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Biomedical subjects

G Stark

Publications and source records attributed to G Stark.

At least 37 records · Page 2Linked to original sources

Zinc and copper plasma levels in Icelandic horses with Culicoides hypersensitivity.

Zinc concentration has been shown to have a potent immunomodulatory capacity, particularly influencing T helper cell organisation and cytokine secretion. Culicoides hypersensitivity (CHS) in horses resembles the early and late phase of type I hypersensitive reactions in man, characterised by a shift from T helper cell subtype 1 to T helper cell subtype 2 cytokine profile. In this pilot study, zinc and copper levels were measured in the plasma of 48 CHS-affected and 56 healthy Icelandic horses age 4-25 years (mean approximately 11 years) kept on 7 farms. Affected horses were divided into 3 groups according to the severity of disease. Time of blood collection and feeding management was constant. No differences in zinc or copper plasma levels and plasma copper/zinc ratio were determined among CHS horses and controls by univariate analysis of variance. Therefore, the most significant influences on zinc and copper plasma levels were affected by the location of housing. However, Spearman correlation showed a negative coefficient between the plasma zinc concentration and the severity of CHS (r = -0.31). Due to a probability value of P = 0.002 the null hypothesis r = 0 is rejected, although only 9% of the total variation of plasma zinc is presently explained by its relationship to CHS. In contrast, the Spearman correlation coefficient between plasma copper levels and severity of CHS was not significant (r = -0.14; P = 0.16). The minor deviations in plasma zinc concentrations in association with the severity of CHS may be real or due to neurohumoral or cytokine-mediated mechanisms, but appear too minimal to be relevant.

Analysis of Variance↗

New approaches to the treatment of advanced prostate cancer.

Several presentations by attendees of the 11th International Prostate Cancer Update addressed recent advances in prostate cancer treatment. A study that examined whether a relationship exists between neuroendocrine (NE) cell differentiation and hormone-refractory prostate cancer (HRPC) concluded that the appearance of NE cells in prostatic carcinoma is an important phenomenon in the development of HRPC. Exisuland, a selective apoptotic antineoplastic drug, was compared to placebo in a recent study and was found to significantly inhibit the increase of prostate-specific antigen in patients who had undergone radical prostatectomy. A new dosing regimen for flutamide (500 mg daily) was found to have no significant differences from the currently recommended dose (250 mg every 8 hours); the new, single daily dose could meet with greater compliance and would reduce drug cost by 30%. The antiproliferative effect of vitamin D on prostatic carcinoma cells was discussed, along with the possible role of vitamin D supplementation during prostate cancer treatment. Finally, a presentation on hospice care acknowledged that referral for such care is unfortunately at times delayed by physicians, patients, and patients' families, leaving insufficient time for all the benefits of that stage of care to be realized.

Journal Article↗

Free radical induced inactivation of creatine kinase: sites of interaction, protection, and recovery.

The study aims at a clarification of the oxidative damage of creatine kinase isoenzymes by X-ray-induced water radiolysis. The radical species generated by this method (under appropriate conditions) are similar to those discussed in the context of mitochondrial energy metabolism. The decay of the enzyme activity is accompanied by a strong decrease of the number of accessible SH groups and by a reduction of the endogenous tryptophan fluorescence. Free radical effects are diminished if irradiation is carried out in the presence of 2-mercaptoethanol. Partial recovery of the activity (repair) is observed if 2-mercaptoethanol is added after irradiation. The experiments suggest a twofold importance of thiol reagents (RSH): to reduce the concentration of free radicals by scavenger reactions and to modify the inactivation mechanism in such a way that efficient repair of enzyme damage may be achieved. Cysteine 282 of MM-CK (Cys-278 in the case of Mi-CK) seems to play a crucial role in this respect. Blockage of the SH group of cysteine 282 by oxidized glutathione effectively protects the enzyme against inactivation by NO(*)(2) radicals. In the absence of nitrogen dioxide and of thiol reagents, however, inactivation seems to proceed via a less specific mechanism involving additional targets of the enzyme.

Animals↗

Cernilton for benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH), nonmalignant enlargement of the prostate, can lead to obstructive and irritative lower urinary tract symptoms (LUTS). The pharmacologic use of plants and herbs (phytotherapy) for the treatment of LUTS associated with BPH has been growing steadily. Cernilton, prepared from the rye-grass pollen Secale cereale, is one of the several phytotherapeutic agents available for the treatment of BPH. OBJECTIVES: This systematic review aims to assess the effects of Cernilton on urinary symptoms and flow measures in men with benign prostatic hyperplasia (BPH). SEARCH STRATEGY: Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library, Phytodok), by checking bibliographies, and by contacting manufacturers and researchers. SELECTION CRITERIA: Trials were eligible if they were: (1) randomized controlled trials or controlled clinical trials comparing Cernilton with placebo or other BPH medications in men with BPH; and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. Main outcome measure for comparing the effects of Cernilton with placebo and standard BPH medications were the change in urologic symptoms scales. Secondary outcomes included changes in nocturia as well as urodynamic measures (peak and mean urine flow, residual volume, prostate size). Main outcome measure for side effects was the number of men reporting side effects. MAIN RESULTS: 444 men were enrolled in 2 placebo-controlled and 2 comparative trials lasting from 12 to 24 weeks. Three studies used a double-blind method although treatment allocation concealment was unclear in all. Cernilton improved "self rated urinary symptoms" (percent reporting satisfactory or improving symptoms) versus placebo and Tadenan. The weighted risk ratio (RR) for self-rated improvement versus placebo was 2.40 [95% CI = 1.21, 4. 75], and the weighted RR versus Tadenan was 1.42 [95% CI = 1.21, 4. 75]. Cernilton reduced nocturia compared with placebo and Paraprost. Versus placebo, the weighted RR was 2.05 [95% CI = 1.41, 3.00], and versus Paraprost, the WMD was -0.40 times per evening [95% CI = -0. 73, -0.07]. Cernilton did not improve urinary flow rates, residual volume or prostate size compared to placebo or the comparative study agents. Adverse events were rare and mild. The withdrawal rate for Cernilton was 4.8% compared to 2.7% for placebo and 5.2% for Paraprost. REVIEWER'S CONCLUSIONS: The Cernilton trials analyzed were limited by short duration, limited number of enrollees, gaps in reported outcomes, and unknown quality of the preparations utilized. The comparative trials lacked a proven active control. The available evidence suggests Cernilton is well tolerated and modestly improves overall urologic symptoms including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton.

Humans↗

Beta-sitosterols for benign prostatic hyperplasia.

OBJECTIVES: This systematic review aimed to assess the effects of beta-sitosterols (B-sitosterol) on urinary symptoms and flow measures in men with of benign prostatic hyperplasia (BPH). SEARCH STRATEGY: Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library, Phytodok), by checking bibliographies, and by contacting manufacturers and researchers. SELECTION CRITERIA: Trials were eligible for inclusion provided they (1) randomized men with BPH to receive B-sitosterol preparations in comparison to placebo or other BPH medications, and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. Main outcome measure for comparing the effectiveness of B-sitosterols with placebo and standard BPH medications was the change in urologic symptom scale scores. Secondary outcomes included changes in nocturia as well as urodynamic measures (peak and mean urine flow, residual volume, prostate size). Main outcome measure for side effects was the number of men reporting side effects. MAIN RESULTS: 519 men from 4 randomized, placebo-controlled, double-blind trials, (lasting 4 to 26 weeks) were assessed. 3 trials used non-glucosidic B-sitosterols and one utilized a preparation that contained 100% B-sitosteryl-B-D-glucoside. B-Sitosterols improved urinary symptom scores and flow measures. The weighted mean difference (WMD) for the IPSS was -4.9 IPSS points (95%CI = -6.3 to -3.5, n = 2 studies). The WMD for peak urine flow was 3.91 ml/sec (95%CI = 0.91 to 6.90, n = 4 studies) and the WMD for residual volume was -28.62 ml (95%CI = -41. 42 to -15.83, n = 4 studies). The trial using 100% B-sitosteryl-B-D-glucoside (WA184) show improvement in urinary flow measures. B-sitosterols did not reduce prostate size. Withdrawal rates for men assigned to B-sitosterol and placebo were 7.8% and 8. 0%, respectively. REVIEWER'S CONCLUSIONS: The evidence suggests non-glucosidic B-sitosterols improve urinary symptoms and flow measures. Their long term effectiveness, safety and ability to prevent BPH complications are not known.

Humans↗

Serenoa repens for benign prostatic hyperplasia.

OBJECTIVES: This systematic review aimed to assess the effects of Serenoa repens in the treatment of Benign Prostatic Hyperplasia (BPH). SEARCH STRATEGY: Trials were searched in computerized general and specialized databases (MEDLINE, EMBASE, Cochrane Library, Phytodok), by checking bibliographies, and by contacting manufacturers and researchers. SELECTION CRITERIA: Trials were eligible if they (1) randomized men with BPH to receive preparations of Serenoa repens (alone or in combination) in comparison with placebo or other BPH medications, and (2) included clinical outcomes such as urologic symptom scales, symptoms, or urodynamic measurements. Eligibility was assessed by at least two independent observers. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes was extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of Serenoa repens with placebo or other BPH medications was the change in urologic symptom scale scores. Secondary outcomes included changes in nocturia and urodynamic measures. The main outcome measure for side effects was the number of men reporting side effects. MAIN RESULTS: 2939 men from18 randomized trials lasting 4 to 48 weeks were assessed. 16 trials were double-blinded and treatment allocation concealment was adequate in 9 studies. Compared with placebo, Serenoa repens improved urinary symptom scores, symptoms, and urinary flow measures. The weighted mean difference (WMD) for the urinary symptom score was -1.41 points (scale range 0-19), (95%CI = -2.52, -0.30, n = 1 study) and the risk ratio (RR) for self rated improvement was 1.75 (95%CI = 1.21, 2.54, n = 6 studies). The WMD for nocturia was -0.76 times per evening (95%CI = -1.22, -0.32; n = 10 studies). The WMD for peak urine flow was 1.93 ml/sec (95%CI = 0.72, 3.14, n = 8 studies). Compared with finasteride, Serenoa repens produced similar improvements in urinary symptom scores (WMD = 0.37 IPSS points (scale range 0-35), 95%CI = -0.45, 1.19, n = 2 studies) and peak urine flow (WMD = -0.74 ml/sec, 95%CI = -1.66, 0.18, n = 2 studies). Adverse effects due to Serenoa repens were mild and infrequent. Withdrawal rates in men assigned to placebo, Serenoa repens or finasteride were 7%, 9%, and 11%, respectively. REVIEWER'S CONCLUSIONS: The evidence suggests that Serenoa repens improves urologic symptoms and flow measures compared with placebo. Serenoa repens produced similar improvement in urinary symptoms and flow compared to finasteride and is associated with fewer adverse treatment events. The long term effectiveness, safety and ability to prevent BPH complications are not known.

Androgen Antagonists↗

T1-deficient and T1-Fc-transgenic mice develop a normal protective Th2-type immune response following infection with Nippostrongylus brasiliensis.

The IL-1 receptor-related protein T1 is expressed on the surface of Th2, but not Th1 cells. Studies with anti-T1 monoclonal antibodies have suggested that T1 is critical for development of normal Th2-type responses. To elucidate the role of T1 in vivo, we generated T1-deficient mice and a T1-transgenic strain which secretes soluble T1-Fc fusion protein into the serum. These were analyzed for the Th2 immune response induced by infection with the parasitic nematode Nippostrongylus brasiliensis. Although Th2 cytokine production by lymph node cells was similar in all groups of N. brasiliensis-infected mice, a decrease in IL-5 production by lung lymphocytes was detected in both T1-deficient and T1-Fc-transgenic mice compared to control littermates. This difference in IL-5 production did not influence blood eosinophilia, but recruitment of eosinophils into lung tissue, especially in T1-Fc-transgenic mice was slightly decreased. However, induction of all other immune parameters was normal and both T1-deficient and T1-Fc-transgenic mice were able to clear the parasite infection within 12 days with kinetics similar to those in control mice. Therefore, in contrast to previous suggestions, we conclude that the T1 protein is not obligatory for normal development of Th2 immune responses.

Animals↗

Inverse dose-rate effects at the level of proteins observed in the presence of lipids.

PURPOSE: Radical-chain mechanisms such as lipid peroxidation are known to show an inverse dose-rate effect, i.e. the radiation effect increases with decreasing dose rate at identical doses applied. The present study was intended to investigate whether an inverse dose-rate effect can be transferred from the level of lipids to the level of proteins. METHOD: Functional inactivation or structural modification by 80kV X-rays of two classes of proteins was investigated: membrane proteins with a natural environment of lipids like the Ca-ATPase of the sarcoplasmic reticulum, succinate dehydrogenase and F0F1-ATPase from the inner mitochondrial membrane. The second class comprises the water-soluble proteins cytosolic creatine kinase (MM-CK) and bovine serum albumin (BSA). Their modification by free radicals of water radiolysis was investigated in the absence and presence of lipid vesicles. RESULTS: For all proteins investigated, an inverse dose-rate effect was observed in the presence of lipids. This also holds for the water-soluble proteins MM-CK and BSA. In the latter two cases, the dose-rate effect disappeared either in the absence of (unsaturated) lipids or in the presence of alpha-tocopherol. CONCLUSION: The largely identical results obtained for a variety of different proteins indicate that inverse dose-rate effects are a normal consequence of radiation induced protein damage in the presence of lipids. In view of the high amount of cellular lipids, this should also hold for the situation in vivo, although due to the comparatively high concentration of intracellular antioxidants the dose-rate dependence might be strongly reduced or even virtually abolished.

Animals↗

Efficacy of the novel calcium antagonist R(+)-semotiadil in limiting the ventricular rate during atrial flutter in isolated guinea pig hearts.

Ca2+ antagonists slow the ventricular rate by blocking conduction in the anterograde direction through the atrioventricular (AV) node. The aim of this study was to investigate the efficacy of the novel Ca2+ antagonist semotiadil compared with verapamil and diltiazem on the filtering capacity of the AV node during simulated atrial flutter in isolated guinea-pig hearts perfused by the method of Langendorff. During sinus rhythm, semotiadil as well as verapamil and diltiazem induced comparable depressant effects on AV-nodal conduction time and, during tachycardia, a comparable enhancement of this effect. The time constant (tau-on) for the drug-specific rate-dependent effect on AV-nodal conduction slowing was longest in the presence of verapamil compared with the long tau-on of semotiadil and the short tau-on of diltiazem. Verapamil and semotiadil exhibited a significantly greater effect than diltiazem on the mean ventricular cycle length (VCLmeun), on the maximal ventricular cycle length (VCLmax) and on the standard deviation of the VCL (SD(VCL)) during atrial flutter. Therefore the kinetics of the rate adaptation of AV-nodal conduction time in the presence of Ca2+ antagonists predicts the filtering capacity of the AV node during atrial flutter. Semotiadil has a verapamil type of action on ventricular cycle length during atrial flutter, whereas the disadvantageous prolongation of maximal VCL as well as the dispersion of VCL with semotiadil was only about half those found with verapamil.

Animals↗

Pulmonary embolism and intracardiac thrombi--individual therapeutic procedures.

Mobile right heart thrombus is a severe but rare presentation of thromboembolic disease and usually coexists with an already massive pulmonary embolism (PE). But looking at the literature there is no clear consensus on therapeutic management. We therefore tried to find possible therapeutic guidelines and to evaluate an optimal diagnostic procedure looking at three patients who presented at our department with mobile right heart thrombus in the last year. The first patient with a small (diameter = 1 cm) thrombus in the right ventricle and peripheral pulmonary embolism underwent successful thrombolytic therapy without any complications. Patients II and III showed large intracardiac masses, in patient III extending into the superior vena cava, with central PE. These two patients underwent pulmonary arteriotomy. The diagnostic line in each case was transthoracal echocardiography followed by a helix lung CT scan. Only patients with small intracardiac thrombi and thrombotic masses in the peripheral pulmonary arteries but with hemodynamically significant PE should be treated with thrombolytic agents.

Coronary Thrombosis↗

Osteomyelitis of the spine and abscess formation in the left thigh after stent-graft implantation in the superficial femoral artery.

PURPOSE: To present a rare case of abscess formation around a covered stent in the superficial femoral artery. METHODS AND RESULTS: Two weeks after balloon dilation of a left superficial femoral artery (SFA) occlusion, during which a Hemobahn covered stent had been placed to treat dissection, a 77-year-old nondiabetic male developed intolerable pain and swelling of his left thigh. An abscess had formed around the stent, which was patent; intravenous antibiotic therapy quelled the symptoms, and the patient discontinued his oral antibiotic regimen weeks after discharge. General septicemia ensued. Acute lower limb ischemia and excruciating back pain prompted readmission. The SFA stent-graft occlusion required femoropopliteal bypass; the abscess and spondylodiskitis that had developed in the T12 and L1 vertebrae responded to intravenous antibiotics. The patient is without signs of infection at 6 months. CONCLUSIONS: Local and systemic infections associated with intraluminal prostheses are rare, and prophylactic antibiotic therapy is not commonly employed. Balloon- or device-induced arterial injury may expose the arterial wall to bacterial colonization, suggesting that patients receiving lengthy stents or experiencing arterial injury during angioplasty should receive antibiotics as a precautionary measure.

Abscess↗

Free radical-induced inactivation of creatine kinase: influence on the octameric and dimeric states of the mitochondrial enzyme (Mib-CK).

Free radicals of X-ray-induced water radiolysis, either directly or indirectly via their reaction products, reduce the activity of both dimeric cytoplasmic muscle-type creatine kinase (MM-CK) and octameric mitochondrial creatine kinase (Mi-CK) to virtually zero. Similarly values of the characteristic D(37)-dose of enzyme inactivation (dose required to reduce enzyme activity to 37%) were found for the two isoenzymes of CK under identical conditions. Octamer stability was not significantly affected within the dose range considered. However, both the dissociation of octamers into dimers by a transition-state analogue complex (TSAC), and the reassociation of the dimers into octamers, showed dose-dependent reduction. Binding of the TSAC to the active centre was found to protect the enzyme against inactivation by free radicals. No protection was observed for the radiation-induced decrease of the endogenous tryptophan fluorescence. The experimental results are in line with the following interpretation: (i) the reduction of Mi(b)-CK dimer association is due to free radical-induced modification of Trp-264, situated at the dimer/dimer interface; (ii) the active-site Trp-223 is not a prime target for free radicals and is not involved in the inactivation of the enzyme; (iii) the inhibition of TSAC-induced dissociation of Mi(b)-CK, like enzyme inactivation, is primarily due to a modification of the active-site Cys-278.

Animals↗

Deficient T cell fate specification in mice with an induced inactivation of Notch1.

Notch proteins are cell surface receptors that mediate developmental cell specification events. To explore the function of murine Notch1, an essential portion of the gene was flanked with loxP sites and inactivation induced via interferon-regulated Cre recombinase. Mice with a neonatally induced loss of Notch1 function were transiently growth retarded and had a severe deficiency in thymocyte development. Competitive repopulation of lethally irradiated wild-type hosts with wild-type- and Notch1-deficient bone marrow revealed a cell autonomous blockage in T cell development at an early stage, before expression of T cell lineage markers. Notch1-deficient bone marrow did, however, contribute normally to all other hematopoietic lineages. These findings suggest that Notch1 plays an obligatory and selective role in T cell lineage induction.

Animals↗

Radiolytic and photodynamic modifications of ion transport through the plasma membrane of OK cells: a comparison.

PURPOSE: This study seeks to compare functional modifications of the plasma membrane induced either by water radiolysis (80 kV X-rays) or by visible light in the presence of the photosensitizer photofrin II. The two methods generate different kinds of free radicals and other reactive species such as singlet oxygen. Their effect on the electrical properties of the plasma membrane is investigated. METHOD: The patch-clamp technique (whole-cell and inside-out configuration) was applied to the plasma membrane of an epithelial cell line (opossum kidney (OK) cells). RESULTS: Generation of the reactive species gave rise to a decay of the membrane potential, to an inactivation of K+-channels, and to an increase of the leak conductance of the membrane. All three effects were strongly involved in photomodification of the membrane. Following X-ray exposure (doses up to 1000 Gy) on the other hand, the decay of the membrane conductance caused by inactivation of ion channels was predominant, while the increase of the leak conductance and the depolarization were comparatively minor responses. CONCLUSION: Photomodification of the plasma membrane by visible light in the presence of the membrane-active sensitizer photofrin II is of considerably greater consequence for the electrical properties of the membrane, compared with exposure to ionizing radiation of the membrane and its aqueous environment. The differences are thought to reflect the types of reactive species produced by the two methods and their site of generation.

Animals↗

[Marine toxins].

The consumption of seafood, which is contaminated by toxines of red tides, is a common cause of disease in tropic regions. The most important diseases, which are caused by red tides are Paralytic Shellfish Poisoning (PSP), Diarrhetic Shellfish Poisoning (DSP), Neurotoxic Shellfish Poisoning (NSP), Amnesic Shellfish Poisoning (ASP), Ciguatera Fish Poisoning (CFP).

Americas↗

Photofrin II sensitized modifications of ion transport across the plasma membrane of an epithelial cell line: I. Electrical measurements at the whole-cell level.

Photofrin II is a photosensitizer frequently applied in photodynamic therapy. Light-induced tumor cell inactivation observed in the presence of this substance has been suggested to start with modifications at the level of cellular membranes. In the present study electrophysiological techniques are applied in order to investigate the action of photofrin II on functional properties of the plasma membrane of opossum kidney (OK) cells (as an epithelial model system) and of fibroblasts. Illumination of the cells in the presence of photofrin II (or Zn-phthalocyanine) leads to comparatively fast depolarization of the membrane potential. It is caused by a strong change of the membrane conductance which proceeds in two phases. Both phases contribute to a loss of ion selectivity of the plasma membrane between K+ and Na+. In the first phase, specific pathways for K+, which determine the resting potential under physiological conditions, are inactivated. The second phase is distinguished by a marked increase of a nonselective conductance. The increase of the latter - after light-induced initiation - continues in the dark. The conclusions are derived from light-induced, time-dependent changes of the membrane conductance and of the shape of the current-voltage relationship detected under different experimental conditions.

Animals↗

Photofrin II sensitized modifications of ion transport across the plasma membrane of an epithelial cell line: II. Analysis at the level of membrane patches.

In the first part of this study, photofrin II sensitized membrane modifications of OK-cells were investigated at the level of macroscopic membrane currents. In this second part, the inside-out configuration of the patch-clamp technique is applied to analyze the phenomena at the microscopic level. It is shown that the characteristic single channel fluctuations of the electric current disappear after the start of illumination of membrane patches in the presence of photofrin II. This holds for all three types of ion channels investigated: the large-conductance Ca2+-dependent K+ channel (maxi-KCa), a K+ channel of small conductance (sK), and a stretch-activated nonselective cation channel (SA-cat). Part of the experiments show a transient activation of the channels (indicated by an increase of the probability in the open-channel state) before the channels are converted into a closed nonconductive state. Inactivation of all three channel types proceeds by a continuous reduction of their open probability, while the single channel conductance values are not affected. The process of photodynamically induced channel inactivation is followed by a pronounced increase of the leak conductance of the plasma membrane. The latter process - after light-induced initiation - is found to continue in the dark. The ionic pathways underlying the leak conductance also allow permeation of Ca2+ ions. The resulting Ca2+-flux may contribute to the photodynamically induced increase of the intracellular Ca2+ concentration observed in various cell lines.

Animals↗