Biomedical subjects
Publications and source records attributed to R Jacob.
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Submicron ultrahigh-molecular-weight polyethylene (UHMWPE) wear particles from total joint prostheses may contribute to implant failure through particle-mediated aseptic loosening. The purpose of this study was to examine the microstructure of virgin UHMWPE powder to determine its morphology for future comparison with wear debris. A new method of low-voltage scanning electron microscopy (LVSEM) in an oil-free vacuum was applied, which produced high-resolution images of UHMWPE micromorphology, while minimizing specimen damage and obviating the need for image processing. GUR 415 UHMWPE virgin powder particles were examined by using routine high-voltage SEM, LVSEM, and image analyses. LVSEM showed that UHMWPE particles were composed of submicron-size spherical subparticles connected by numerous nanometer-size fibrils. These spherical subparticles had a highly textured surface morphology seen only by LVSEM. Fracture of the nanometer-size fibrils was observed. Routine high-voltage SEM obfuscates the intricate and delicate UHMWPE micromorphology as well as the damage done by the accompanying high-voltage electrons. This study suggests that the micromorphology of wear particles previously studied with routine high-voltage SEM was overlooked or damaged, justifies the need for LVSEM in future studies, and raises the question of what is the true morphology of polyethylene wear debris retrieved from human tissues.
A sympathetic overactivity plays a major role in the pathogenesis of cardiovascular diseases in Westernized affluent societies. Of importance is an increased caloric intake and psychosocial stress which are associated with a raised central sympathetic outflow and unfavourable changes in metabolic parameters. Normalization of central sympathetic outflow could thus be a major therapeutic target. The newly developed antihypertensive drugs moxonidine and rilmenidine reduce the excitatory activity of neurons of the rostral ventrolateral medulla (RVLM) via binding to imidazoline receptors. Using radio telemetry, it is shown that, in contrast to the first generation centrally acting drug clonidine, moxonidine did not result in rebound of blood pressure after drug withdrawal in rats with spontaneous hypertension. In accordance, moxonidine is characterized by a low affinity for alpha-adrenoceptors and exhibits few side-effects. It is proposed that normalization of central sympathetic outflow represents a causal approach for improving crucial features of the metabolic syndrome.
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BACKGROUND: Due to a high rate of false negative results, cytologic examinations of scrapings are currently not very common in diagnosing squamous cell carcinomas of the upper aerodigestive tract. The purpose of the present study was to determine whether cytometric and cytologic examinations are suitable in diagnosing squamous cell carcinomas of the oral cavity and oropharynx. METHODS: Cytologic and cytometric examinations of rinsing fluid from the mouth and throat were performed in 14 patients with histologically confirmed squamous cell carcinomas of the oral cavity and oropharynx. The patients were asked to rinse their mouth and throat with 10 ml of Ringer's solution. The rinsing fluid was centrifuged and fixed. The sediment was then smeared onto glass slides and stained according to the technique of Feulgen. Quantitative DNA measurements were then performed using a TV-based image analysis system. The DNA indices, 2 c DI, 5 c EE, and DNA entropy were determined from the single-cell measurements. RESULTS: The results of the carcinoma patient group were compared to those obtained in 19 patients without any evidence of cancer (control group). With this method, malignant and benign cells could be distinguished in all cases, i.e., all patients with a carcinoma could be identified as positive by this examination, whereas patients without evidence of cancer were identified as negative in all cases. CONCLUSIONS: The results of this pilot study show that quantitative DNA measurements might be a suitable tool for non-invasive screening of patients who are at high risk for developing a carcinoma in the upper aerodigestive tract and for follow-up of patients in order to detect tumor recurrence after successful initial treatment.
To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.
Carcinoma of the penis has a well documented metastatic pattern, regional lymph nodes being the predominant site of involvement. Distant metastasis is extremely rare, with a reported incidence of 1-10%. Osseous metastasis is even rarer and no case of metastasis to the spine has been reported previously. We present a case of carcinoma of the penis metastasizing to the spine.
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The influence of an intake of garlic powder (1% added to a standard chow for an 8 week period) on the susceptibility to ventricular arrhythmias under radical reperfusion was investigated in the isolated rat heart perfused with a modified Krebs-Henseleit solution and the generating system hypoxanthine/xanthine oxidase. The incidence of ventricular fibrillation (VF) after the reopening of the LAD was significantly reduced in the garlic group as compared to the untreated controls (VF: 50% vs 89%). As this protective effect might relate to radical scavenging capacities, two in vitro radical generating test systems were chosen where the garlic activity could be determined. Dose-dependently, garlic was able to capture the radicals. Interestingly, only the garlic extract, was active. The ethanol extract hardly showed any radical scavenging ability. According to this result, we concluded that an intact alliin-alliinase system is important for the activity of garlic. Further investigations were done with different tissues under oxidative stress conditions. The kinetics of each organ, were measured chemiluminometrically. Especially liver and kidney of garlic fed rats showed inhibiting effects. Finally, an attempt was made to relate these radical scavenging and lipidperoxidation inhibiting effects to respective garlic compounds. Two substances, allylmercaptane and diallyldisulfide, were proposed.
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Human small intestinal lactase-phlorizin hydrolase (LPH) is synthesized as a single-chain polypeptide precursor, prepro-LPH, that undergoes two sequential cleavage steps: the first in the endoplasmic reticulum to pro-LPH (215-kDa) and the second, following terminal glycosylation in the Golgi apparatus, to mature 160-kDa LPH (denoted LPH beta). The LPH beta molecule is subsequently targetted to the brush-border membrane. Characterization of the N-terminal profragment (denoted LPH alpha) of pro-LPH using an epitope-specific, anti-peptide polyclonal antibody reveals that LPH alpha (i) has an apparent molecular weight of approximately 100,000, (ii) is not associated with LPH beta after cleavage of pro-LPH has occurred, and (iii) is not transported to the cell surface or secreted into the extracellular medium. In biosynthetic labeling experiments, a clear precursor/product relationship could be demonstrated between pro-LPH and the LPH alpha and LPH beta polypeptides. Further, LPH alpha has a significantly shorter half-life than LPH beta. LPH alpha is neither N- nor O-glycosylated, despite the presence of 5 potential N-glycosylation sites. LPH alpha, which is rich in cysteine and hydrophobic amino acid residues, may fold rapidly into a tight and rigid globular domain in which carbohydrate attachment sites are no longer accessible to glycosyltransferases. When expressed independently in COS-1 cells, the LPH beta polypeptide forms a misfolded, transport-incompetent molecule. We propose a role for the LPH alpha domain within the pro-LPH molecule as an intramolecular chaperone during folding in the ER.
In fura-2-loaded ECV304 cells ionomycin elicited a saturable biphasic change in intracellular Ca2+ concentration ([Ca2+]i), where the initial phase represented mobilization of intracellular stores and the sustained component represented Ca2+ influx. To examine whether ionomycin could stimulate influx via a store-dependent mechanism. Mn2+ entry was monitored by the quenching of fura-2 fluorescence: influx was enhanced even after ionomycin wash-out, provided that internal stores were not refilled with Ca2+. Moreover, the maximal rate of histamine-stimulated Mn2+ entry was unaffected by ionomycin, suggesting a common route of entry. The Ca(2+)-entry blocker SK&F 96365 inhibited both the ionomycin-induced Mn2+ entry and the sustained [Ca2+]i response to the ionophore (leaving the initial peak [Ca2+]i response unaffected). In other experiments, although addition of ionomycin further increased the plateau phase induced by 100 microM histamine, the increase was completely abolished by pretreatment with the store Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA). Furthermore, in store-depleted cells, re-addition of 1 mM extracellular Ca2+ (in the presence of CPA plus histamine) led to a rapid rise in [Ca2+]i, dependent on Ca2+ influx, with kinetics that were not enhanced by ionomycin. These data suggest that ionomycin acts primarily at the level of the internal Ca2+ stores, so that, at the concentrations used here (< or = 1 microM), it increases Ca2+ (and Mn2+) influx via activation of endogenous entry pathways and not by plasmalemmal translocation.
Lactase-phlorizin hydrolase (LPH), a small intestinal brush-border glycoprotein, is synthesized as a single chain precursor (pro-LPH, M(r) = 215,000-230,000) that undergoes cleavage to the final mature form (LPHm, M(r) = 160,000 in the human). In the human and pig small intestine as well as in the colon carcinoma cell line Caco-2, this cleavage takes place intracellularly prior to insertion into the brush-border membrane. To assess the role of proteolytic cleavage on the transport, function, and sorting of LPH a stable Madin-Darby canine kidney cell line was generated which expresses LPH (denoted as MDCK-ML). Biosynthetic labeling experiments demonstrated that the transport kinetics and posttranslational processing pattern of LPH in this cell line are similar to those in intestinal cells. Moreover, the enzymatic activity was found to be indistinguishable from that of brush-border LPH (LPHm). The sorting of LPH was studied by biosynthetic labeling of cells grown on filters followed by cell surface immunoprecipitation. Here, we could demonstrate that the cleaved LPHm molecule was predominantly found at the apical membrane, whereas complex glycosylated uncleaved pro-LPH (pro-LPHc) was targeted to both domains, the apical as well as the basolateral. In pulse-chase experiments at 20 degrees C pro-LPH was arrested in the trans-Golgi network, and cleavage to LPHm did not take place. By contrast, when the chase temperature was raised to 37 degrees C transport of pro-LPHc resumed, and cleavage to LPHm occurred. We conclude that the proteolytic cleavage of pro-LPHc to LPHm is a post-trans-Golgi network event and is most likely not implicated in the sorting of LPH by exposition of otherwise masked sorting elements.
The fatty acid (FA) composition of the phospholipids of rat heart sarcolemma was studied after a 10-week feeding period of diets containing 10% of each of coconut oil, corn oil, linseed oil, and fish oil in comparison to a low fat diet. The major modifications observed were the following: (1) a general increase of the n-6 FA family upon corn oil administration; (2) a dual effect of linseed oil in increasing 18:2 n-6 (more than did corn oil) and decreasing 20:4 n-6 and 22:4 n-6. At the same time n-3 FA increased significantly; and (3) a significant fall in the n-6 FA following fish oil, and a marked rise in the n-3 FA. The 10-fold increase in 22:6 n-3 supports the hypothesis of an inhibition of arachidonate synthesis, as well as that of the competition for the incorporation sites of phospholipids. In general, the n-3 FA diets produced the replacement of the n-6 FA by the n-3 FA in membrane phospholipids, and led to a significant increase of the double bond index (DBI).
The aim of the study was to compare in terms of patient comfort, surgical requirements and anaesthetic safety, the difference between epidural and general anaesthesia in patients undergoing surgery of the anal canal. The study was undertaken on 50 adult patients undergoing anal surgery. By random allocation 25 were given a general anaesthetic while 25 were given a low-dose epidural using 0.375% bupivacaine. Advantages and disadvantages of both methods were noted in the study. It was concluded that low-dose epidural is a more effective means of providing analgesia, while maintaining adequate sphincter tone for surgery on the anal canal, than general anaesthesia.
BACKGROUND: Independently of the problem of atherogenesis, the amount and type of fat intake influences the risk of cardiac arrhythmias. However, the relative effectiveness of different fats and the underlying mechanisms are controversial. The aim of the present study was to compare the effects of various oil-enriched diets on the risk of ventricular arrhythmias in rat hearts under conditions of ischaemia and reperfusion and to help clarify the mechanisms underlying the differing effects of the oils on the occurrence of arrhythmias. METHODS: Over a 10-week period, we studied five groups of young male Wistar rats given a low-fat chow diet or one enriched with 10% hydrogenated coconut oil, corn oil, linseed oil or sardine oil. Electrocardiograms were recorded from the isolated hearts (Langendorff preparation) perfused with a modified Krebs-Henseleit solution. Ischaemia was induced by a 20 min occlusion of the left anterior descending coronary artery. In another series of experiments, a 10 min occlusion was followed by a 20 min reperfusion period. The times between the first occurrence of extrasystole and the incidence of ventricular tachycardia and fibrillation were determined. The size of the ischaemic zone was assessed using malachite green. The fatty acid composition of the myocardial tissue was analysed using gas chromatography. RESULTS: An increase in the risk of ventricular arrhythmias under conditions of both ischaemia and reperfusion was obvious in the rats that consumed large quantities of saturated fatty acids (coconut oil) and in the group with a very low intake of fat. Polyunsaturated fatty acids (PUFAs), particularly fish oil, exerted a protective effect. The incidence of ventricular fibrillation was 75% in the low-fat group, 67% in the coconut-oil group, 44% in the corn-oil group, 40% in the linseed-oil group and 10% in the fish-oil group. The time until the first occurrence of extrasystole, the incidence of ventricular tachycardia and the incidence of reperfusion-induced ventricular fibrillation were influenced in a similar manner. The size of the ischaemic zone was significantly reduced in the groups given diets enriched with PUFAs. All protective effects were abolished, however, by cyclooxygenase inhibition with aspirin. The fatty acid composition of myocardial tissue, the ratio of n-3 to n-6 fatty acids and the double-bond index were significantly affected by the various diets. CONCLUSION: Whereas saturated fatty acids are obviously proarrhythmic, diets enriched with n-6 or n-3 PUFAs both exert antiarrhythmic effects. Although n-3 fatty acids seem to be more effective, cardioprotection cannot simply be related to the replacement of n-6 by n-3 fatty acids in cardiac membrane phospholipids, given the beneficial effects of corn oil. In any case, replacement of n-3 by n-6 fatty acids is not the underlying mechanism. The overall reduction of prostaglandin formation cannot be the primary mechanism because the beneficial effects of diets rich in PUFAs were abolished by cyclooxygenase inhibition. We conlcude that, besides prostacyclin (PGI2 or PGI3), membrane fluidity and accompanying alterations in functional membrane proteins (e.g. protection from calcium overload) are key factors apart from vascular effects that influence the size of the ischaemic zone.
The radical scavenging capacity of garlic (allium sativum) has been investigated in vitro in radical generating systems by electron paramagnetic resonance (EPR) and low-level chemiluminescence measurements. Garlic (both the homogenate of 10% in physiological saline solution and its supernatant) was able to reduce the radicals generated by the Fenton reaction and trapped by phenyl-butyl-nitron for EPR measurements. Also radicals present in cigarette smoke could be reduced by garlic as judged from chemiluminescence in the presence of tert.-butyl-hydroperoxide. According to the in vitro measurements garlic contains substances which have significant radical scavenging capacity.
The susceptibility to ventricular arrhythmias under the conditions of cardiac ischemia and reperfusion was investigated in the Langendorff heart preparation of rats fed for eight weeks a standard chow enriched with 2% of pulverized wild garlic leaves. The isolated hearts were perfused with a modified Krebs-Henseleit solution. The incidence of ventricular fibrillation (VF) during 20 min occlusion of the descending branch of the left coronary artery (LAD) was significantly reduced in the wild garlic group as compared to untreated controls (20% vs 88%). The same holds for the size of the ischemic zone (33.6% vs 40.9% of heart weight). In the reperfusion experiments (5 min after 10 min ischemia), ventricular tachycardia (VT) occurred in 70% of the wild garlic group vs 100% in untreated controls and VF in 50% vs 90%. The time until occurrence of extrasystoles, VT or VR was prolonged. No significant alterations in cardiac fatty acid composition could be observed. Although the prostacyclin production was slightly increased in hearts of the wild garlic group, inhibition of cyclooxygenase by acetylsalicylic acid (ASA; aspirin) could not completely prevent the cardioprotective effects suggesting that the prostaglandin system does not play a decisive role in the cardioprotective action of wild garlic. Furthermore, a moderate angiotensin converting enzyme (ACE) inhibiting action of wild garlic was found in vitro as well as in vivo that could contribute to the cardioprotective and blood pressure lowering action of wild garlic. Whether a free radical scavenging activity of wild garlic is involved in its cardioprotective effects remains to be established.