An alternative hypothesis on the role of chemically induced protein droplet (alpha 2u-globulin) nephropathy in renal carcinogenesis. Based on associations between the accumulation of protein droplets containing alpha 2u-globulin in proximal tubular epithelial cells and increased incidences of renal tubular neoplasms in male rats, it has been suggested that the carcinogenicity of chemicals that cause alpha 2u-globulin nephropathy is unique to animals that synthesize this protein. Chemicals that caused alpha 2u-globulin nephropathy and renal carcinogenicity in male rats have not been shown to produce renal tumors in animals that lack the capability for hepatic alpha 2u-globulin synthesis, including female rats, male NBR rats, or mice of either sex. Because humans do not synthesize alpha 2u-globulin it has been suggested that chemicals which cause renal toxicity associated with alpha 2u-globulin accumulation do not pose an increased cancer risk to humans. In this review on the association between alpha 2u-globulin nephropathy and renal carcinogenesis, it is apparent that (a) there are data inconsistent with the hypothesis linking these occurrences, (b) alternative mechanisms of renal toxicity and carcinogenicity are plausible, (c) data on quantitative dose-response correspondences between the various stages of alpha 2u-globulin nephropathy and renal carcinogenicity are limited, and (d) a greater understanding of the molecular changes occurring during renal carcinogenesis is needed before assuming that the current hypothesis is correct. Future research aimed at resolving issues raised in this paper should help determine whether or not the association between alpha 2u-globulin nephropathy and renal carcinogenesis represents a cause-and-effect relationship.


[Two patients with liver cirrhosis who presented with alpha-fetoprotein values diagnostic of hepatocarcinoma but without evidence of neoplasms]. Two liver cirrhosis (LC) patients with all major risk factors for hepatocellular carcinoma (HCC) had, at presentation, serum alfa-fetoprotein levels (AFP) higher than 500 ng/ml, usually considered diagnostic for HCC. They had elevated serum ALT levels too. No neoplastic liver lesions were detected by imaging techniques in both cases. During the following three months we noted a progressive improvement of clinical conditions with contextual normalization of AFP and ALT values. Therefore we suggest, when AFP is strongly elevated in LC patients but no hepatic lesion is detectable, a check for AFP and ALT time-course, before diagnosis HCC.


[Efficacy and tolerability of iloprost in the treatment of digital vasculitis secondary to connective tissue diseases]. The authors have evaluated the effects of long-term treatment of digital vasculitis secondary to various types of connective tissue disease, Systemic Lupus Erythematosus (SLE), Progressive Systemic Sclerosis (PSS), Sjögren's Syndrome (SS), using iloprost. The drug has proven to be effective both in reducing pain and clinical symptoms induced by vasospastic phenomena, as well as in promoting the healing of serious acral ischemic lesions. In the patient with LES, clinical modifications of the local vasculitic phenomena have been associated with a contemporaneous remission of the disease. The persistence of the drug's clinical effects even after suspension of treatment, instrumental and biohumoral changes and concomitant systemic effects on the disease lead to the conclusion that the drug's effect, is not merely due its vasodilating action and its ability to interfere with the coagulative process, but rather must be sought within the context of a morpho-structural repair of the microcirculation.


Evaluation of methods for estimating renal medullary blood flow. Although only 10-15% of renal blood flow enters the medulla, renal medullary hemodynamics have been implicated as a key factor for the ability of the kidney to excrete concentrated or diluted urine and to be involved in sodium homeostasis. Due to the obvious importance of medullary hemodynamics, several methods have been developed or modified for estimating regional renal blood flow. The aim of the present paper is to evaluate critically the most commonly used methods available today. Those which are considered in this paper are: (1) albumin accumulation (Lilienfield), (2) rubidium-86 uptake, (3) transit time-indicator dilution, (4) red cell velocity tracking, (5) red cell flux (fluorescently labeled red cells) and (6) laser-Doppler flowmetry. Depending on the method of choice, the reported control values for renal medullary blood flow differ up to tenfold. Overall, it appears that the discrepancies in values obtained from the different methods will not be resolved until the methods are compared directly in the same animal and during different experimental conditions. Furthermore, one needs to understand and describe accurately the involved errors so that proper corrections can be made. It seems likely, however, that the majority of the techniques can be used to study relative changes, but attempts should not be made to draw conclusions about the absolute flow value. In this regard, the laser-Doppler method seems to be superior in its simplicity of use and its large advantage of continuous and relatively noninvasive measurement.


In vitro autoradiography reveals predominantly AT1 angiotensin II receptors in rat kidney. Angiotensin II (Ang II) receptor subtypes in the rat kidney were investigated by using type 1 (AT1) and type 2 (AT2) Ang II receptor antagonists to discriminate specific 125I-[Sar1,Ile8] Ang II binding sites with in vitro autoradiography. DuP 753, a nonpeptide Ang II antagonist specific for the AT1 sites, potently displaced binding in glomeruli (Ki = 23.9 +/- 3.3 nM) and proximal tubules (Ki = 43.4 +/- 17 nM). By contrast, the AT2 antagonists, PD 123177 and CGP 42112A, were very weak in competing for specific 125I-[Sar1,Ile8] Ang II binding sites. AT1 receptors, as determined in the presence of an excess concentration (10 microM) of the AT2 antagonist, PD 123177, account for 95% of total renal Ang II receptors, whereas AT2 receptors, as determined in the presence of an excess concentration (10 microM) of the AT1 antagonist, DuP 753, represent approximately 5% of total renal Ang II receptors. In addition, the reducing agent, dithiothreitol, produces a dose-dependent inhibition of Ang II receptor binding with an IC50 of 2 mM, a characteristic of the AT1 receptors. These findings indicate that the AT1 receptor is the predominant subtype at multiple anatomical sites in the rat kidney.


Measurement of human active renin heterogeneity. A method for the separation and quantitation of multiple forms of active renin in human plasma is described. Shallow gradient isoelectric focusing of plasma resolved active renin into seven distinct components in each of 10 healthy normal individuals. Plasma renin activity focused at isoelectric points of 5.71, 5.57, 5.47, 5.22, 5.08, 4.93, and 4.82 with corresponding proportions of 16.3, 15.4, 21.1, 20.3, 14.0, 10.0, and 2.5%. Silicon dioxide treatment of plasma significantly increased the yield of renin in the focusing gels. Although each individual plasma sample contained the same seven renin forms, there was variability in the relative proportions of the multiple renin forms between individuals. This variance was significantly greater than the variance introduced by the determination itself. The same seven active renin forms were also present in human renal cortical tissue. In conclusion, a method for the determination of multiple renin forms in plasma and renal cortical tissue is presented. At least seven active multiple renin forms were resolved in human plasma and renal cortex.


On the glomerular mechanism of the renal protein excretion. Studies in the isolated perfused rat kidney. The glomerular permeability of the isolated perfused kidney is manifold higher than in vivo, although structural changes at the glomerular filtration barrier are not described. It has been proposed that in vivo high molecular weight plasma proteins are concentrated at the glomerular endothelium forming an additional filtration barrier ('concentration polarization'). To test this hypothesis, isolated rat kidneys were perfused with substrate-enriched Krebs-Henseleit solutions containing albumin (50 g/l) or albumin/globulin (40/10 g/l), or with plasma. The pO2 was 675 mm Hg. Furthermore, experiments were carried out with the addition of erythrocytes with and without a reduced O2 supply (pO2 35 mm Hg). Independent of the composition of the perfusate a continuously increasing glomerular permeability was observed immediately after perfusion was started. After about 10 min, a steady state value for the glomerular permeability was reached. The addition of globulin to the perfusate or perfusion with plasma did not prevent the initial increase of the permeability. However, after addition of 5% erythrocytes to the perfusate the increase of permeability was much less pronounced. Neither the reduction of the O2 supply nor the addition of erythrocytes to a higher concentration than 5% had any further effect on the glomerular permeability. These data show that concentration polarization of high molecular weight proteins does not take place at the endothelium of the glomerulus. Independent of their ability to carry O2 erythrocytes play an important role in the glomerular filtration process.


Renal transport of endogenous amino acids. I. Comparison between immature and adult rats. In the late neonatal period of male Wistar rats (10 days old) concentrations in plasma were higher for 5 of 24 amino acids compared to adult animals (2 months old): beta-alanine, tyrosine, glycine, histidine, and the dipeptide anserine. The plasma concentrations of tryptophan, valine and leucine were lower in young than in adult rats. The renal clearances of amino acids were lower in young rats, both in relation to 1 g b.w. and related to 1 g kidney weight. In the latter case the differences became more distinct because the relative kidney weight was higher in young than in adult animals (1.17 +/- 0.07 vs. 0.82 +/- 0.03 g/100 g b.w.) and significant age differences in renal water content did not exist. The apparently more effective tubular reabsorption capacity in young rats can be explained as follows: Because of the significantly lower GFR in 10-day-old rats compared with adults (0.46 +/- 0.03 vs. 1.10 +/- 0.09 ml/min/1 g kidney), the glomerularly filtered load of amino acids is generally lower in young rats (exceptions: tyrosine, glycine). Therefore, the amino acid transporting carrier systems are able to reabsorb the absolutely lower amounts of amino acids from the ultrafiltrate in immature animals. This hypothesis is supported if one relates the renal amino acid clearance to the clearance of inulin. In this way it is possible to show that there are absolutely no differences between both age groups indicating mature transport systems for endogenous amino acids as early as in 10-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Antinociceptive effect of mexiletine in diabetic mice. We examined the effect of mexiletine on the threshold for pain perception as determined by the application of mechanical noxious stimuli (tail-pinch) in diabetic mice. Mexiletine produced a pronounced analgesic effect in diabetic mice in a dose-dependent manner. Mexiletine (10(-5)M) significantly inhibited the K(+)-evoked release of substance P from the slices of spinal cord of diabetic mice. These results suggest that the reduction of release of substance P from the nociceptive afferent terminal in the spinal cord is involved in the mechanisms of mexiletine analgesia in diabetic mice.


Renal transport of endogenous amino acids. II. Influence of treatment with triiodothyronine or dexamethasone in immature and adult rats. Repeated administration of triiodothyronine (T3, 20 micrograms/100 g b.w., once daily for 3 days) or dexamethasone (60 micrograms/100 g b.w., once daily for 3 days) caused significant changes of amino acid plasma concentrations in young (10 days old) and adult rats (2 months old). After treatment with T3, in young animals concentrations of beta-alanine, aspartic acid, glutamic acid, ornithine, asparagine, leucine, taurine, serine, alanine, and glutamine were enhanced, whereas those of tyrosine, arginine, and threonine were significantly diminished. In adult rats only slight changes occurred after both T3 and dexamethasone. In the kidney, the reabsorbed fraction of amino acids was enhanced after both T3 and dexamethasone treatment in young rats, whereas in adult rats the two hormones were without influence on tubular reabsorption of amino acids. Taken together, both different plasma concentrations of amino acids and changes in amounts of amino acids reabsorbed in the tubuli, in adult rats the fractional excretion of amino acids was nearly unchanged following hormone treatment (exception: significant increase in taurine clearance). But in young animals the fractional excretion was reduced in 15 of 22 amino acids after dexamethasone and in 12 of 23 amino acids after T3 treatment, indicating stimulatory effects of both hormones on tubular amino acid carrier systems in immature animals.


Ill-defined choroidal neovascularization within ocular histoplasmosis scars. Seven patients with scars typical of ocular histoplasmosis syndrome presented with new symptoms of decreased vision or metamorphopsia. In each patient the symptoms corresponded to an atrophic or "punched-out" histoplasmosis scar in the macula. Clinically, a small amount of subretinal fluid overlying the scars and slight hyperfluorescence were seen on fluorescein angiography. These findings were due to a choroidal neovascular membrane growing within the margins of the atrophic scar. The membranes were difficult to diagnose because of the absence of hemorrhage, pigmentation, or growth of vessels beyond the margins of the scar. Clinicians should be aware that these patients may have early and growing choroidal neovascularization and may need to undergo photocoagulation or to be followed closely.


[Prematurity: developments during the last decade at Erasmus Hospital. II. Long-term follow-up]. Morbidity and mortality of these preterm infants weighing < 1000 g at birth was reported in another paper. The mortality and neuro-developmental prognosis improved clearly in the last 3 years. A particular attention is given for protecting these babies against brain lesions. These ELBW have a high risk of neurodevelopmental disturbances. Therefore, a multidisciplinary team follows the neurological evolution to assess the quality of neonatal care and detect and treat developmental abnormalities as early as possible. We present the weight and height evolutions, the neurological, social and familial outcome of our 15 survivors. Economical and ethical discussions are open.


[Ethics versus ethos: current ethical problems in palliative oncology]. Difficult moral concerns and choices are a characteristic of palliative cancer medicine. Problems in patient information, palliative chemotherapy, treatment with unconventional remedies and clinical drug development are given as examples. The physician-scientist as member of a clinical cancer research institution particularly faces ethically troublesome situations. It is argued that next to the acquisition of bioethical competence by 'doing' staff, members working in scientific and medical frontiers should specifically be trained to identify, analyse and resolve ethical dilemmas. In conclusion, a biomedical ethics programme is presented which will be instituted at a new cancer center, comprising the establishment of a humanities research group, ethical liaison, consultation and information services as well as a system of inhouse bioethical quality control.


[Pathophysiology of bronchial asthma].

[Pathophysiology of bronchial asthma]. Until recently asthma was considered to be caused mainly by bronchospasm of the smooth airway musculature. Accordingly beta-adrenergic agonists were the drugs of choice. During the last decade, however it has become increasingly clear that ongoing chronic inflammation of the bronchial wall plays a prominent role in the disease process. During the early bronchoconstriction after allergen challenge, histamine is probably the most important mediator. The late reaction is characterized by an inflammatory infiltration of the bronchial wall, notably by eosinophils and lymphocytes. A complex interplay of mediators as leukotrienes, prostaglandins and PAF may lead to a chronic inflammation. Inflammatory changes are seen in bronchial biopsies and broncho-alveolar lavage fluid even of mild and asymptomatic asthmatic patients. Based on this new disease concept, antiinflammatory drugs have become the mainstay of therapy even in mild to moderate asthmatics. Beta-adrenergic agonists remain the most important drug for the relief of acute bronchospasm.


Elevated HbA1 due to foetal haemoglobinaemia in children. A common artifact of certain ion-exchange chromatography methods. Foetal haemoglobin (HbF) is known to elute with glycosylated haemoglobins (HbA1) in mini-column ion-exchange chromatography, thus producing falsely elevated values for HbA1 in subjects with foetal haemoglobinaemia. We studied the occurrence of this methodological artifact in 266 patients with suspected or known insulin-dependent diabetes mellitus (IDDM) and in 205 healthy children of various age groups. HbA1 was measured using ion-exchange chromatography with prefabricated mini-columns and HbA1c and HbF by high-performance liquid chromatography (HPLC). In healthy children of over 5 years of age, the HbA1 values were usually within the reference limits for adults. However, 69% of the children younger than 1 year of age and 7% of those 1-5 years of age had HbA1 levels above 10%. Their HbA1c values were normal but the HbF values were high. Six of the 223 patients with IDDM (2.7%) and three of the 43 patients with stress glucosuria (7%) had much higher HbA1 than HbA1c values. The discrepancy was again related to the presence of raised concentrations of HbF. We conclude that foetal haemoglobinaemia is more prevalent than was previously known, especially among children younger than 5 years of age. Presence of HbF will bias the use of HbA1 as a diagnostic aid or as an index of metabolic control in children with IDDM. Methods specific for HbA1c, such as HPLC, should be used in paediatric patients.


Evidence of a stimulatory effect of cyclic AMP on pancreatic lipase and colipase synthesis in rats. The effects of endogenous and exogenous cyclic AMP on the synthesis of pancreatic lipase, colipase, and amylase were studied. Pancreatic lobules were prepared and incubated with forskolin, dibutyryl cyclic AMP (dbcAMP), and dibutyryl cyclic GMP (dbcGMP), respectively, in the presence of 35S-cystine. The individual pancreatic enzymes were isolated by polyacrylamide gel electrophoresis, and the incorporation of radioactive cystine into lipase, colipase, and amylase was determined. Incubation with forskolin (25 microM) rapidly increased lipase synthesis rate within 30 min, followed by an increase in colipase synthesis rate after 60 min of incubation. Amylase synthesis rate did not change during the 1st h of incubation but decreased slightly when incubated for 2 h. Incubation of pancreatic lobules with dbcAMP (1 mM) for 1 h also stimulated the incorporation of cysteine into lipase and colipase by 21% and 25%, respectively, whereas incubation with dbcGMP had no effect on the synthesis rates of lipase and colipase. Neither dbcAMP nor dbcGMP had any effect on synthesis rate of amylase. It is concluded that cyclic AMP might be an important intracellular signal for the synthesis of pancreatic lipase and colipase in the rat.


Biliary stenting: cosmetic or clinical value? Since the initial description of endoscopic placement of transpapillary stents, this technique has gained wide acceptance in the management of pancreatico-biliary diseases. We now know by and large what can be achieved and what the complications are. Studies comparing endoscopic and surgical treatment in pancreatic cancer patients show an initial advantage of the endoscopic method, which is partly counterbalanced by the late complications of stent blockage. Clinical studies are necessary to define better the subgroups of patients that benefit most from the various treatment modalities. Further improvement is necessary to solve the problem of late stent occlusion.


Systemic therapy in disseminated melanoma. There is no standard treatment for advanced melanoma. As long as metastases are satellites or in-transit metastases localized in a leg or arm, the prospects for curative treatment by isolation perfusion are good. But as soon as metastases have spread via the circulation, curative treatment with cytotoxic agents becomes virtually impossible. When the tumor burden is not too extensive, however, palliative treatment can be of clinical value. Some combinations of cytotoxic agents or combinations of biologic response modifiers have been shown to induce worthwhile remissions. Toxicity remains a problem, however. The advantages of the newer immunological approaches, especially with interleukin-2 (IL-2) and T-cell lymphocytes, is that treatment for a short period may result in good remissions at an early stage. Much clinical research is still needed to improve these costly approaches.


Hypothesis for the control of clotting factor VIII inhibitory antibodies by decreasing potency of helper T-cell-recognized epitopes in factor VIII. The study of the immunobiology of FVIII inhibitors may lead to new therapies for this potentially severe complication of haemophilia A and to new principles for the use of therapeutic proteins. In order to characterize the idiotype-anti-idiotype networks regulating FVIII inhibitors, we developed rabbit anti-idiotypic sera to 7 murine inhibitors and found at least 12 independent FVIII loci to which inhibitors could be raised. Rabbit antisera to the FVIII peptide, Ser1687-Thr1695, characterized one functional site to which about 46% of patients' inhibitor sera reacted. The multiplicity of inhibitor-recognized epitopes in FVIII makes it impractical, at the present time, to develop clinically useful specific anti-idiotypic therapies for FVIII inhibitors. Alternatively, one might induce genomic mutations in recombinant FVIII molecules to decrease immunogenicity of epitopes recognized by T helper cells. Methods to design such altered therapeutic proteins are presented, based on changing the longitudinal hydrophobic strip-of-helix which is in or near many T-cell-presented epitopes.


Adhesion molecules involved in the interaction of LGL/NK cells and human endothelial cells stimulated with Salmonella bacteria. Previously we showed that pretreatment of LGL/NK or HUVE cells with Salmonella bacteria augments the adhesion of LGL/NK cells to endothelium. Here we analyse the roles of HUVEC adhesion molecules VCAM-1, ICAM-1 and E-selectin, and the counter-receptors VLA-4, LFA-1 and SLex in the increase of LGL/NK adhesion to HUVEC, stimulated with Salmonella Minnesota mR595 bacteria, LPS or TNF-alpha. On Salmonella-stimulated HUVEC, VCAM-1 and ICAM-1 were the major binding structures involved, and their effect was additive in monoclonal antibody inhibition experiments. We could demonstrate the induction of both structures on cultured HUVEC after 24 h of Salmonella stimulation in flow cytometric analysis. For Salmonella-stimulated LGL/NK, the principal binding structure was LFA-1. Stimulation of LGL/NK cells did not alter the expression of the adhesion structures (subunits CD11a/CD18, CD49d/CD29), as determined by flow cytometric analysis, and thus the increased adherence is presumably produced by an increased avidity of the receptors on LGL/NK cells. Pretreatment of endothelium or lymphocytes with various stimuli, including Salmonella bacteria or LPS, leads to an activation state which provides for characteristic anchorage sites for the increased migration of LGL/NK cells towards the site of inflammation.


Human blood dendritic cells exhibit a distinct T-cell-stimulating mechanism and differentiation pattern. In this study, the mechanisms underlying stimulation of T-cell proliferation by human blood dendritic cells (BDC) and their differentiation have been defined with a panel of monoclonal antibodies (MoAbs). It was found that the MoAbs against LFA-1 (CD11a), CD11c, LFA-3 (CD58), ICAM-1 (CD54) or HLA-DR could significantly suppress T-cell proliferation in an allogeneic mixed lymphocyte reaction (P < 0.05), while being unable to inhibit clustering of BDC with T cells. Addition of anti-CD18 or CD45 MoAbs increased the size of clusters after 18 h of culture, but had no effect on the proliferation of T cells (P < 0.05). The suppressive effect of the MoAbs may be viewed not as an inhibition of contact between BDC and T cells, but rather as a blocking of co-stimulatory signals for T-cell activation, which are mediated by interaction of the adhesion molecules. After depleting the BDC preparations of monocytes, we used a double staining in FACS analysis to demonstrate that BDC do not express specific T (CD3), B (CD20 and CD21) and myeloid cell markers (CD11b, CD13 and CD14), but abundant class II antigens. This pattern remained unaltered after 8 days of culture in the presence of 100 U/ml GM-CSF, although a threefold increase of HLA-DQ and ICAM-1 molecules on the cultured cells was observed.


Amino acid concentrations in plasma and skeletal muscle after transurethral resection syndrome. The concentrations of amino acids in plasma and skeletal muscle were measured 1 and 4 hours after transurethral prostatic resection in three patients who developed symptoms of the transurethral resection syndrome. The irrigating solution contained 1.5% of glycine and 1% of ethanol. The concentrations of glycine in plasma and muscle were equal within an hour of the operation, and at four hours the abnormally high glycine concentration persisted in muscle, though it had decreased rapidly in plasma. Our data suggest that skeletal muscle is a quantitatively important reservoir for glycine when this amino acid is supplied in potentially toxic amounts, but that the plasma glycine concentration returns to normal as the patient's clinical condition improves.


A comparison between two hypotonic irrigating solutions used in transurethral resections of the prostate: sorbitol (2%)-mannitol (1%) and 1.5% glycine solutions. Two hypotonic but non-haemolysing irrigating solutions, sorbitol-mannitol (2% + 1%) and glycine (1.5%), were compared in 40 TURP cases using a continuous resection technique. Ethanol (1%) was added to the irrigating fluid as a marker to make possible early detection of fluid absorption by breath analysis. Mannitol and sorbitol were determined in plasma and urine; glycine and ethanol were determined in plasma. Apparent absorbed fluid volumes were calculated from the immediate postoperative plasma concentrations of ethanol, mannitol, sorbitol and glycine and from the elimination of mannitol in urine during 24 hours following the operation. The use of a continuous operating technique with a suprapubic trocar resulted in very small absorptions (less than 1 l) in this series. The concentrations of the two solutes in the sorbitol-mannitol irrigating fluid were balanced so that the plasma concentrations immediately postoperatively were of the same order when absorption occurred. The sorbitol concentration declined more rapidly than the mannitol concentration in conformity with previous findings. In most cases the peak plasma level was observed immediately postoperatively but in some cases at a later time (during the interval 0-2 hours), indicating absorption from a depot of fluid accumulated extravesically in addition to direct intravenous absorption. The best estimate of fluid absorption seems to be obtained from the urinary elimination of mannitol, followed by estimates based on the plasma mannitol concentration immediately postoperatively. The plasma ethanol level determined at the same time gave an estimate of the same order, whereas plasma sorbitol and glycine levels gave lower estimates (owing to rapid redistribution and metabolism).(ABSTRACT TRUNCATED AT 250 WORDS)


Plasma protein homeostasis in chronic hemodialysis patients. The concentrations of 25 plasma proteins were measured in 29 patients with chronic renal insufficiency. All the patients had terminal renal failure and were treated with intermittent hemodialysis, but were otherwise in good general condition at the time of investigation. The plasma levels of 8 proteins with M(r) < 50 kD were significantly elevated compared to normal subjects. In contrast, only 2/17 proteins of greater size were found in increased concentrations. The degree of increase in concentration differed substantially between individual low molecular weight proteins, suggesting a complex metabolism in addition to delayed renal elimination. Acute phase proteins and immunoglobulins were not affected by renal insufficiency per se, although erythrocyte sedimentation rates were generally high. The synthesis of acute phase proteins increased normally during the course of inflammation. We conclude that although the sedimentation rate is of no value, complicating inflammatory processes can be traced by quantitative analysis of acute phase proteins, including C-reactive protein, even in patients with severe chronic renal insufficiency.


A prospective clinical five year follow up study after open synovectomy of the knee joint in patients with chronic inflammatory joint disease. The prognostic power of clinical, arthroscopic, histologic and immunohistologic variables. Arthroscopy and clinical examination was performed on the knee joint of 26 patients with chronic inflammatory joint disease, before and at 6 and 12 months after open synovectomy. Biopsies were examined by histologic and immunohistologic methods. Clinically the patients improved until 6 months after synovectomy, and the improvement was maintained for 5 years. Patients with the best clinical function prior to synovectomy also had the best long term results (p = 0.024). The state of the cartilage was the best predicting variable with a significant prognostic power (p = 0.01). Thus patients with normal cartilage at the time of synovectomy had the best clinical score five years later. The patients with most resynovitis 12 months after surgery did less well at five year clinical follow up (p = 0.032) than those with little or no resynovitis. Absence or low number of IgA-positive plasma cells in the cellular infiltrate at 12 months after surgery correlated with a good clinical score five years after surgery (p = 0.036). This suggests that a high number of IgA-positive plasma cells may be indicative of a more aggressive, destructive disease.


Histochemical demonstration and microanalysis of possible calcium binding sites in the enamel organ of rat incisors. The rat incisors obtained from rats perfused with high-calcium solution containing 30 to 50 mM CaCl2 were processed for rapid freeze/freeze-substitution and embedded in epoxy resin. GBHA staining, a histochemical staining for calcium, or unhydrously prepared sections revealed a large number of granular Ca-GBHA reactions in the enamel organ, most of which being located along the lateral plasma membranes of the ameloblasts. In the ameloblast layer, the reaction was negative in the presecretory stage, became intense in concert with the onset of enamel matrix formation, and remained so by the end of the transitional stage where the reaction gradually diminished. In the maturation stage, similar GBHA reactions emerged only in association with the smooth-ended ameloblasts and were absent in the ruffle-ended ameloblasts. Some granular reactions of much smaller diameter were occasionally noted in other cells of the enamel organ at both the secretory and maturation stages. Electron microscopy confirmed large electron-dense granules, each showing distinct peaks for Ca and P by microanalysis, associated with the cytoplasmic aspect of lateral plasma membranes of secretory, transitional, and smooth-ended ameloblasts. The present study thus revealed a strong calcium-binding property of the cytoplasmic aspect of lateral plasma membranes of secretory ameloblasts and its fluctuation in the maturation ameloblasts under the given experimental conditions. A necessity for an extensive analysis of membrane constituents of the enamel organ was proposed for better understanding of cellular roles in calcium regulation during amelogenesis.


[Cardiac interactions between ketanserin and the calcium antagonist nifedipine]. Ketanserin and calcium antagonists are frequently used for the treatment of arterial hypertension in the elderly. The possibility that combined treatment with ketanserin and the calcium antagonist nifedipine have a pro-arrhythmic effect was investigated in 20 normal volunteers aged > 60 years with normal or slightly elevated blood pressure. Each subject received monotherapy with ketanserin or nifedipine for 1 week and the combined treatment during the following week. Clinical and biochemical parameters, ECG and 24-hour ECG recording were monitored before and at the end of the first and second treatment weeks. Ketanserin and nifedipine given in monotherapy or in combination did not modify, on average, blood pressure, heart rate, the biochemical variables and the QT interval. In the 24-hour ECG recordings, 2 normal subjects developed a marked increase in the frequency of ventricular ectopics, couplets and ventricular tachycardia after combined treatment. Therefore, the present investigation does not exclude the possibility that combined treatment with ketanserin and nifedipine could increase the prevalence of arrhythmia in some elderly patients.


[Decreased narcissism in the aged and in suicide]. The elderly have less narcissism (= self-representation, narcissistic information, attention or libido) at their disposal to invest their own ego as well as the environment narcissistically. It therefore becomes more difficult to enlarge one's own self on encountering new persons, new environments and new customs. Some elderly may therefore feel more and more isolated and commit suicide. The rate of suicide attempts in the Canton (state) Basel-city shows a statistically significant decrease with higher age (p < 0.001) up to the age group of 60-69. Men of the age group > 80, however, manifest a significant increase in the rate of suicide attempts. The rate of fatal suicides for Swiss women increases with growing age, though not reaching statistical significance. In Basel-city, the suicide rate for women shows a rising tendency only up to the age group of 50-59 years. For Swiss men from 30-69 there is a steady, but not significant increase, which is still more pronounced from 60-69 to 70-79 (p < 0.05) and from 70-79 to > 80 (p < 0.01). For men of Basel-city the suicide rate shows, however, a clear peak in the age group 30-29 and, after a downwards trend until 40-49, an increase to a peak in the age group 60-69. From there the suicide rate stays level with a slightly decreasing trend. These statistical data seem generally to confirm, at least as a tendency, that suicide rates increase with growing age, i.e. with diminishing narcissism at one's disposal. The exception, the peak of suicides in young adults, is probably due to drug dependents who have taken their own lives. When working with elderly people, it is important to consider this reduction in narcissism and to work with them on an individual psychotherapeutic and eventually psychopharmacological but parallel also on a group basis. The individual psychotherapy should be directed toward supporting their self-confidence. In the supervision of two groups of elderlies, one of which was composed of older people who suffered from paranoid ideas, it was striking that during 75 sessions of working with this group the delusions receded and the patients became more and more communicative and no longer thought of committing suicide. In prevention it is important that the elderly be encouraged to seek participation in some group and/or family activities, though even then the individual freedom of each one not to participate in such events should be respected.


[A third kind of psychosis. Analysis of the literature]. Undoubtedly there exist atypical functional psychoses which differ significantly from schizophrenia and manic depressive illness. However, the atypical psychoses are conceptualized in various ways and they represent a quite heterogenous group of disorders. Regarding their main characteristics, they can be classified as 1. schizoaffective psychoses with a predominantly atypical phenomenology, 2. cycloid psychoses with a predominantly atypical course, and 3. psychogenic psychoses with a predominantly atypical etiology. For heuristic and clinical reasons it is recommendable: 1. to separate atypical psychoses from schizophrenia and manic depressive disorder and 2. to handle each of the three depicted forms of atypical psychoses as a different and independent group, regardless of possible overlaps.


[Effect of diagnostic habits on the incidence of psychiatric diagnoses]. In this study, we analyzed the frequency of ICD-9-diagnoses in 2,868 inpatients (spanning 3 consecutive years) who had been admitted to the Psychiatric Hospital at the University of Tübingen. "Paranoid schizophrenia" (15.8%), "endogenous monopolar depression" (11.2%), "alcohol dependency" (9.9%), "neurotic depression" (6.5%) and "schizoaffective psychosis" (5.3%) turned out to be the most frequently diagnosed illnesses. The diagnosis of 6 mental illnesses described more than 50% of our patient population. In a concurrent study physicians employed at the hospital filled out a questionnaire about their diagnostic style. According to the data physicians were not aware of their narrow diagnostic style. A comparison of physicians within each ward resulted in moderate diagnostic agreement insofar as their diagnoses was based on 4-digit-ICD-categories. When using 3-digit-diagnostic main categories, diagnostic agreement appeared to be higher.


Pure sensory stroke heralding large hemispheric infarction. A 49-year-old with long-standing hypertension and diabetes developed numbness and sensory loss over the left side of the body consistent with a diagnosis of Pure sensory stroke (PSS). However, CT showed a subcortical infarction in the middle cerebral artery (MCA) territory, which evolved a few hours later towards a large hemispheric infarction associated with severe neurologic worsening. Doppler ultrasounds showed ipsilateral carotid occlusion and contralateral severe stenosis. These findings suggest that PSS may sometimes herald large infarction in the MCA territory in association with carotid occlusion.


Does chronic lung failure lead to cognitive failure? This study seeks to find out whether impaired cognition is associated with Chronic Obstructive Pulmonary Disease (COPD). Two experiments have been carried out to address two aspects of selective attention: a focused attention paradigm with a random and a facilitated condition and a divided attention paradigm with and without interference. Twenty-eight COPD patients and 28 matched healthy controls took part in both experiments. Reaction time (RT) was the variable considered. COPD patients had slower RTs than controls, however facilitation and interference had the same effect on both groups. No correlation was found between neuropsychological measures and lung failure indices. A threshold model in the lung-failure/brain-failure trade-off is envisaged.


Neuropsychological evaluation of bleeding cirrhotic patients. The cognitive profile was evaluated after an acute episode of esophageal bleeding in 26 patients with non-alcoholic hepatic cirrhosis and no previous history of acute hepatic encephalopathy. The neuropsychological test battery employed had been calibrated and standardized for age, sex, and education on a sample of 321 normal subjects. Cognitive deficits were found in some of the patients but it was not possible to selectively identify the tests that they failed or to establish a scale of severity for their scores. Further, there was no significant correlation between the psychometric and metabolic parameters. It would seem that the influence of chronic liver disease on brain functions builds up to a threshold effect, a hypothesis that calls for longitudinal studies.


[Verbal ability of Alzheimer's disease patients and very elderly control patients using the Aachen aphasia test]. We assessed language function, using the Aachen aphasia test (AAT), in 14 subjects with Alzheimer's disease and 6 control patients. Aphasia did not occur in control patients, but in 11 of 14 Alzheimer's disease patients. Impairment of object naming was the most prevalent abnormality. Performance in AAT subtests repetition, written language, object naming, comprehension and token test correlated strongly with Mini-Mental State scores.


[Multiple intracranial and spinal meningiomas]. Meningeomas are regarded as benign tumors that as a rule can be totally removed. The great prevalence of the benign types of meningeomas does not exclude their recurrence. In some cases (6-8% in the recent literature) a solitary globular tumor represents only the most visible actual growth in context of a systemic tumoral disease spreading over a wide area of arachnoid with simultaneous or delayed growth. In a series of 188 patients operated in St. Gall because of meningeomas, 13 (8%) have multiple simultaneous or delayed tumors, in one case in the spine, without neurofibromatosis. Several operations had to be performed on each patient. The prognosis quoad valetudinem is eventually worse than a solitary tumor. We present a detailed description of our cases and a résume of the literature.


Quantitative evaluation of the brain electrical activity of patients suffering from chronic obstructive bronchopneumonopathy (COBP). The authors subjected 66 patients suffering from COBP with chronic respiratory insufficiency (22 with EGA values within standard limits, 44 with irregular PO2 and PCO2 values) to an electroencephalography with BEAM (brain electrical activity mapping). In the absence of clinically noticeable symptoms or neurologic signs of central type, more than 65% of the patients showed an increase of slow activities together with a reduction of the alpha activity presumably imputable only to the respiratory pathology.


[Value of intravenous urography versus ultrasound in preoperative assessment of prostatic hyperplasia]. Even 60 years after its first clinical application intravenous urography (IVU) is still an essential part of basic diagnostic measures in benign hyperplasia of the prostate (BPH). We compared the value of the IVU to the ultrasound examination in the preoperative evaluation prospectively in 79 patients. Out of a total of 16 pathological findings (20%), only 5 findings (6.3%) could be proved in the IVU. If there was no clinical relevance, however, no treatment was necessary; neither did the pathological findings influence the strategy of surgery. Indirect signs of a tumour in 3 IVU's could be identified ultrasonically as parapelvic or cortical cysts, respectively. In addition to reliable and reproducible estimates of prostatic size, ultrasonography provides information on the residual volume, dilatation of the upper urinary tract, renal masses or stone disease. We recommend ultrasound examination as a helpful method in the preoperative evaluation of BPH. IVU should be considered only for answering specific and clinically relevant questions.


Trends in ambient levels of DDT and HCH residues in humans and the environment of Delhi, India. Monitoring of DDT and HCH residues in abiotic and biotic components of the environment of Delhi during 1988 to 1989 revealed low to moderate levels of these insecticides in soil, earthworms, birds, buffalo milk, water, freshwater clams, fish, human fat, human blood and breast milk samples. Total HCH residues were less than those of DDT in all the samples. This survey indicates (in spite of the continued use of DDT and HCH in the country) a general decline in the levels of DDT residues in most of the samples studied when compared to previous surveys. Although the levels of DDT and HCH residues in fish and river water were below the permissible limits, those in human samples remained fairly high.


Lack of protective immunity against reinfection with hepatitis C virus. Some individuals infected with hepatitis C virus (HCV) experience multiple episodes of acute hepatitis. It is unclear whether these episodes are due to reinfection with HCV or to reactivation of the original virus infection. Markers of viral replication and host immunity were studied in five chimpanzees sequentially inoculated over a period of 3 years with different HCV strains of proven infectivity. Each rechallenge of a convalescent chimpanzee with the same or a different HCV strain resulted in the reappearance of viremia, which was due to infection with the subsequent challenge virus. The evidence indicates that HCV infection does not elicit protective immunity against reinfection with homologous or heterologous strains, which raises concerns for the development of effective vaccines against HCV.


Tyrosine phosphorylation of CD22 during B cell activation. Ligation of the antigen receptor on B cells induces the rapid phosphorylation of tyrosine on a number of cellular proteins. A monoclonal antibody that recognized a tyrosine-phosphorylated cell surface protein that was present in activated B cells was generated. Amino acid sequence analysis showed that this 140-kilodalton protein was CD22, a B cell-specific cell surface glycoprotein and putative extracellular ligand of the protein tyrosine phosphatase CD45. Tyrosine phosphorylation of CD22 may be important in B cell signal transduction, possibly through regulation of the adhesiveness of activated B cells.


Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Plasticity of the developing visual system has been regarded as the best model for changes of neuronal connections under the influence of the environment. N-methyl-D-aspartate (NMDA) receptors are crucial for experience-dependent synaptic modifications that occur in the developing visual cortex. NMDA-mediated excitatory postsynaptic currents (EPSCs) in layer IV neurons of the visual cortex lasted longer in young rats than in adult rats, and the duration of the EPSCs became progressively shorter, in parallel with the developmental reduction in synaptic plasticity. This decrease in NMDA receptor-mediated EPSC duration is delayed when the animals are reared in the dark, a condition that prolongs developmental plasticity, and is prevented by treatment with tetrodotoxin, a procedure that inhibits neural activity. Application of L-glutamate to outside-out patches excised from layer IV neurons of young, but not of adult, rats activated prolonged bursts of NMDA channel openings. A modification of the NMDA receptor gating properties may therefore account for the age-dependent decline of visual cortical plasticity.


Transport proteins in bacteria: common themes in their design. Bacterial transport proteins mediate passive and active transport of small solutes across membranes. Comparison of amino acid sequences shows strong conservation not only among bacterial transporters, but also between them and many transporters of animal cells; thus the study of bacterial transporters is expected to contribute to our understanding of transporters in more complex cells. During the last few years, structures of three bacterial outer membrane transporters were solved by x-ray crystallography. Much progress has also occurred in the biochemical and molecular genetic studies of transporters in the cytoplasmic membranes of bacteria, and a unifying design among membrane transporters is gradually emerging. Common structural motives and evolutionary origins among transporters with diverse energy-coupling mechanisms suggest that many transporters contain a central module forming a transmembrane channel through which the solute may pass. Energy-coupling mechanisms can be viewed as secondary features added on to these fundamental translocation units.


Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein. Fibronectin type III domains are found in many different proteins including cell surface receptors and cell adhesion molecules. The crystal structure of one such domain from the extracellular matrix protein tenascin was determined. The structure was solved by multiwavelength anomalous diffraction (MAD) phasing of the selenomethionyl protein and has been refined to 1.8 angstrom resolution. The folding topology of this domain is identical to that of the extracellular domains of the human growth hormone receptor, the second domain of CD4, and PapD. Although distinct, this topology is similar to that of immunoglobulin constant domains. An Arg-Gly-Asp (RGD) sequence that can function for cell adhesion is found in a tight turn on an exposed loop.


Mechanism of DNA strand transfer reactions catalyzed by HIV-1 reverse transcriptase. Two DNA strand transfer reactions occur during retroviral reverse transcription. The mechanism of the first, minus strand strong-stop DNA, transfer has been studied in vitro with human immunodeficiency virus 1 reverse transcriptase (HIV-1 RT) and a model template-primer system derived from the HIV-1 genome. The results reveal that HIV-1 RT alone can catalyze DNA strand transfer reactions. Two kinetically distinct ribonuclease (RNase) H activities associated with HIV-1 RT are required for removal of RNA fragments annealed to the nascent DNA strand. Examination of the binding of DNA.RNA duplex and single-stranded RNA to HIV-1 RT during strand transfer supports a model where the enzyme accommodates both the acceptor RNA template and the nascent DNA strand before the transfer event is completed. The polymerase activity incorporated additional bases beyond the 5' end of the RNA template, resulting in a base misincorporation upon DNA strand transfer. Such a process occurring in vivo during retroviral homologous recombination could contribute to the hypermutability of the HIV-1 genome.


A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels. The overall sequence similarity between the voltage-activated K+ channels and cyclic nucleotide-gated ion channels from retinal and olfactory neurons suggests that they arose from a common ancestor. On the basis of sequence comparisons, mutations were introduced into the pore of a voltage-activated K+ channel. These mutations confer the essential features of ion conduction in the cyclic nucleotide-gated ion channels; the mutant K+ channels display little selectivity among monovalent cations and are blocked by divalent cations. The property of K+ selectivity is related to the presence of two amino acids that are absent from the pore-forming region of the cyclic nucleotide-gated channels. These data demonstrate that very small differences in the primary structure of an ion channel can account for extreme functional diversity, and they suggest a possible connection between the pore-forming regions of K+, Ca2+, and cyclic nucleotide-gated ion channels.


Stability and properties of double and triple helices: dramatic effects of RNA or DNA backbone composition. Studies of a series of short oligonucleotide double and triple helices containing either all RNA, all DNA, or a mixture of the two show strand-dependent variation in their stability and structure. The variation in stability for both groups falls over a range of greater than 10 kilocalories per mole. In forming the triple helix, RNA is favored on both pyrimidine strands, whereas DNA is favored on the purine strand. In general, relatively unstable duplexes form particularly stable triplexes and vice versa. Structural data indicate that the strands in hybrid helices adopt a conformation that is intermediate between molecules containing all DNA and all RNA. Thus, RNA-DNA hybrids were not forced into the conformation of the RNA (A-form). The provocative stability of the triplex with an RNA third strand+DNA duplex points to novel antisense strategies and opens the possibility of an in vivo role of these structures. Overall, the data emphasize the fundamental role of sugars in determining the properties of nucleic acid complexes.


A multifunctional aqueous channel formed by CFTR. The cystic fibrosis gene product (CFTR) is a complex protein that functions as an adenosine 3,5-monophosphate (cAMP)-stimulated ion channel and possibly as a regulator of intracellular processes. In order to determine whether the CFTR molecule contains a functional aqueous pathway, anion, water, and urea transport were measured in Xenopus oocytes expressing CFTR. Cyclic AMP agonists induced a Cl- conductance of 94 microsiemens and an increase in water permeability of 4 x 10(-4) centimeter per second that was inhibited by a Cl- channel blocker and was dependent on anion composition. CFTR has a calculated single channel water conductance of 9 x 10(-13) cubic centimeter per second, suggesting a pore-like aqueous pathway. Oocytes expressing CFTR also showed cAMP-stimulated transport of urea but not the larger solute sucrose. Thus CFTR contains a cAMP-stimulated aqueous pore that can transport anions, water, and small solutes. The results also provide functional evidence for water movement through an ion channel.


Porins in the cell wall of mycobacteria. The cell wall of mycobacteria is an efficient permeability barrier that makes mycobacteria naturally resistant to most antibiotics. Liposome swelling assays and planar bilayer experiments were used to investigate the diffusion process of hydrophilic molecules through the cell wall of Mycobacterium chelonae and identify the main hydrophilic pathway. A 59-kilodalton cell wall protein formed a water-filled channel with a diameter of 2.2 nanometers and an average single-channel conductance equal to 2.7 nanosiemens in 1 M potassium chloride. These results suggest that porins can be found in the cell wall of a Gram-positive bacterium. A better knowledge of the hydrophilic pathways should help in the design of more effective antimycobacterial agents.


Antisense and antigene properties of peptide nucleic acids. Peptide nucleic acids (PNAs) are polyamide oligomers that can strand invade duplex DNA, causing displacement of one DNA strand and formation of a D-loop. Binding of either a T10 PNA or a mixed sequence 15-mer PNA to the transcribed strand of a G-free transcription cassette caused 90 to 100 percent site-specific termination of pol II transcription elongation. When a T10 PNA was bound on the nontranscribed strand, site-specific inhibition never exceeded 50 percent. Binding of PNAs to RNA resulted in site-specific termination of both reverse transcription and in vitro translation, precisely at the position of the PNA.RNA heteroduplex. Nuclear microinjection of cells constitutively expressing SV40 large T antigen (T Ag) with either a 15-mer or 20-mer PNA targeted to the T Ag messenger RNA suppressed T Ag expression. This effect was specific in that there was no reduction in beta-galactosidase expression from a coinjected expression vector and no inhibition of T Ag expression after microinjection of a 10-mer PNA.


Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. Experimental autoimmune encephalomyelitis (EAE), a demyelinating disease of the central nervous system that can be induced in susceptible strains of mice by immunization with myelin basic protein (MBP) or its immunodominant T cell determinants, serves as a model of human multiple sclerosis. Tolerance to MBP in adult mice was induced by intraperitoneal injection of synthetic peptides of immunodominant determinants of MBP and prevented MBP-induced EAE. Furthermore, tolerance-inducing regimens of peptides administered to mice after the disease had begun (10 days after induction with MBP) blocked the progression and decreased the severity of EAE. Peptide-induced tolerance resulted from the induction of anergy in proliferative, antigen-specific T cells.


Intrinsic quantal variability due to stochastic properties of receptor-transmitter interactions. Synaptic events at the neuromuscular junction are integer multiples of a quantum, the postsynaptic response to transmitter released from one presynaptic vesicle. At central synapses where quanta are small, it has been suggested they are invariant due to occupation of all postsynaptic receptors, a concept neglecting inherent fluctuations in channel behavior. If this did occur, the quantal release model would not apply there and could not be used to localize sites of synaptic modification. Monte Carlo simulations of quanta include transmitter diffusion and interactions with postsynaptic receptors that are treated probabilistically. These models suggest that when there are few postsynaptic channels available at a synapse, their stochastic behavior produces significant intrinsic variance in response amplitude and kinetics, and saturation does not occur. These results were confirmed by analysis of inhibitory quanta in embryonic and adult Mauthner cells involving a small and large number of channels, respectively. The findings apply to excitatory synapses as well.


Surgical treatment of metastatic spine disease. The results of surgical intervention for metastatic disease on 56 consecutive patients since 1980 were reviewed. Two patients underwent a second procedure to stabilize remote levels of spinal involvement, for a total of 58 surgeries. All 56 patients presented with pain. After surgery, significant relief was noted by 51 (91%). Twenty-seven patients presented with neurologic compromise. After operation, neurologic improvement was noted in 20 (74%). No patient's neurologic function deteriorated secondary to surgical intervention. Twenty-one patients were bedridden before surgery secondary to pain or paresis. After operation, improvement in activity level was achieved in 16 (76%) of these patients. In summary, the goal of surgical treatment of metastatic spine disease is to improve the quality of the remaining life, by the relief of pain and preservation or restoration of neurologic function. The dismal consequences of prolonged bed rest, paraplegia, and a painful premature demise can be avoided with thoughtful and timely surgical intervention.


Age-related phenomena in the lumbar intervertebral discs. Lipofuscin and amyloid deposition. In 69 lumbar intervertebral discs from 69 autopsies, lipofuscin was seen in discs from individuals older than 50 years of age and amyloids in the discs of individuals older than 40 years of age. In 261 intervertebral disc tissue specimens collected at the time of surgery for disc herniation, lipofuscin was seen in the discs of individuals older than 20 years of age and amyloids in the discs of individuals older than 15 years of age. It is speculated that amyloids and lipofuscin are a sign of aging in the intervertebral disc as in other tissues. Furthermore, amyloids and lipofuscin were seen in the operated discs of young individuals than in the autopsy cases.


Chronic benign cervical pain syndromes. Surgical considerations. The results of surgical intervention for chronic benign pain syndromes are generally poor. In this review, pertinent ablative and modulatory techniques are reviewed, with specific reference to their utility for benign pain syndromes. With the possible exception of facet rhizotomy, the ablative modalities have little role in the management of benign pain syndromes. The more extensive techniques of cordotomy, dorsal root entry zone lesioning, ganglionectomy, and rhizotomy, have erratic results and high rates of complication. No long-term studies exist to support the use of facet rhizotomy. It is minimally invasive, however, and has little morbidity. In patients with benign refractory posterior column pain, facet rhizotomy may be worth consideration. Modulatory devices may have a role in benign pain syndromes. While the use of indwelling epidural catheters remains investigational, dorsal column stimulation has been widely studied. In representative reports, significant pain relief has been observed in up to 60% of patients (mean follow-up of two years). In the carefully selected patient, this may represent a valuable therapeutic adjunct.


[A case of systemic lupus erythematosus complicated with monoclonal CD5 + B cell proliferation suspected as chronic lymphocytic leukemia]. A case of systemic lupus erythematosus (SLE) complicated with monoclonal CD5 + B cell proliferation in peripheral blood and bone marrow is reported. A 59-year-old man suffering from left chest pain was admitted to the hospital because of thrombocytopenia (platelets 1.9 x 10(4)/mm3). The diagnosis of SLE was made from (1) pleuritis (2) autoimmune thrombocytopenia (3) positive anti-DNA antibodies, positive LE cell preparation (4) positive antinuclear antibodies. Prednisolone 60mg per day was started. From that time monoclonal CD5 + B cells began to increase in peripheral blood (maximum lymphocyte counts 11000/mm3, CD5 + B cells 77.6%) and bone marrow, and the complication of chronic lymphocytic leukemia (CLL) was suspected. It is said that patients of CLL often have various autoantibodies, and in about 15% of CLL patients complicate autoimmune hemolytic anemia, but those who develop collagen diseases are rare. And while lymphoid malignancies occur more often in the patients of SLE in comparison with normal subjects, the reports of the patients who complicate the proliferation of monoclonal CD5 + B cells like CLL are very few. But from many facts that indicate the relation between CD5 + B cell or its proliferation and the production of autoantibodies or autoimmune diseases, we consider this case worth to be reported.


The impact of a family-centered case management approach. Two urban programs of family-centered case management services were established for families of children with both a developmental disability and a chronic health condition. These are children who present significant caregiving demands due to the long-term and severe nature of their disabilities. Thirty-two mothers were interviewed within the family's first month in the project and reinterviewed approximately one year later. The results indicate that more families received respite care, nursing services, training in the care of the child, educational services and transportation to school at follow-up than had been receiving those services at baseline. However, families still indicated high service needs for recreational activities, life planning, regular day care, legal services, and speech therapy at follow-up. Mothers indicated that program services were helpful in obtaining services, financing, information, support, and advocacy. Although maternal life satisfaction improved with program participation, non-handicapped siblings continued to have difficulties coping. The model employed is described and the practice and policy implications of the findings discussed.


[The patient with incurable cancer and palliative medicine in Mexico]. This paper analyzes the potential advantages of palliative care for cancer patients in Mexico. The increasing incidence of cancer, the limited rate of cure of the most frequent cancers and limited resources make palliative care a realistic treatment option. In accordance to World Health Organization recommendations, I propose the development of palliative care in Mexico.


A double-blinded multicenter trial of somatostatin in the treatment of acute pancreatitis. To evaluate the effect of somatostatin in the treatment of acute pancreatitis, 63 patients were randomly allocated to continuous intravenous infusion for three days of 250 micrograms of somatostatin (Dura Scan, Odense, Denmark) per hour (n = 33), or placebo (n = 30). Patients with a first attack of pancreatitis, serum amylase level of more than 450 units per liter and symptoms for less than 24 hours were eligible for participation in the study. Apart from a slightly significant faster decrease in serum amylase concentrations, we were unable to demonstrate any significant benefit from somatostatin with regard to paraclinical values and clinical course.


Intraarterial 5-FU-infusion and simultaneous radiotherapy as palliative treatment of recurrent rectal cancer. Palliative treatment of recurrent rectal cancer remains to be a challenge. From 1989 to 1991 13 patients with recurrent rectal cancer were treated with intraarterial infusion of 5-Fluorouracil and simultaneous radiotherapy in a palliative intent. Seven patients had received postoperative adjuvant radiotherapy with 56 to 60 Gy. Three patients had been treated with systemic chemotherapy. Radiotherapy of the recurrence was performed with 19.8 to 30.6 Gy in the pre-irradiated patients and with 50.4 to 59.4 Gy in the others. One complete remission, three partial remissions and nine minor responses were observed. Three patients had complete pain relief after the treatment, in the remaining patients major pain reduction was achieved. Palliation lasted from three to twelve months (median: five months). Our results indicate that locoregional chemo- and radiotherapy are a effective modality in recurrent rectal cancer.


[Disorders of the protease-antiprotease system of a bronchial washout in patients with bronchiectasis and the means for their correction]. Patients with bronchiectatic disease show imbalance between the activity of proteolytic enzymes and their inhibitors contained by bronchial wash-out, manifesting in a reduction of the inhibitory potential and a rise of the activity of trypsin-like proteinases. After the standard basic treatment the protease-antiprotease system in bronchial wash-out shows a definite improvement. Endobronchial therapy with contrykal given in a dose of 20-30 thousand ATpE for 5-7 days does not ameliorate imbalance in the protease-antiprotease system in bronchiectatic disease patients as compared to the common basic therapy.


[The immediate and late results of treating patients with nonspecific lung diseases by using the local administration of kontrikal and antibiotics]. An analysis was made of the short- and long-term (1.5-2 years) results of the treatment of 75 patients with acute abscess and 101 with lingering pneumonia using different routes of administration of proteinase inhibitors and antibiotics. The high efficacy was demonstrated of the local intrapulmonary and endobronchial administration of the proteinase inhibitor contrykal and antibiotics. The treatment method suggested was found to compare favourably with the common route of the drug administration. The treatment is well tolerated and promotes the shortening of the times of the patients' stay in the hospital, reduces the number of complications and residual phenomena, prevents the disease relapses and their transformation to chronic nonspecific pulmonary diseases. The clinical recovery of the patients with acute lung abscess was reached in 91.4% of cases whereas in the reference group, only in 66.7%. In the patients with lingering pneumonia, the recovery was noted in 85.4%, in the reference group, in 27.5% of cases.


[The clinico-laboratory dynamics in the reaferon treatment of glomerulonephritis patients with the nephrotic syndrome]. Overall 40 chronic glomerulonephritis patients with nephrotic syndrome were treated by reaferon. All the patients underwent clinical and laboratory examinations and nephric biopsy. As a result of the treatment, all the patients demonstrated an increase of the level of glomerular filtration, stabilization of protein and lipid metabolism along with the lowering of diurnal proteinuria. Reaferon exerted a beneficial effect on cellular factors of immunity. In some cases, the use of reaferon can be a definite alternative of the conventional treatment methods.


Activation of coagulation and fibrinolysis following OKT3 administration to renal transplant recipients: association with distinct mediators. Treatment with OKT3 induces cytokine release and activates the complement system. Since both phenomena may affect coagulation and fibrinolysis we studied these systems in 8 renal transplant recipients during OKT3 treatment. In 8 of 9 patients a similar pattern was observed: plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels were increased as compared to pretreatment levels (p less than 0.05) at 15 min after the first OKT3 dose and reached peak values at 1 h. No significant changes were observed upon subsequent OKT3 administrations or in a control group of 8 patients. In one patient upon the first OKT3 administration only complement activation, and no cytokine release was observed, whereas plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-alpha 2-antiplasmin-complex levels increased only at 15 min. In conclusion, we demonstrate a biphasic activation of coagulation and fibrinolysis upon the first OKT3 dose; the initial phase seems to be associated with complement activation, the later phase with cytokine release.


Platelet factor XIII increases the fibrinolytic resistance of platelet-rich clots by accelerating the crosslinking of alpha 2-antiplasmin to fibrin. Platelet clots resist fibrinolysis by plasminogen activators. We hypothesized that platelet factor XIII may enhance the fibrinolytic resistance of platelet-rich clots by catalyzing the crosslinking of alpha 2-antiplasmin (alpha 2AP) to fibrin. Analysis of plasma clot structure by polyacrylamide gel electrophoresis and immunoblotting revealed accelerated alpha 2AP-fibrin crosslinking in platelet-rich compared with platelet-depleted plasma clots. A similar study of clots formed with purified fibrinogen (depleted of factor XIII activity), isolated platelets, and specific factor XIII inhibitors indicated that this accelerated crosslinking was due to the catalytic activity of platelet factor XIII. Moreover, when washed platelets were aggregated by thrombin, there was evidence of platelet factor XIII-mediated crosslinking between platelet alpha 2AP and platelet fibrin(ogen). Specific inhibition (by a monoclonal antibody) of the alpha 2AP associated with washed platelet aggregates accelerated the fibrinolysis of the platelet aggregate. Thus in platelet-rich plasma clots, and in thrombin-induced platelet aggregates, platelet factor XIII actively formed alpha 2AP-fibrin crosslinks, which appeared to enhance the resistance of platelet-rich clots to fibrinolysis.


Effect of sodium pentosan polysulphate on the thrombogenicity of prothrombin complex concentrates. The addition of pentosan polysulphate sodium (NaPPS) to thrombogenic prothrombin complex concentrates (PCC) dose-dependently reduces or abolishes thrombus formation in rats in the stasis model acc. to Wessler. However, no reduction of thrombogenicity was found in PCC preparations manufactured in the presence of NaPPS.


Fibrinolytic effects of pro-urokinase combined with low-dose urokinase compared to high-dose urokinase in patients with acute myocardial infarction. 20 patients (6 females, 14 males) aged between 47 and and 75 years (mean: 62.6 yrs.) with acute myocardial infarction (onset of symptoms within 6 hours) were treated intravenously with either 200,000 U urokinase (UK) and 4.5 million U pro-urokinase (pro-UK) within 60 min (group I, N = 10), or 2.5 million U UK within 5 min (group II, N = 10). Blood samples for haemostatic and fibrinolytic function tests were taken prior to and repeatedly during the 24 hours following treatment. Peak fibrinolytic activity measured by fibrin plates was equivalent in both regimens. Average decreases, with lowest levels within 60 to 120 min following thrombolytic therapy, were observed of 27% and 70% for plasminogen, of 71% and 91% for alpha-2-antiplasmin, and of 20% and 74% for fibrinogen in group I and II, respectively. The reptilase time reached maximum values of 1.5- and 4.5-fold within 60 to 180 min. Peak levels of D-dimers and thrombin-antithrombin III complexes in group II were 2.6 and 3.2 times those of group I. After 24 hours, in contrast to group I, all these parameters still remained significantly different from pretreatment values in group II. These data indicate that, contrary to high-dose UK, pro-UK in combination with low-dose UK causes minor systemic fibrinolytic effects and is, therefore, assumed to be largely clot-specific, although the fibrinolytic potential is equivalent for both regimens.


Autoactivation of human blood coagulation factor XII on dextran derivatives of different molecular weight. We prepared a derivative of dextran T40 (average M(r) 43,000) from which fractions of different M(r) but with equal charge density were obtained and tested for their ability to promote autoactivation of human blood coagulation factor XII. The mechanism of autoactivation appeared dependent upon the M(r) of the polymer used. Thus, with polymers of 38,000 M(r) or higher only alpha-factor XIIa was formed and the reaction could be completely described in terms of a simple second-order mechanism of autoactivation. With smaller polymer molecules beta-factor XIIa became a major reaction product and as a result of this the autoactivation kinetics did not adhere to the second-order mechanisms thus far described.


The effect of fasting and cholecystokinin stimulation on normal and neoplastic tissue in the rat pancreas. Pancreatic nodules were produced in rats by either feeding raw soya flour alone or by injection of azaserine plus raw soya flour feeding. The resulting nodules were studied to determine whether there was any functional difference between this tissue and the relatively normal internodular pancreas. Tissue DNA and trypsin content were significantly elevated in nodules compared to the adjacent tissue. With fasting, protein and enzyme content increased significantly and equally in both nodular and internodular tissues. RNA levels fell significantly and the decrease was more pronounced in nodular tissue. The responsiveness of the multinodular pancreas to cholecystokinin was examined by measuring pancreatic secretion basally and in response to cholecystokinin. Both the volume and protein content secreted by the multinodular pancreas were greatly elevated above control levels. When corrected for pancreatic weight, the difference remained significant and appeared to be due to increased basal secretion by the nodular pancreas. These studies demonstrate that azaserine-raw soya flour induced nodules are functionally efficient. Furthermore, the secretory response to cholecystokinin of these nodules is equal to or higher than that of normal tissue.


Comparative characterization of two toxic phospholipases A2 from Indian cobra (Naja naja naja) venom. Indian cobra venom contains many phospholipase A2 (PLA2) toxins. In the present study two toxic PLA2s have been purified from the Indian cobra (Naja naja naja) venom by column chromatography. The NN-XIa-and NN-XIb-PLA2s have mol. wts between 10,700 and 15,000. The NN-XIa-PLA2 induces myotoxic effects, oedema and neurotoxicity in mice and has an i.p. LD50 of 8.5 mg/kg body weight. The NN-XIa-PLA2 is also cytotoxic to Ehrlich ascites tumour cells. The other PLA2, NN-XIb, in contrast has an i.p. LD50 of 0.22 mg/kg body weight, and it induces acute neurotoxicity. The NN-XIb-PLA2 is devoid of the other biological activities which are exhibited by NN-XIa-PLA2.


Experimental treatment protocols for scorpion envenomation: a review of common therapies and an effect of kallikrein-kinin inhibitors. Nine fatal cases from the sting of the scorpion Leiurus quinquestriatus are presented. All victims showed association of CNS and cardiovascular manifestations. Either the CNS or the cardiovascular effects could occur first in the early phases of the scorpion envenoming syndrome; the CNS manifestations, however, always preceded the terminal hypotension and cardiac arrest. Pharmacokinetic studies in rabbits following s.c. injection of the labelled venom showed that rapid absorption took place with about 70% of the maximum blood concentration reached within 15 min. Intramuscular injection of antivenom did not significantly affect the absorption of the venom or the other pharmacokinetic parameters. The total area under concentration time curve was not significantly different from that following i.v. injection, showing that nearly complete absorption of the venom from the s.c. site would occur in 7-8 hr. The i.v. infusion of venom into anaesthetized rats, at a rate comparable to the absorption rate from s.c. sites, allowed the determination of the minimum lethal dose (MLD) with reasonable accuracy. In rescue experiments, anaesthetized rats were injected s.c. with multiple MLD of venom and infused i.v. with drugs commonly used in the treatment of scorpion envenomation. The prepared potent specific antivenoms, but not the commercial polyvalent antivenom, rescued all animals from the lethal effect of the venom, even when injected late. Atropine, atropine+phentolamine, chlorpromazine, hydrocortisone and indomethacin were able, in varying degrees, to rescue some rats injected with 2 MLD of venom. Phentolamine, propranolol, hydralazine and calcium gluconate significantly prolonged the survival time, but did not rescue any animals. Chlorpheniramine, saline and 1/4 saline + 5% dextrose were without any effect. Aprotinin, the kallikrein-kinin inhibitor, was able to rescue half of the animals from the lethal action of the venom. Electrocardiographic studies showed that L. quinquestriatus venom, irrespective of the route of administration, causes myocardial ischaemia and either inferior or anterior wall infarction. This was associated with an initial moderate and a terminal severe bradycardia together with a variety of rhythm and conduction defects. Except for minor and transient electrocardiographic changes, either the prepared antivenoms or aprotinin protected rabbits and rats from the cardiac effects of the venom.


Lack of dexamethasone modulation of mRNAs involved in the glucocorticoid signal transduction pathway in two cell systems. Glucocorticoids are final effectors of the stress response. These hormones exert negative feedback action at multiple levels of the hypothalamic-pituitary-adrenal axis and regulate a large number of central nervous system and peripheral target genes. The inactive form of the glucocorticoid receptor in the cytoplasm appears to be bound to heat shock proteins of the 90K family (hsp90 alpha and hsp90 beta). This interaction facilitates binding of glucocorticoid to its receptor and, therefore, its activation. The chicken ovalbumin upstream promoter transcription factor (COUP-TF) binds on a negative glucocorticoid response element in the 5' regulatory region of the proopiomelanocortin gene and prevents the repressive effect of glucocorticoids on this gene. The aim of this study was to examine the effect of glucocorticoids on the steady-state mRNAs of their own receptor, the two hsp90s, and COUP-TF. Quantitative Northern blot analysis in primary leukocytes and Epstein-Barr virus-transformed human lymphocytes (EBV-THL) basally and after a 24-hour exposure to 50 nM dexamethasone was performed. Treatment of primary leukocytes or normally growing EBV-THL with dexamethasone had no effect on the mRNA level of glucocorticoid receptor, hsp90 alpha, hsp90 beta, or COUP-TF. Similar treatment of EBV-THL grown in charcoal-stripped media, resulted in minimal changes in the mRNAs of these factors. Our findings suggest that glucocorticoids do not regulate the steady-state mRNA levels of these core components of the mammalian stress response in human primary and Epstein-Barr virus-transformed lymphocytes.


Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats. Serotonin, via 5-HT2 receptors, exerts an excitatory effect on CA1 neurons and may play a role in ischemia-induced excitotoxic damage. To evaluate the role of serotonin in ischemia, both neurochemical and histopathological studies were performed. Neurochemical studies included rats that were subjected to 12.5 or 20 minutes of normothermic ischemia by two-vessel occlusion plus hypotension, and extracellular serotonin levels were measured in the hippocampus (12.5 minutes' ischemia, n = 5) or striatum (20 minutes' ischemia, n = 13) by microdialysis. In the histopathological study the effect of 8 mg/kg ritanserin, a 5-HT2 antagonist, administered continuously from 30 minutes prior to ischemia until 1 hour of recirculation was evaluated in five rats subjected to 10 minutes of ischemia. After 3 days, the numbers of normal-appearing neurons in the CA1 subregions were counted. Ischemia of 12.5 minutes' duration induced a fourfold increase in serotonin in the hippocampus (mean +/- SEM baseline, 1.86 +/- 0.25 pmol/ml perfusate; during ischemia, 8.14 +/- 0.89 pmol/ml; p < 0.05 by analysis of variance). Twenty minutes of ischemia induced a 25-fold increase in serotonin in the dorsolateral striatum (baseline, 0.98 +/- 0.15 pmol/ml; ischemia, 24.4 +/- 5.93 pmol/ml; p < 0.001). The histopathological study demonstrated severe ischemic damage in all CA1 subregions of nontreated animals (medial, 34 +/- 16 normal-appearing neurons, middle, 52.2 +/- 22.9 neurons; lateral, 56.6 +/- 21.8 neurons). Treatment with ritanserin significantly attenuated ischemic damage (medial, 117.6 +/- 6.5 neurons; middle, 131.4 +/- 4.9 neurons; lateral, 130 +/- 7.5 neurons; p < 0.01 different from nontreated). Taken together, these results suggest that serotonin plays a detrimental role, mediated by 5-HT2 receptors, in the development of ischemic damage.


[The treatment of alveolar hemorrhages with helevin]. The author described the clinical results and the scheme of helevin therapy used to arrest bleedings from the well after removal of a tooth in 115 patients. The causes of the bleeding were of a general nature in 87 (75.7%) and local in 28 (24.3%) patients. The results were good when the bleeding was not severe (89.6% of cases) and poor when it was grave; in grave cases other methods of hemostasis should be resorted to.


Effects of nicardipine on tube formation of bovine vascular endothelial cells in vitro. The purpose of this study was to assess the effect of nicardipine, a Ca2+ channel blocker, on angiogenesis in vitro. Bovine carotid artery endothelial cells were cultured between type I collagen gel layers with 10(-9) to 10(-5) M nicardipine. The morphological changes were monitored by phase-contrast microscopy and photographed. The total length of tubular structures was measured with an image analyzer system. Endothelial proliferation and migration assays were also performed with the same doses of nicardipine. Cultured endothelial cells form tubular structures between collagen gel layers. Tube formation of endothelial cells was suppressed by culture with 10(-9) to 10(-5) M nicardipine in a dose-dependent manner. Migration of endothelial cells was also suppressed by the same doses of nicardipine. However, proliferation of endothelial cells was not enhanced. Nicardipine acts as an inhibitor of angiogenesis in vitro by inhibiting the migration of endothelial cells. This result suggests that nicardipine may have therapeutic potential in angiogenic disorders such as tumor growth, atherogenesis, and diabetic retinopathy.


[Osteomyelitis in congenital analgesia]. Presentation of a case of a congenital analgia, who showed as a complication a chronical osteomyelitis of the mandible with formation of sequester and fracture. Partial resection of the mandible and immediate reconstruction was done performing simultaneously a rebuilding of the atrophied alveolus by the use of split ribs and fixation with a long miniplate.


[The detection of group-specific antigens in hair after its contact with blood and ejaculate]. The aim of this study was the detection of AB0 antigens extrinsic for a person in his (her) hair. The hair was kept for 1-7 days in whole or diluted blood (96 experiments) and semen (11 experiments). Only the group-specific antigens, intrinsic for the subjects whose hair was examined, were detectable in the hair after this exposure.


[The determination of buccal epithelial cells in forensic medical cytological research]. The morphology of isolated cells of multi-layer squamous non-horny epithelium (buccal, vaginal, urethral, rectal), stained with 0.05% nigrosine solution, was under study, and the sizes of these cells and their nuclei were measured. Specific markers were detected in the buccal epitheliocytes, that permit their reliable differentiation from other epitheliocytes studied by the size of the cells and nuclei, by a characteristic structure of the cytoplasm, etc. The findings may be used for the diagnosis of the origin of isolated cells of the buccal mucosa.


The acute effect of FK506 and cyclosporine on endothelial cell function and renal vascular resistance. We have previously documented that cyclosporine exerts a direct cytotoxic effect on endothelial cells and causes an increase in renal vascular resistance (RVR) in the rat. In the present study we investigated whether FK506, a novel immunosuppressive agent thought to be less nephrotoxic than CsA, impairs endothelial cell function in vitro and affects RVR in vivo. In vitro eicosanoid release and endothelin release were measured in bovine aortic endothelial cells in culture exposed for 1, 6, and 24 hr to increasing concentrations of FK506 (1 nM to 10 microM) or CsA (0.5, 10 microM). No significant changes in TxB2 and 6-keto-PGF1 alpha (the stable breakdown products of TxA2 and PGI2, respectively) and endothelin release were found after 1 and 6 hr of incubation with all the concentrations of FK506 and CsA considered. FK506 did not affect endothelin release even after 24 hr of incubation. In contrast, cell exposure to CsA was associated with a dose-dependent increase in TxB2, 6-keto-PGF1 alpha, and endothelin release that reached statistical significance after incubation with 10 microM CsA. FK506 did not induce cell detachment or lysis at any concentration and time considered, while 10 microM CsA induced a significant reduction in cell count accompanied by cell lysis. In vivo studies showed that a single i.v. injection of FK506 to rats within a broad range of doses (28 ng/kg to 2.8 micrograms/kg) did not modify RVR. This was true even for a dose as high as 20 mg/kg, while 20 mg/kg CsA caused a dramatic increase in RVR. We conclude that FK506, unlike CsA, does not induce endothelial cell injury in vitro. Whether this explains the differences in renovascular resistance observed in vivo after acute injection of FK506 and CsA is an attractive possibility that needs to be further explored.


Late-onset acute rejection in orthotopic liver transplantation--associated risk factors and outcome. A retrospective review of 375 consecutive orthotopic liver transplants was performed to determine the incidence and outcome of late rejection episodes ([LR] rejection occurring more than 6 months following transplant). A total of 31 episodes in 26 patients were identified. Eighteen of these episodes were associated with subtherapeutic levels of cyclosporine. Of these, 7 were due to noncompliance, 2 were due to biliary strictures, and 1 was due to malabsorption in a cystic fibrosis patient. All 31 episodes were treated initially with steroids, and 22 had a complete response, although one progressed to chronic rejection over a year later. Of the remaining 9, 1 received FK506 with a complete response, and 8 received OKT3. Of the 8 patients who received OKT3, 5 had a complete response, 1 received RS61443 following OKT3 and progressed to chronic rejection, and the remaining 2 received further steroids. Of these 2, 1 had a complete response following the steroids while the second was converted to FK506 with a complete response. Compared with 315 acute rejection episodes ([AR] occurring less than 6 months posttransplant), patients with late rejection episodes had an equivalent response to steroids (63.2% AR reversed vs. 71% LR reversed) but a lower response rate to OKT3 (91.5% AR reversed vs. 62.5% LR reversed). There was, therefore, a higher rate of persistent rejection (61% AR episodes vs. 15.4% LR episodes) but no increase in the incidence of chronic rejection (7% AR episodes vs. 7.7% LR episodes). We conclude that LR is a relatively common occurrence following liver transplant, which is most often associated with low cyclosporine levels. Many of these episodes are due to noncompliance, but biliary problems must also be investigated. The incidence of resistant rejection is higher in this group of patients but is not associated with a concurrent increase in chronic rejection.


An optimal rice-based oral rehydration solution: the effect of different concentrations of amylase on production of short chain polymers of glucose. As part of a plan to develop a rice-based oral rehydration solution containing short polymers of glucose instead of glucose, we determined the concentration of amylase that would yield the largest amount of short chain polymers. Thai rice (25 g) was boiled with 500 ml of distilled water for 30 min. Of 200 ml supernatant rice water obtained, 100 ml were digested with different amounts of amylase after cooling to 50 degrees C for 60 min, boiled for 5 min, and centrifuged (10,000 g, 25 degrees C) for 60 min. The resulting supernatant (80 ml) was freeze-dried; 1.75 g of the powder obtained were dissolved in 3.5 ml of water, passed through a Bio-Gel P2 column to separate short chain polymers (2-9 molecules of glucose) and long chain polymers (> 9 molecules of glucose), which were identified by spectrophotometry (lambda = 190 nm) or by high performance liquid chromatography. Ten mg of amylase (equivalent to 12,000 modified Wohlgemath units) per 100 ml of rice water was optimal for the production of short polymers of glucose from rice.


The effects of FK506 and cyclosporine on the exocrine function of the rat pancreas. The effects of FK506 on exocrine function of the pancreas in Sprague-Dawley rats were examined and compared with those of cyclosporine. FK506 did not affect the levels of amylase and lipase in the pancreas of rats given the drug orally in a daily dose of 1 or 5 mg/kg for 2 weeks. Furthermore, the pancreas of the rats showed good exocrine secretion of enzymes such as amylase and lipase on stimulation with carbachol in vitro. Cyclosporine 50 mg/kg given in the same way as FK506 also was free of effect on enzyme levels in the rat pancreas, but the exocrine secretion of the enzyme from the pancreatic lobules on stimulation with carbachol was impaired. It is concluded that FK506 does not affect pancreatic exocrine function in rats.


The spectrum of cystic fibrosis mutations. Although the major mutation causing cystic fibrosis accounts for almost 70% of mutant chromosomes screened, almost 300 sequence alterations have been identified in the gene during the past two and a half years. At least 230 of these mutations are probably associated with disease. This rapid accumulation of data is in part due to the highly coordinated effort by members of the Cystic Fibrosis Genetic Analysis Consortium. The information is not only essential to genetic diagnosis, but also will aid in understanding the structure and function of the protein, and possibly in correlating genotype with phenotype.


Iterated patterns of brain circuitry (or how the cortex gets its spots). The prominence of repeating patterns of circuitry in the mammalian brain has led to the general view that iterated modular units reflect a fundamental principle of cortical function. Here we argue that these intriguing patterns arise not because the functional organization of the brain demands them, but as an incidental consequence of the rules of synapse formation.


Lineage versus environment in embryonic retina: a revisionist perspective. The idea that microenvironmental cues act alone late in development to determine a cell's phenotype has dominated recent discussion of, retinal development, and has successfully displaced the notion of any role for cell lineage in the process of cell determination. We argue that there is, in fact, evidence favoring a degree of lineage restriction during the development of the vertebrate retina. We propose that environmental factors modulate a process of progressive lineage restriction. In this model, progenitor cells are viewed as having unequal potential, and their progeny are viewed as being committed to one of the major retinal cell classes before the stage at which they become postmitotic.


Visceral nociceptors: a new world order? There has been a long-standing controversy as to whether or not internal organs are innervated by a special category of 'visceral nociceptor'. Recent experimental studies on the afferent supply of some viscera have thrown new light on this issue by demonstrating the presence of several categories of visceral sensory receptor, including high-threshold receptors, 'silent' nociceptors and intensity-encoding receptors. Advances in the understanding of how the CNS processes nociceptive signals have also helped to clarify the issue. The authors of this report, originally having different points of view, present here a common and closer approach to the visceral nociceptor controversy.


Neuroscience training in the USA and Canada: observations and suggestions. Neuroscience training programs in the USA and Canada are awarding about 1000 PhDs each year. This number exceeds the faculty vacancies in these programs by a ratio of three to one. Nonetheless, virtually all graduates are finding employment, usually after a period of postdoctoral experience. On the other hand, recent surveys suggest that there are many other concerns to be addressed. These include an attrition of women during training and within the faculty ranks, a low percentage of minorities throughout the neuroscience community, and a relative lack of federal training funds.


Training neuroscientists for the 21st century. Maintaining the highest possible level of talented researchers relies critically on the ability to recruit, train and retain the best young students to the neurosciences. This article addresses the need for trainers to look beyond technical skills, on which research training conventionally concentrates, to some para-scientific skills that may help assure survival during the apparently perennial periods of scarce resources.


Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Sulfated glycoprotein 2 (SGP-2) from rat, and similar molecules from cow, dog, human, pig, ram and quail are known by 11 or more acronyms. SGP-2 is associated with the responses of brain and other tissues to injury; it and related molecules are also normally secreted by the adrenal gland, the liver and the testes. The mRNA of this protein is found in increased levels in Alzheimer's disease. In rats, after perforant path or excitotoxin lesions, levels of the protein or mRNA are elevated in astrocytes, and also in neurons. In rats, brain SGP-2 is regulated by gonadal and adrenal steroids. However, these increases after brain lesions may relate to a function that is associated with the human protein, namely that of inhibiting complement-mediated cell lysis. Other activities suggested for SGP-2 are lipid transport and cell-cell interactions, which are consistent with sequence data that predict binding of dinucleotides, heparin and lipids. The emerging neurobiology of SGP-2 encompasses the subjects of cell death, synaptic remodelling, neuroendocrinology and neurodegenerative diseases.


Modulation of pH by neuronal activity.

Modulation of pH by neuronal activity. Although the requirement for a strict regulation of pH in the brain is frequently emphasized, recent studies indicate that neuronal activity gives rise to significant changes in intracellular and extracellular pH. Given the sensitivity of many ion channels to hydrogen ions, this modulation of local pH might influence brain function, particularly where pH shifts are sufficiently large and rapid. Studies using pH-sensitive microelectrodes have demonstrated marked cellular and regional variability of activity-dependent pH shifts, and have begun to uncover several of their underlying mechanisms. Accumulating evidence suggests that regional and subcellular pH dynamics are governed by the respective localization of glial cells, ligand-gated ion channels, and extracellular and intracellular carbonic anhydrase.


An enzymatic mechanism for potassium channel stimulation through pertussis-toxin-sensitive G proteins. Many neurotransmitters inhibit secretion from electrically excitable cells by activating pertussis-toxin-sensitive G proteins that modulate voltage-gated ion channels. Recent electrophysiological studies of metabolically intact cells from mammalian and molluscan neuroendocrine systems have implicated protein phosphatases in this process. In this article David Armstrong and Richard White review these studies and suggest a biochemical pathway that might link one of the G proteins to protein phosphatase activity.


Membrane ion channels of endothelial cells. It is becoming clear that endothelial cells in the vascular system have important functions. In the microvessels they play an active role in regulating vascular permeability, while in large vessels, endothelial cells contribute to the control of smooth muscle tone. Control of both permeability and tone involve a range of mechanisms, in which changes in [Ca2+]i appear to play a major role. As elevation of [Ca2+]i can be caused by either release from intracellular stores or increased entry across the plasmalemma, and as the latter will be modulated by the resting membrane potential, the ion channels controlling the membrane potential are critical to an understanding of endothelial function. Patricia Revest and Joan Abbott summarize the properties of endothelial ion channels, and explore the ways in which the channels could control permeability, secretion and smooth muscle tone.