and fibrosis were severe and compatible with results of total loss of lung function on the irradiated side. We conclude that data relating to therapeutic responses and treatment programs in malignant mesothelioma should be better correlated internationally, if the problems associated with the evaluation of treatment and the management of patients with mesothelioma are to be improved.     

Comparison of some salivary variables between vegetarians and omnivores

The aim of the study was to compare salivary variables in a group of vegetarians with a group of omnivores. Twenty-nine vegetarians, 19 women and 10 men, mean age 35 yr, and 28 omnivores, 20 women and 8 men, mean age 35 yr, were compared in terms of salivary secretion rate, pH, buffer capacity, mutans streptococci and lactobacilli. The vegetarians had a significantly higher secretion rate, but there were no other significant differences regarding the salivary variables. The difference in secretion rate may have been caused by some lifestyle factor(s) differing between vegetarians and omnivores which probably mainly include nutrient(s), texture and roughness of the food.     

Hand grip increases shoulder muscle activity: An EMG analysis with static handcontractions in 9 subjects

We examined 4 shoulder muscles-the supraspina-tus, infraspinatus, the middle portion of the deltoid and the descending part of the trapezius-with electromyography (EMG) in abducted and flexed arm positions, in 9 healthy subjects. the subjects were asked to produce a static handgrip force of 30% and 50% of maximal voluntary contraction (MVC) in 8 different arm positions. in all positions, the subjects held a dynamometer in the hand. the myoelectric activity in the shoulder muscles with only the dynamometer in the hand was compared to the EMG activity when static contractions were added. There was an association between static handgrip and shoulder muscle activity, as revealed by EMG. the EMG activity increased in the supraspinatus muscle in humeral flexion from and above 60° and in 120° abduction. in the infraspinatus muscle, the changes were less; a significant increase, however, was noticed in flexion. in the deltoid muscle there was a tendency towards increased activity in positions lower than 90°, in the higher arm positions, the activity decreased. There was no significant alteration regarding the EMG activity of the trapezius.

Our findings imply that high static handgrip force, particularly in elevated arm positions, increases the load on some shoulder muscles. the stabilizing muscles (the rotator cuff) were more influenced than the motor muscles by hand activity. Handgrip activity is important to evaluate while assessing shoulder load in manual work and in clinical evaluations of patients with shoulder pain.     

Functional mri of human brain activation combining high spatial and temporal resolution by a cine flash technique

Functional mapping of human brain activation has been accomplished at high spatial and temporal resolution (voxel size 4.9 μl, temporal increment 100 ms). The approach was based on oxygenation-sensitive long-echo time FLASH MRI sequences synchronized to multiply repeated cycles of visual stimulation in a CINE acquisition mode. This high temporal resolution revealed that stimulus-related signal intensity changes in human visual cortex display an initial latency followed by increases extending over several seconds. Furthermore, the temporal characteristics of the complete CINE MRI signal time course depended on the absolute and relative durations of activation and control periods and, for example, caused an apparent absence of a poststimulation “undershoot” phenomenon. Complementing hyperoxygenation due to rapid hemodynamic adjustments, these results suggest signal intensity modulation by enhanced oxygen consumption and concomitant deoxygenation during prolonged and/or repetitive stimulation.     

The Stockholm breast cancer screening trial — 5-year results and stage at discovery

In screening programmes it is important to assess a preliminary effectiveness of the screening method as soon as possible in order to forecast survival figures. In March 1981 a controlled single-view mammographic screening trial for breast cancer was started in the south of Stockholm. The population invited for screening mammography consisted of 40,000 women aged 40–64 years, and 20,000 women served as a well-defined control group. The main aim of the trial was to determine whether repeated mammographic screening could reduce the mortality in the study population (SP) compared to the control population (CP).The cumulative number of advanced mammary carcinomas in the screening and the control populations from the first five years of screening have shown a tendency towards more favourable stages in the screened population aged 40–64 years. A breakdown by age suggests an effect in age group 50–59 years, but not yet in age groups 40–49 and 60–64 years.When comparing the rates of stage II+ cancer, an increased number is found in the study group. As the total rate of breast cancer is higher in SP than in CP, there ought to be a concealed group of stage II+ cancers in the CP which makes the comparison biased. A new approach has been designed, where an estimation of the hidden number of stage II+ cancers in CP is added to the clinically detected cases, and in this respect a comparison has shown a decrease in the cumulative number of advanced cancers in the SP in relation to the CP (p<0.05). According to this it could be important to add the estimated number of undetected, hidden cases in the control group in order to utilize the difference in detection rate in the screening- and control group respectively.     

Intranasal immunization of mice with group B streptococcal protein rib and cholera toxin B subunit confers protection against lethal infection

Intranasal immunization of mice with Rib, a cell surface protein of group B streptococcus (GBS), conjugated to or simply coadministered with the recombinant cholera toxin B subunit, induces systemic immunoglobulin G (IgG) and local IgA antibody responses and confers protection against lethal GBS infection. These findings have implications for the development of a human GBS vaccine.     

Amyloid peptide enhances nail rusting: novel insight into mechanisms of aging and Alzheimer's disease

Oxidative stress is believed to play a major role in the dysfunction and degeneration of neurons that occurs in Alzheimer's disease (AD). Amyloid beta-peptide forms insoluble aggregates in the brains of AD patients and it has been shown that the neurotoxic actions of amyloid beta-peptide involve membrane lipid peroxidation. However, it is not known how amyloid beta-peptide induces oxidative stress. Here we describe a simple experiment that we performed 6 years ago that demonstrates that amyloid beta-peptide is itself a source of oxyradicals. The weights of iron nails were recorded and the nails were then incubated in one of three different solutions: water (control), 1mM amyloid beta-peptide (1-40) in water, and 1mM bovine serum albumin in water. After 1 month of incubation the nails were then removed, allowed to dry, and then their weights determined. The weights of all the nails decreased, but the amount of weight decrease in the nails that had been incubated in the presence of amyloid beta-peptide was approximately twice that of the nails incubated in the control solutions. These data provide direct evidence that amyloid beta-peptide generates, or facilitates the production of, oxyradicals thereby enhancing metal oxidation.     

Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice

We have disrupted expression of the mitochondrial Friedreich ataxia protein frataxin specifically in murine hepatocytes to generate mice with impaired mitochondrial function and decreased oxidative phosphorylation. These animals have a reduced life span and develop multiple hepatic tumors. Livers also show increased oxidative stress, impaired respiration and reduced ATP levels paralleled by reduced activity of iron-sulfur cluster (Fe/S) containing proteins (ISP), which all leads to increased hepatocyte turnover by promoting both apoptosis and proliferation. Accordingly, phosphorylation of the stress-inducible p38 MAP kinase was found to be specifically impaired following disruption of frataxin. Taken together, these findings indicate that frataxin may act as a mitochondrial tumor suppressor protein in mammals.