Polymers containing enzymatically degradable bonds. VI.Hydrophilic gels cleavable by chymotrypsin

New types of hydrophilic gels based on N-(2-hydroxypropyl)methacrylamide which contain oligopeptide sequences in the crosslinks were prepared. These gels are enzymatically degradable by chymotrypsin. The rate of their degradation may be varied within a broad range by changes in the length and detailestructure of the oligopeptide sequence in the crosslinks and by changing their network density.     

Partial purification and characterization of anhydrotetracycline oxygenase of Streptomyces aureofaciens

Anhydrotetracycline oxygenase was purified both by affinity chromatography and by hydrophobic interaction chromatography. Molecular weight of anhydrotetracycline oxygenase was determined to be 115,000 by Sephadex G-200 gel filtration. Using preparative isoelectric focusing the isoelectric point of the enzyme was estimated to be 5.3. The enzyme showed a sensitivity to thiol-specific inhibitors. During the hydrophobic interaction purification step, the activity dropped considerably. Reactivation occurred when a heat treated crude extract was added to the reaction mixture.     

Hypertension and ischemic heart disease

Hypertension is one of the major risk factors for ischemic heart disease and appropriate control of blood pressure is the cornerstone of both primary and secondary ischemic heart disease prevention. Effective blood pressure (BP) control is recommended in primary prevention, i.e., maintaining blood pressure <140/90 mmHg, while in secondary prevention values <130/85 mmHg used to be recommended. Treatment of hypertension in patients with ischemic heart disease is based on ACE inhibitors and/or AII antagonists (trials HOPE, EUROPA, and PEACE) in combination with beta blockers or with verapamil if beta blockers are not tolerated.According to epidemiologic data, cardiovascular mortality increases with blood pressure, starting as low as from the 110/70 mmHg level. Czech, European, and American guidelines from the early 21st century recommend that blood pressure in patients with ischemic heart disease (IHD) be maintained below 130/80 mmHg. Data from the INVEST a ACCORD trials led, however, to reappraisal of these strict recommendations and the blood pressure values currently recommended in secondary prevention correspond to high-normal blood pressure, i.e., 130–139 mmHg/80–89 mmHg.INVEST is the largest clinical trial that focused on hypertonic patients with IHD. Its results showed that verapamil is an appropriate alternative to beta blockers and that while lowering of blood pressure below 140/90 mmHg is necessary, its further decrease below 130/80 mmHg is not associated with any additional benefit.Trials with beta blockers demonstrated that lowering of heart rate (HR) improves the patients' prognosis. This hypothesis was definitely verified by trials BEAUTIFUL a SHIFT. The recommended heart rate for patients in secondary prevention is 50–70 bpm.     

Hydrogels for Site-Specific Drug Delivery to the Colon: In Vitro and in Vivo Degradation

Novel hydrogels based on N,N-dimethylacrylamide, N-t-butylacrylamide, and acrylic acid cross-linked with azoaromatic compounds of varying length and electron density of the azo bond were synthesized. The cross-links are degradable by microbial azoreductases present predominantly in the colon, and the gels appear to be suitable for colon-specific drug delivery. The degradability in vitro and in vivo was found to be related to the degree of swelling of the gels. The higher the degree of swelling, the higher the degradability. However, structural and electronic factors were also shown to influence reduction of azo bonds.     

Lysophosphatidic acid (LPA)—a perspective marker in ovarian cancer

To compare plasma lysophosphatidic acid (LPA) levels in ovarian cancer patients in women with benign ovarian tumors and in women with no ovarian pathology. We correlated clinico-pathological parameters with plasma LPA levels. Capillary electrophoresis with indirect ultraviolet detection was used to analyze the plasma LPA levels of 159 patients (81 patients with ovarian cancer, 27 women without ovarian or uterine pathologies, and 51 patients with benign ovarian tumors) during a 5-year period. Patients with ovarian cancer had a significantly higher plasma LPA level (n = 81; median (med), 11.53 μmol/l; range, 1.78–43.21 μmol/l) compared with controls with no ovarian pathology (n = 27; med, 1.86 μmol/l; range, 0.94–9.73 μmol/l), and patients with benign ovarian tumor (n = 51; med, 6.17 μmol/l; range, 1.12–25.23 μmol/l; P < 0.001). We found that plasma LPA levels were associated with the International Federation of Gynecology and Obstetrics stage. The histological subtype and grade of ovarian cancer did not influence the plasma LPA levels in this study. The plasma LPA level can be a useful marker for ovarian cancer, particularly in the early stages of the disease.     

Optimization of cardiac resynchronization therapy in non-responders

BackgroundCardiac resynchronization therapy plays important role in treatment of heart failure patients with low left ventricular ejection fraction. However, a significant number of patients do not improve after implantation. Optimization of atrioventricular and interventricular delay could improve clinical status of these patients.ObjectivesThe purpose of this study was to compare optimization of atrioventricular (AV) and interventricular (VV) delays with aortic velocity-time integral (VTI) and with maximal value of the first derivative of a left ventricular pressure signal (LVdP/dt_max).MethodsFifteen non-responders were optimized with aortic VTI method and QuickOpt. After 3 months the follow up echocardiography and clinical evaluation were done. Ten non-responders were optimized with LVdP/dt_max and QuickOpt. After 3 month follow up echocardiography and clinical evaluation were done.ResultsIn the first group of patients (age 74.3 years (65.3, 84.3), 83.4% male, etiology 66% ischemic heart disease, NYHA class before optimization III 66.7%, III-IV 33.3%, LVEF 23.0% (15.0; 32.0)), no correlation between AV and VV delays setting obtained from aortic VTI and QuickOpt was found. Optimization generated shorter QRS complex. After 3 months of follow up, there was no change in echo parameters or NYHA class. In the second group of patients (age 76.7 years (66.6, 82.4), 90% male, etiology 60% ischemic heart disease, NYHA class before optimization III 50%, III-IV 50%, LVEF 29.5% (10.0; 35.0)), no correlation between AV and VV delays setting obtained from LVdP/dt_max and QuickOpt was found. Optimization in this group of patients also generated shorter QRS complex. After 3 months, increase in LVEF was observed, but other echo parameters and NYHA class remained unchanged.ConclusionUsing aortic VTI guided optimization in CRT devices did not bring any profit for non-responder patients. Echocardiography parameters and NYHA status did not changed in 3 months follow up. Using invasive LVdP/dt_max leads to a change in left ventricular ejection fraction, but NYHA class remains unchanged.     

Avulsion of the Hamstring Muscle Group: A Follow-Up of 6 Adult Non-Athletes with Early Operative Treatment: A Brief Report

Background  Complete proximal avulsions of the hamstring muscle group may cause significant morbidity and loss of function. These pelvis-near musculoskeletal injuries are mostly acquired during sports activities in a hip flexion and knee extension. Here we present a study group of 6 middle-aged to elderly patients suffering a complete proximal hamstring avulsion and following early surgical refixation. Early surgical refixation leads to complete resumption of the activities of daily life without loss of function. Materials and methods  The 6 patients (3 men and 3 women) included in this study had an average age of 59.07 ± 4.47 years at the time of injury. All of them suffered a complete avulsion of the hamstring muscle group. Surgical refixation was accomplished with the corkscrew anchor refixation system (Arthrex Manufacturing, Inc., Naples, FL). The cases were retrospectively analyzed using a hip joint evaluation system, the Harris Hip Score, and radiological follow-up by magnetic resonance imaging (MRI). Data are given as mean ± SEM. Student’s t-test was used for normal distribution of the data. Results  The mean follow-up time was 31.83 ± 18.9 months (range: 10–118 months). All patients were rated not to have a significant difference in function compared with the uninjured side. None of the patients suffered any handicaps resulting from surgery or the injury. A complete consolidation in all patients was observed in the follow-up MRI. Conclusions  Early surgical intervention and subsequent therapy in a complete hamstring avulsion injury may prevent loss of hip-joint stability and prevent the sequalae of degradative hip or vertebral events.     

Klinische Bedeutung der AktivitÄtsbestimmung der Blut-Cholinesterasen bei neurologischen Patienten und bei mit organophosphaten arbeitenden Personen

Zusammenfassung Es wurden die Ergebnisse der Erythrocyten-Acetylcholinesterase- und der plasmatischen Cholinesterase-Untersuchung bei 826 Patienten der Nervenklinik mit verschiedener Diagnose und bei 69 Risikoarbeitern, die mit subtoxischen Organophosphatdosen chronisch in Berührung kamen, mitgeteilt. In der Kontrollgruppe waren 51 gesunde Personen. Die Ursachen der signifikanten Herabsetzung der Erythrocyten-Acetylcholinesterase in der Gruppe der Risikoarbeiter wurden besprochen.

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Clinical significance of acetylcholinesterase levels in neurological patients and in subjects in contact with organophosphate compounds

Summary A survey of erythrocyte and plasma cholinesterase levels in the group of 826 neurological patients with various diagnoses, and of 69 workers exposed for a long time to subtoxic doses of Organophosphate compounds. In the control group there were 51 healthy subjects. An analysis was made of the etiology of the significant decrease in erythrocyte cholinesterase levels both in the group of the neurological patients and that of the exposed workers.

     

Ontogenetic development of rhythmic thalamo-cortical phenomena in the rat

MARE?, P., D. MARE?OVÁ, S. TROJAN AND J. FISCHER. Ontogenetic development of rhythmic thalamo-corticalphenomena in the rat. BRAIN RES. BULL. 8(6) 765–769 1982.—Three rhythmic cortical phenomena (rhythmic afterdischarges, incremental responses and self-sustained after-discharges formed by spike-and-wave rhythm) were elicited by electrical stimulation of thalamic nuclei during ontogenesis in rats. All three phenomena could be recorded for the first time at the age of 12 days and they matured until the 18th postnatal day. Possible explanation for the delayed development of these rhythmic thalamo-cortical phenomena in comparison with single thalamo-cortical responses are discussed.     

Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment

The synthesis, characterization, and in vitro evaluation of a combination delivery of multiblock poly(N-2-hydroxypropyl)methacrylamide (HPMA), gemcitabine (GEM) and paclitaxel (PTX) conjugates is described in this study. Multiblock copolymer conjugates of a large molecular weight (M_w > 200 kDa) were studied and compared to traditional, small molecular weight (M_w < 45 kDa) conjugates. Stability of the conjugates in different pH was assessed, and their cytotoxicity in combination toward A2780 human ovarian cancer cells was evaluated by combination index analysis. Treatment duration (4 and 72 h) and sequence of addition were explored. In addition, an HPMA copolymer conjugate with both GEM and PTX in the side chains was evaluated in a similar manner and compared to a physical mixture of individual conjugates. Conjugates with narrow molecular weight distribution (M_w/M_n < 1.1) were obtained via RAFT polymerization, and drug loadings of between 5.5 and 9.2 wt% were achieved. Conjugates demonstrated moderate stability with less than 65% release over 24 h at pH 7.4, and near complete drug release in the presence of the lysosomal enzyme cathepsin B in 3 h. In combination, the cytotoxic effects of a mixture of the conjugates were primarily additive. Synergistic effects were observed when A2780 human ovarian cancer cells were treated simultaneously for 4 h with multiblock conjugates (CI < 0.7). When both GEM and PTX were conjugated to the same copolymer backbone, moderate antagonism (CI 1.3–1.6) was observed. These results demonstrate that multiblock HPMA copolymer–GEM and –PTX conjugates, when delivered as a mixture of individual agents, are promising for the treatment of ovarian cancer.