Ethambutol in tuberculosis.

Ethambutol gained rapid acceptance as a substitute for PAS in tuberculosis therapy because of improved patient tolerance and convenience of administration. Ocular toxicity was recognized early on but was thought to be a problem only at higher dosages. There have, however, been a number of reports of serious visual impairment on conventional dosage, with permanent blindness in some cases, and painfully slow recovery in others. The precise mechanism for the optic neuritis is not clear, and toxicity is difficult to predict in the individual patient. Ethambutol appears to contribute only marginally to modern short course regimens and should be replaced with a less toxic agent.


Growth factors and oncogenes in human solid tumors: clinical aspects.

Growth factors, growth factor receptors and oncogenes have been extensively studied in human tumors for some years. The purpose of this paper is to review the clinical results obtained in human cancers and their predisposing conditions or high risk groups as well as their relation with clinical, pathological characteristics and their prognosis.


Isolation and characterization of VP-16 resistant human leukemia cell line.

VP-16 resistant cells, designated VP-16K6-1 (K6-1) were isolated from human acute lymphoblastic leukemia cell line RPMI 8402. IC50 value against VP-16 were 11-fold higher than their sensitive parental cell line. The membrane permeability of the drug was not responsible for resistance in K6-1 cells. K6-1 cells showed resistance in drug-induced DNA strand breaks (single strand breaks) determined by the alkaline sucrose gradient sedimentation method. Dot-blot analysis of RNA extracted from 2 cell lines showed that the mRNA levels of DNA topoisomerase II in K6-1 cells decreased slightly compared with that of parent cells. However, Topo II activities were similar in wild-type and K6-1 cells. In addition, K6-1 cells exhibited cross-resistance only to VM-26. These data suggest that a reduced intracellular Topo II level may contribute to drug resistance as an important factor in K6-1 cells.


Reduced DNA topoisomerase II in VP-16 resistant mouse breast cancer cell line.

VP-16 resistant cells, FvprB350 (50B-3), were isolated from mouse breast cancer cell line FM3A. 50B-3 cells showed 84-fold higher resistance than their parent cells. Reduced drug uptake was not found in resistant cells. Quantitative analysis of drug-stimulated DNA cleavage activity using 3'32P end-labeled pBR322 restriction fragments showed that VP-16 stimulated DNA-topoisomerase II cleavable complex forming activity in crude nuclear extract from 50B-3 cells was approximately one-fifth as compared with that of FM3A wild-type cells. Dot-blot analysis of RNA extracted from the two cell lines showed that mRNA levels of topoisomerase II in 50B-3 cells drastically decreased and catalytic activity was also 1/2-1/3 as compared with that of parent cells. 50B-3 cells showed cross resistance to VM-26, m-AMSA, adriamycin. These findings suggest that reduced topoisomerase II activity (cellular levels) and cleavable complex forming activity may be significant factors in the marked drug resistance.


Glucose metabolism and beta receptor function in atopic asthmatics.

Severe asthma and diabetes have been reported not to co-exist in the same patient. Various studies have attributed this to the possible association of asthma with hyperinsulinism, increased responsiveness to insulin or to beta-blockade. Previous studies have not addressed all these possible mechanisms in the same patient. In this prospective study, 7 atopic asthmatics and 7 age and sex-matched healthy controls underwent glucose, insulin and glucagon tolerance tests. The results showed no evidence of hyperinsulinism or increased responsiveness to insulin. Intravenous administration of glucagon, however, showed a lesser increase of glucose and insulin in asthmatics. Since glucagon has a beta-agonist effect on the liver and activates glycogenolysis and gluconeogenesis via beta-receptor stimulation and stimulates insulin secretion by activating adenylate cyclase of pancreatic beta-cells through beta-receptors, the results of glucagon tolerance test in our study may therefore suggest the presence of partial beta-blockade in atopic asthmatics.


Biologic activities of HIV-1 envelope glycoprotein: the effects of crosslinking.

We have examined the biologic activities of native and recombinant preparations of human immunodeficiency virus envelope glycoprotein (gp120), both derived from the HIV-1B strain. Antibody to gp120 was used to evaluate the effects of crosslinking gp120 on signalling by the CD4 receptor. Our results indicate that native and recombinant gp120 produce identical effects in our assay systems. Crosslinking gp120 amplified its chemoattractant activity for lymphocytes and monocytes and increased the peak intracellular calcium level, compared with binding of gp120 alone. The induction of inositol trisphosphate (IP3) production, induction of interleukin 2 receptors (IL2R), and inhibition of lymphocyte proliferation following treatment with gp120 were not enhanced by the addition of crosslinking antibody.


T lymphocyte subsets in chronic uremic patients treated with maintenance hemodialysis.

Blood T lymphocyte subsets have been studied using monoclonal antibodies in 10 chronic uremic patients treated with maintenance hemodialysis. Both total T lymphocytes identified by the antibody OKT3, and the helper-inducer T lymphocyte subset identified by the antibody OKT4 were found to be significantly lower than normal. The cytotoxic-suppressor T cell subset was only moderately, even if significantly reduced, so that the T4/T8 ratio in uremic patients was significantly lower than normal. These data provide an additional contribution to the interpretation of immunological and hematological deficiencies observed in chronic uremia.


Can virostatic chemotherapy and/or adoptive allogeneic immunotherapy eradicate in vivo Friend's virus infection?

While none of the three drugs which exert an in vitro anti-HIV effect, neither AZT nor the other two, acriflavine and elliptinium, which we have shown to be more efficient than AZT, is able to eradicate Friend's virus in vivo, the combination of the 3 drugs at much smaller doses than when given alone seems able to eradicate it in almost 30% of the infected animals. This possible eradicating effect of virostatics in combination is compared with the results we had previously obtained with lymphocytes of virus-immunized allogeneic donors.


The role of calcium antagonists in the treatment of atherosclerosis and hypertension.

Results of animal studies suggest that calcium antagonists can inhibit the development of experimentally induced atherosclerosis. Although the biological process underlying this phenomenon has not been fully elucidated, several mechanisms have been proposed. Notably, calcium antagonists may suppress free radical-induced damage of the vascular endothelial cells with the consequent transport of low-density lipoproteins across the vascular endothelium and the accumulation of the lipids in the intima. Studies have shown that calcium antagonists can inhibit the stimulatory effects of epidermal growth factor on intracellular calcium concentrations and DNA synthesis in cultured rat aortic smooth muscle cells, but not those of platelet-derived growth factor or somatomedin C. Further experimental studies have demonstrated that calcium antagonists stimulate prostacyclin production and inhibit 12-hydroxyeicosatetraenoic acid-induced vascular smooth muscle cell migration, therefore preventing platelet aggregation and intimal thickening, respectively. Despite the encouraging results in animals, comparatively few clinical studies have been undertaken to establish the efficacy of calcium antagonists in the prevention of cardiovascular disease in hypertensive patients. This, in part, is due to the technical difficulties associated with measuring coronary artery stenosis, but the recent development of a technique for the video-densitometric analysis of coronary angiograms has enabled stenotic regions to be quantified. Using this approach, a retrospective study has been undertaken of the efficacy of long-term treatment with a calcium antagonist on the progression of coronary atherosclerosis. Results are encouraging and a prospective long-term, multicenter trial is proposed.


Clinical effects of calcium antagonists in hypertensive diabetics.

The incidence of hypertension and coronary artery disease among diabetic patients is approximately two to three times greater than in nondiabetics. Recent evidence suggests that even moderately elevated blood pressure levels may result in diabetic complications involving the eyes or kidneys. However, treatment of diabetic patients with antihypertensive drugs may have a deleterious metabolic effect. Previous studies have suggested that calcium antagonists may reduce insulin secretion and therefore impair glucose tolerance. This has not been substantiated clinically; in general, it would appear that calcium antagonists have a minimal hyperglycemic effect. To establish whether interruption of excitation-contraction coupling in arterial smooth muscle and altered stimulus-secretion coupling occur at pharmacologically equivalent doses of calcium antagonist, the effect of nicardipine on insulin output and vascular resistance was studied in the isolated perfused rat pancreas and in eight hypertensive patients with impaired glucose tolerance during oral glucose tolerance testing (OGTT). Baseline insulin output in vitro was 86 +/- 22 ng/min at 8.0 mM glucose and 2.5 mM calcium. Application of 10 nM nicardipine reduced insulin output to 86% of baseline, whereas output was reduced to 16% by 1 microM nicardipine and to 6% by 10 mM nicardipine. Changes in duodenopancreatic outflow indicated maximal vasodilation of the pancreas at all three concentrations of nicardipine (10 nM-10 mM). In vivo nicardipine 30 mg t.i.d. for 2 weeks reduced systolic blood pressure from 168 +/- 2 mm Hg to 136 +/- 4 mm Hg (p < 0.001) and diastolic blood pressure from 96 +/- 3 mm Hg to 78 +/- 2 mm Hg (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)


The influence of nicardipine in patients with high risk of stroke.

Blood pressure and clinical status of 1,736 patients with cerebrovascular disease were observed during 12 months of treatment with nicardipine. The most common diagnoses were chronic cerebral ischemia (53.2%), transient ischemic attacks (TIA; 25.1%), and cerebral infarct (8.7%); 50.1% of patients were classed as hypertensive [systolic blood pressure (SBP) > or = 160 mm Hg or diastolic blood pressure (DBP) > or = 90 mm Hg]. Most patients (91.2%) received a daily dose of 60 mg nicardipine. Additional treatments included diuretics (37%), beta-blockers (11.5%), other antihypertensive drugs (15.8%), platelet antiaggregants (25.1%), and cardiotonic drugs (15.1%). A total of 282 patients (16.2%) were lost to follow-up, 21 (1.2%) patients withdrew due to side effects, 32 (1.8%) died, and 9 (0.5%) patients had treatment interrupted due to concomitant illness. In the hypertensive subgroup, blood pressure (SBP/DBP) was reduced from a mean baseline value of 175 +/- 22/97 +/- 14 mm Hg to 152 +/- 17/85 +/- 11 mm Hg at 3 months and 149 +/- 23/81 +/- 11 mm Hg after 12 months of treatment. The incidence of TIA or stroke among these patients was reduced from 29 cases (3.5%) during the first 3 months to 11 cases (1.54%) during months 4-12 (p < 0.01). In normotensive patients there were 18 (2.15%) cases during months 1-3 and 13 (1.55%) cases during months 4-12 (difference not significant). In the 280 patients treated with nicardipine alone, the most frequent side effects during the first month were facial flushing (6.8%), gastrointestinal problems (5%), dizziness (3.2%), headache (3.2%), drowsiness (3.2%), and hypotension (1.1%). Most of these side effects were transient.(ABSTRACT TRUNCATED AT 250 WORDS)


The influence of nicardipine on left ventricular hemodynamics and compliance in patients with coronary heart disease.

The hemodynamic effects of nicardipine were studied in 10 normotensive patients (nine men, one woman; age 43-70 years, mean 56 years) and five patients with mild to moderate hypertension (four men, one woman; age 46-72 years, mean 62.8 years); in all patients coronary heart disease was confirmed by angiography. Hemodynamic parameters were determined before and after intravenous administration of nicardipine in cumulative doses of 2.5, 7.5, and 12.5 mg for 10 min each. Nicardipine significantly reduced systolic aortic pressure, diastolic aortic pressure, and mean aortic pressure in normotensive patients [139 +/- 8.7 vs. 114 +/- 9.2 mm Hg (p < 0.001), 73 +/- 9.1 vs. 56 +/- 7.9 mm Hg (p < 0.001), 97 +/- 7.8 vs. 7.8 +/- 7.9 mm Hg (p < 0.001), respectively] and in hypertensive patients [166 +/- 7.4 vs. 128 +/- 8.6 mm Hg (p < 0.001), 83 +/- 9.4 vs. 56 +/- 10.9 mm Hg (p < 0.001), 110 +/- 15.5 vs. 78 +/- 12.0 mm Hg (p < 0.001), respectively]. Systemic vascular resistance was decreased significantly in hypertensive patients [1,363 +/- 188 vs. 707 +/- 137.7 dyn sec cm-5 (p < 0.001)] and in normotensive patients [1,110 +/- 225.3 vs. 682 +/- 92.4 dyn sec cm-5 (p < 0.001)]. Heart rate increased from 68 +/- 6.8 to 83 +/- 11.4 beats/min (p < 0.001) in normotensive patients but the increase from 72 +/- 14.7 to 80 +/- 14.2 beats/min in hypertensive patients was not significant. Mean pulmonary artery pressure did not change significantly in hypertensive patients and increased slightly in normotensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)


The influence of nicardipine in type 2 diabetic patients with slight hypertension.

A double-blind, placebo-controlled study was carried out over 120 days to assess the metabolic tolerance and patient acceptability of nicardipine in 20 patients with Type 2 diabetes mellitus and slight hypertension. Following a 21-day washout period during which all patients received placebo, 13 men and 7 women (mean age 45 years, systolic blood pressure 150-165 mm Hg or diastolic blood pressure 85-100 mm Hg) were randomly assigned to treatment with oral nicardipine 60-90 mg/day (n = 9) or placebo (n = 11). No significant differences were observed between the nicardipine- and placebo-treated groups in terms of fasting and postprandial blood glucose concentrations, fasting plasma insulin levels, or glycosylated hemoglobin A1c after 60 and 120 days' treatment. There was also no change in the plasma levels of total cholesterol, HDL-cholesterol, triglycerides, and apolipoproteins. Side effects were minor and did not differ significantly between groups. All patients who had received nicardipine for 120 days wished to pursue treatment. Nicardipine, which was well tolerated, appears to be an interesting alternative for the treatment of mild essential hypertension in Type 2 diabetic patients, although further studies are required to establish its effects on renal function in this population.


Calcium entry blockade and agonist-mediated vasoconstriction in hypertensive patients.

The effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipine.


The effects of nicardipine in elderly hypertensive patients.

Hypertension becomes more prevalent with advancing age, and the hemodynamic pattern differs from that in younger patients. In the elderly, elevated blood pressure is primarily due to reduced compliance of large vessels, resulting in an increase in total peripheral resistance, but in younger subjects it mainly reflects an increase in cardiac output. Vasodilator drugs, such as calcium antagonists, might therefore be expected to be particularly effective in lowering blood pressure in the elderly. Clinical experience has confirmed the safety and antihypertensive efficacy of these drugs, with some workers suggesting that calcium antagonists are particularly effective in the elderly. A 6-month multicenter study involving 2,184 patients has shown a direct correlation between pretreatment blood pressure and the degree of blood pressure reduction observed during nicardipine treatment with or without other antihypertensive drugs. Isolated systolic hypertension was significantly reduced but diastolic blood pressure was not affected. The incidence of side effects among elderly hypertensive patients, both with and without concomitant disease, was slightly lower than in younger patients.


Clinical effects of calcium antagonists in silent ischemia.

A number of studies have addressed the response to calcium antagonists, used alone or combined with other therapy, in patients with silent myocardial ischemia (SMI). Nifedipine, the first calcium antagonist to be studied, was shown to be superior to pindolol in patients with effort angina. Although both nifedipine and diltiazem significantly reduced episodes of ST depression, compared with placebo, in patients with stable effort angina, the addition of nifedipine to diltiazem removed the beneficial effect of diltiazem in another study. Studies have shown a reduced incidence of ischemic episodes during nicardipine treatment in patients with ambulatory ischemia, predominantly SMI, and rest angina due to coronary artery spasm. Other workers similarly reported that verapamil was superior to both placebo and propranolol in reducing painful and painless ischemia in patients with angina at rest. It has been demonstrated that, compared with placebo, nifedipine reduced ischemic episodes by 50% and also markedly reduced total ischemic time in totally asymptomatic men with coronary artery disease and SMI. It was suggested that the well-documented increase in SMI occurring between 0600 and 1200 h was reduced, but not eliminated, by nifedipine. Diltiazem may also attenuate the circadian variation in SMI. Nifedipine has been shown to be particularly effective in SMI when combined with a beta-blocker. This has been substantiated in a large group of patients; both drugs reduced the number of episodes of SMI when used as monotherapy, and the combination decreased the incidence by 95%. These findings collectively indicate that calcium antagonists are effective in reducing or preventing SMI.(ABSTRACT TRUNCATED AT 250 WORDS)


Origin and metabolism of serotonin.

A brief review is given of the distribution of serotonin in tissues. The enzymatic steps in the biosynthesis and metabolism of serotonin are described, and factors involved in the regulation of the in vivo metabolism of serotonin are reviewed.


Vascular effects of serotonin and ischemia.

Circulating 5-hydroxytryptamine originates in the gastrointestinal tract, where it overflows to the blood: part of that serotonin is taken up and stored by the platelets. When the latter aggregate, the released serotonin feeds back on the platelets to amplify the aggregation process; this amplification can be blocked with 5-HT2-serotonergic antagonists such as ketanserin and naftidrofuryl. Serotonin is taken up and destroyed by the endothelial cells; these cells also release endothelium-derived relaxing factor (EDRF) when exposed to the monoamine. The release of EDRF evoked by serotonin is not blocked by 5-HT2-serotonergic antagonists and involves a pertussis toxin-sensitive G-protein. When serotonin reaches vascular smooth muscle it usually causes it to contract; this, in most blood vessels, is prevented by 5-HT2-serotonergic antagonists. The contractions evoked by serotonin are reduced considerably in the presence of a normal endothelium. The same is true for contractions evoked by aggregating platelets, which release enough serotonin to activate receptors on both the endothelial cells (release of EDRF) and on vascular smooth muscle (contraction). Thus, 5-HT2-serotonergic antagonists favor vasodilatation not only because they brake the amplifying effect that serotonin exerts on further platelet aggregation, but also because, by blocking the direct activation of the vascular smooth muscle by platelet-released serotonin, they facilitate the occurrence of endothelium-dependent relaxations to the platelet products.(ABSTRACT TRUNCATED AT 250 WORDS)


Serotonin 5-HT2 receptors and brain circulation.

Most evidence in the literature concerning the role of serotonin in ischemia originates from brain research. This is partly because the central nervous system is particularly prone to accumulation of 5-HT, due to the neuronal sources of the amine in addition to circulating 5-HT from platelets. In ischemia, platelet invasion, rupture of the blood-brain barrier, liberation of 5-HT from nerve terminals inside the vessel wall, and necrosis of serotonergic neurons favor local increases of the transmitter in the brain. The pathophysiological consequences include amplifications of processes such as vasoconstriction of major and collateral arteries, edema formation, platelet aggregation, and blood sludging. 5-HT2 receptors appear to be the major effector of these actions of serotonin, judging from experimental and clinical pharmacology data with specific or partial 5-HT2 serotonergic antagonists. This review summarizes current knowledge on the key role serotonin plays in the induction or consequences of brain ischemia.


Effects of naftidrofuryl on the contraction and proliferation of cultured myocytes evoked by serotonin.

We investigated the effects of 2-(diethylamino)-ethyl-tetrahydro-alpha-(l-naphthylmethyl)-2-furanpro pionate (naftidrofuryl) on both the contraction and the proliferation of cultured rat aortic myocytes elicited by serotonin. Cells were cultured under controlled conditions, both on microcarrier beads and in microwells. The results show that naftidrofuryl alone had no effect on the properties of vascular smooth muscle cells. However, in the presence of serotonin, naftidrofuryl inhibits the contraction and the proliferation of smooth muscle cells.


Influence of naftidrofuryl, a serotonergic antagonist, on erythrocyte aggregation.

Erythrocyte aggregation is an important determinant of the rheological behavior of blood and may play a critical role in nutritive tissue perfusion at the level of the microcirculation, particularly in situations of low flow. Thus, abnormal red blood cell aggregation may contribute to the pathophysiology of a variety of vascular diseases with associated microcirculatory disturbances. The action of serotonergic antagonists has a hemorheological component, although red blood cell aggregation specifically has not been addressed previously. Therefore, the effect of naftidrofuryl, a 5-hydroxytryptamine-2 receptor antagonist (5-HT2), on erythrocyte aggregation was studied in whole blood obtained from adult human volunteers. Red blood cell aggregation was measured using a Myrenne aggregometer the operation of which is based on nephelometric principles. The results demonstrate that red blood cell aggregation is significantly reduced in comparison to controls on incubation of whole blood in the presence of naftidrofuryl. This inhibitory effect is concentration dependent and reaches a maximum (approximately 30%) between 1 and 10 microM naftidrofuryl. Furthermore, naftidrofuryl (5 microM) also inhibits red blood cell aggregation in the presence of exogenously added serotonin (1 microM) on average by approximately 18%. Significant inhibition of red blood cell aggregation could not be observed in similar experiments using whole blood suspensions essentially devoid of platelets, suggesting that these blood cellular elements are involved in mediating the effects of naftidrofuryl.


The effect of naftidrofuryl on red blood cell aggregation detected in vitro with ultrasound.

Red blood cell aggregates are mainly responsible for the echogenicity of flowing blood. Thus, ultrasound can be used to observe the degree of red blood cell aggregation in slow flow conditions. We quantified blood echogenicity to study aggregation tendency of red blood cells in blood of patients with claudication, patients with suspected venous thrombosis, and normal volunteers without and with in vitro addition of naftidrofuryl (10(-6) M). Normal volunteers showed lower original echogenicity than any group of patients, and claudication patients showed the highest echogenicity. Naftidrofuryl caused a fall in mean echogenicity in all groups, and its effect was pronounced on blood samples with a high original echogenicity.


The effect of naftidrofuryl, a 5-HT2 antagonist, on collateral vascular responses to serotonin and to platelet activation.

Collateral arterial supersensitivity to serotonin has been attributed to a 5-HT2 receptor mechanism because of the effectiveness of ketanserin in reversing that vasoconstrictor response. To assess that hypothesis we employed a chemically unrelated agent, naftidrofuryl, and assessed the responses of the collateral arterial supply 2 weeks after superficial femoral artery ligation to serotonin or to platelet activation induced by endothelial injury in 25 rabbits. Naftidrofuryl was effective in reversing serotonin-induced vasoconstriction in doses ranging from 0.3 to 3.0 micrograms/kg/min. Higher doses reduced blood pressure sufficiently that collateral arterial attenuation ensued. When collateral arterial vasoconstriction was induced by endothelial injury, naftidrofuryl in doses of 1.0 and 3.0 micrograms/kg/min reversed the attenuation (p < 0.001) in a dose-dependent fashion. In the absence of vasoconstriction induced by serotonin or platelet activation, naftidrofuryl in these doses did not produce vasodilatation, suggesting that the agent acted as a blocker rather than as a direct vasodilator. The observations strengthen the hypothesis that supersensitivity of collateral arterial vessels to serotonin reflects a 5-HT2 receptor mechanism.


Effect of serotonergic antagonism on local responses to an acute and selective endothelial trauma in vivo.

Serotonin is liberated during platelet release reaction. It is concluded from in vitro experiments that serotonin influences both platelet activation and thrombus-induced vasoconstriction. The subject of the present study was to assess the impact of the serotonin2 antagonist naftidrofuryl on both thrombogenesis and thrombus-induced vasoconstriction in vivo. In a hamster cheek pouch, vessels form a rich meshwork, allowing repetitive experiments to obtain intraindividual control measurements. With a contactless photochemical process, endothelial cells can be damaged in vivo. Regularly platelets and the coagulation system are activated and thrombi are formed. In larger arterial vessels local vasoconstriction occurs. Thrombogenesis was induced in arterioles with an inner diameter between 17 and 20 microns. It was monitored by the continuous measurement of blood cell velocity to assess initial hemodynamics and the interval elapsing until perfusion stops. Solvent alone had no effect. Naftidrofuryl was given in clinically relevant dosages of 1, 5, and 20 mg/kg intra-arterially. Even 1 mg/kg showed a significant antithrombotic effect. Efficacy increased in a dose-related manner as well as during the time interval of observation (i.e., 2 h after application). As an established antithrombotic standard, acetylsalicylic acid was applied in dosages of 10 and 100 mg/kg. Both dosages were found to be antithrombotic, but not more effective than comparable dosages of naftidrofuryl. Larger arterioles with an inner diameter of about 50 microns have smooth muscle cells. They constrict during thrombogenesis as a local response to substances released by the thrombus. Topical application of papaverine abolished vasoconstriction. A thromboxane antagonist (EP092) was also effective. Naftidrofuryl reduced the vasoconstriction whereas its solvent was without effect.


Naftidrofuryl inhibits contractions to serotonin in intact and de-endothelialized cerebral arteries in vitro.

Excised segments of rabbit middle cerebral artery were cannulated and perfused in vitro at constant flow (1 ml/min). In vessels with intact endothelium, integrity of the intima was checked by determining relaxations to acetylcholine. In another series of segments, the endothelium was destroyed mechanically. Serotonin (5-HT) was added to the perfusate in increasing concentrations (3 x 10(-10) to 10(-4) M). Perfusion pressure served as the index of vasomotor responses of the arterial segment. At therapeutic concentrations, the 5-HT2 antagonist naftidrofuryl did not change perfusion pressure of normal vessels in the absence of 5-HT. Addition of 5-HT to intact vessels had no effect on perfusion pressure, but potentiated the contraction induced by KCl. This reaction was greatly amplified after de-endothelialization. Addition of naftidrofuryl (10(-7) M) to the perfusate strongly inhibited 5-HT's contracting effects on both intact and deendothelialized arterial segments. Naftidrofuryl at 10(-6) M further displaced the dose-effect curve to the right in a competitive manner. These data confirm the potentiating effect of 5-HT on vascular smooth muscle (even in intact vessels) and the anticonstricting effects of naftidrofuryl when 5-HT2 receptors on smooth muscle cells are activated by serotonin.


Role of serotonin in arteriolar thrombosis and secondary vasospasm.

Platelets are implicated both in the thrombotic reaction to an intimal lesion of the arteriolar wall and to the resulting vasospasm even if the two phenomena are not linked directly. The spastic reaction is a consequence of the thrombotic process because without localized platelet activation (thrombus formation) there is no vasospastic reaction, but by pharmacological manipulation, the thrombotic reaction can develop without resulting vasospasm. We developed an original experimental model that allowed us to study the thrombotic reaction secondary to localized endothelial injury in arterioles of the mesentery of the rat, as well as the vasospastic reaction downstream to the site of thrombus formation. In this setting, we studied the reactivity of Sprague-Dawley rats treated with three 5-HT2 serotonergic antagonists (ketanserin, ritanserin, and naftidrofuryl) and that of Fawn-Hooded rats (a strain affected by a congenital reduction of platelet dense granules, with a resulting decrease in platelet content of serotonin, ADP, and catecholamines). Naftidrofuryl had antithrombotic properties similar to those of ritanserin but was less potent than ketanserin. It possessed antispastic activity against the reaction secondary to intravascular platelet activation. Its potency was similar to that of ketanserin but greater than that of ritanserin. Naftidrofuryl had no significant antispastic activity against platelet-derived agents reaching the ateriolar wall from the adventitial side. Compared to the Sprague-Dawley rat, Fawn-Hooded rats had a minimal reduction of the thrombotic process and of the intraluminal induced vasospasm but a similar response to adventitial stimulation of the arterial wall by vasoactive factors released from a neighboring hemostatic plug.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic treatment with naftidrofuryl attenuates the development of vascular hypersensitivity to serotonin in the spontaneously hypertensive rat.

Three-month-old spontaneously hypertensive rats were treated for 1, 2, or 3 months with daily intraperitoneal injections of naftidrofuryl (30 mg/kg). Systolic arterial pressure was measured. Tail arteries were removed and perfused at a constant flow rate of 2 ml/min. A concentration-response curve for serotonin was prepared. A second curve was then constructed in the presence of naftidrofuryl. Chronic treatment with naftidrofuryl had no effect on blood pressure but produced a decrease in the maximal vasoconstrictor response and the sensitivity to serotonin in vitro. The in vitro sensitivity to naftidrofuryl was unchanged. These studies suggest that chronic treatment with a dose of naftidrofuryl that does not modify blood pressure attenuates the in vitro vascular sensitivity to serotonin.


Naftidrofuryl after acute stroke: a review and a hypothesis.

With demographic change, Western populations are becoming older. The prolonged decline in incidence of stroke, already a very costly illness, may soon reverse. This paper briefly reviews medical treatments of acute stroke that have been popular in the past and finds that they have been generally of little value. The place of naftidrofuryl, a drug with a complex pharmacological profile that includes selective S2-receptor blockade, is discussed in greater detail. Two clinical studies have indicated that, although it may not alter death rate in acute stroke, naftidrofuryl therapy enhances recovery from the disabling effects of cerebral infarction. One important consequence of this is a potentially major reduction in time spent in hospital by stroke patients. Hospital bed occupancy has been identified as a principal component in the cost of stroke to health services. Drug treatments that reduce death rate without improving recovery in survivors have an opposite effect, as has been seen in an important trial of glycerol.


Naftidrofuryl in the treatment of subacute stroke.

In a placebo-controlled, double-blind study, 82 patients in the subacute stage of a disabling stroke were studied to assess the effect on clinical improvement of 600 mg naftidrofuryl against placebo. Forty-two patients were treated with the drug and 40 with placebo, in each case administered for 60 days. All patients received 100 mg aspirin and 300 mg dipyridamole daily and entered a similar program of rehabilitation therapy. At the start and the end of the study, the motor functions of the upper and lower limbs, the ability to walk and to perform daily activities, the comprehension and expression of speech, and the mental progress were assessed with quantitative linear scales. In the group treated with active drug, a greater overall tendency of improvement was observed, reaching statistically significant levels for walking and activities of daily life when compared to placebo-treated patients. Overall improvement was negatively influenced by advancing age, but the statistically significant effect of treatment on walking and daily activities was not interfered with by age. Right-sided lesions showed better improvement under active drug than left-sided lesions. This may be due to a correctional effect of naftidrofuryl on hemispatial neglect.


Indirect evaluation of blood oximetry by digitized conjunctival capillarography: effects of naftidrofuryl.

Microcirculatory disturbances are essential elements in peripheral and visceral oxygenation. Microcirculation can be studied by conjunctival angioscopy with morphological studies (arterioles, veinules, and capillaries appearances) and blood flow dynamics by digitized photographies (indirect oxymetric measurements in vivo). We studied the effects of naftidrofuryl on 20 atherosclerotic patients (mean 70 years old). After 3 months' treatment some parameters were significantly improved: interstitial edema, arteriolar sludge, and mainly vascular oxymetry. This means better microcirculatory hemodynamics and thus a better tissular oxygenation.


Peripheral arterial occlusive disease: conservative treatment of intermittent claudication.

Intermittent claudication is the principal symptom in stage II of peripheral arterial occlusive disease. As this is a multilocular manifestation of atherosclerosis, a distinction must be drawn between treatment of the underlying disease with consideration of the individual risk factors and improvement and abolition of the intermittent claudication. Various therapeutic principles exist, and drug therapy is the subject of controversial discussion. On the basis of eight controlled, randomized studies, it was demonstrated that in comparison with placebo a statistically significant increase in the pain-free walking distance can be achieved by oral drug administration within 3-6 months. This drug therapy should be considered for those patients with intermittent claudication who cannot undergo revascularization, angioplasty, or walking training.


Treatment of stage II chronic arterial disease of the lower limbs with the serotonergic antagonist naftidrofuryl: results after 6 months of a controlled, multicenter study.

A study was carried out in patients with intermittent claudication (Fontaine's stage II). The atheromatous origin of the disease was confirmed and localized by angiography or Doppler. One hundred eight-three patients were selected initially (day -30) with a pain-free walking distance on a treadmill (at a speed of 3 km/h and a slope of 10%) ranging from 150 to 300 m. During the first month (washout period) all patients received two placebo tablets daily. At the end of this run-in period (day -30; day 0) and after checking walking distance stability (allowed variation: 20% between the two measurements), patients were included in the study. According to this criterion, 112 patients were selected and 94 remained during the whole study. The study was designed in double-blind, using two parallel, randomly selected groups. Fifty-two patients received naftidrofuryl (2 x 316.5 mg tablets daily with meals) for 6 months; 42 patients received placebo under the same conditions. During this period, clinical and paraclinical examinations were carried out every quarter (day 90 and day 180). After checking the initial homogeneity of the naftidrofuryl and placebo groups, the comparison between the two groups indicates a significant improvement in the naftidrofuryl group after 3 months and 6 months of treatment, for the pain-free walking distance. For the maximal walking distance, a significant improvement was found at day 180. Nonparametric analysis (chi 2 test) also indicated a significant improvement for the naftidrofuryl group. These results confirm that naftidrofuryl is beneficial in the treatment of patients with chronic arterial disease.


Receptor "families" for 5-hydroxytryptamine.

Significant advances in the analysis of 5-hydroxytryptamine (5-HT) receptor subtypes occurred in the 1980s. Although the current status of 5-HT receptor pharmacology may appear confusing to many investigators, the evolving data suggest that 5-HT receptor subtypes can be categorized into three major "families." Each "family" consists of multiple receptor subtypes that share similarities in their molecular, biological, pharmacological, biochemical, and/or physiological properties. These receptor subtypes are present throughout the nervous system as well as in the periphery. A simple framework for the classification of 5-HT receptor subtypes is provided in the present review.


The effect of naftidrofuryl on intermittent claudication: a meta-analysis.

A meta-analysis was performed on four clinical trials, conducted during 1980-1989 in France (two trials) and in the Federal Republic of Germany (two trials). Altogether, 596 patients with peripheral arterial occlusive disease (Fontaine's classification stage II) entered these four multicenter studies. Four hundred fifty-two patients completed the trials, 241 were treated with 600 mg naftidrofuryl orally per day and 211 were given a placebo. The studies were of a double-blind parallel design and lasted for 3 or 6 months. Inclusion and exclusion criteria were comparable, as were the experimental methods used. Occasionally, differences in study design and methods were observed. Risk factors were recorded in three of the four studies. The outcome criterion of pain-free walking distance was studied for the four trials together and showed a significant improvement in the active drug tested group, following both 3- and 6-month duration of treatment. The type of treatment, the severity of the disease, the existence of blood lipid disorders, and smoking were found to be the predictive factors associated with the evolution of pain-free walking distance during 3 months. The meta-analysis confirms the beneficial effect of naftidrofuryl in treating peripheral arterial occlusive disease.


Cloning high molecular weight DNA fragments by the bacteriophage P1 system.

The cloning of high molecular weight genomic DNA promises to provide the means of mapping chromosomes, isolating genes, and understanding long-range effects on gene expression. This review describes the background and some recent advances in cloning of high molecular weight DNA using the bacteriophage P1 system.


Wilms' tumour: reconciling genetics and biology.

Wilms' tumour, a paediatric malignancy of the kidney, is a striking example of the relationship between aberrant development and cancer. Several different genetic loci have been implicated in the aetiology of the tumour; genomic imprinting also plays a role. One Wilms' tumour predisposition gene (WT1), encoding a zinc finger protein, is expressed in a limited set of tissues, including developing nephrons and gonads. The biology and genetics of Wilms' tumour underline the developmental relationship between kidneys and gonads.


Plant transcription factors: present knowledge and future challenges.

By the use of three different experimental approaches, more than 40 cDNA clones encoding putative transcription factors have been isolated from plants. In this review, we compare the relative advantages and disadvantages of each approach, suggest methods for investigating the activity of the factors in vitro and in vivo, and discuss strategies to elucidate their physiological functions during plant growth and development.


Conservation and evolution of transcriptional mechanisms in eukaryotes.

Eukaryotic transcriptional activators play key roles in controlling cell growth and specifying embryonic development. These activators can stimulate promoters from distances up to tens of kilobases by a mechanism that is remarkably conserved in eukaryotes ranging from yeast to humans. Although the primary sequence of certain activators has also been conserved in widely divergent organisms, the regulatory roles that these factors play have been altered over evolution to fit the specific needs of the host.


Mitotic gold in a mold: Aspergillus genetics and the biology of mitosis.

The analysis of fungal mutants has had an extraordinary impact on our understanding of the biochemistry and regulation of mitosis. In this article we review the contribution of work on the filamentous fungus Aspergillus nidulans to the molecular genetics of mitosis.


Mesoderm induction and development of the embryonic axis in amniotes.

The mechanisms controlling the formation of the embryonic axis, and specifically those that give rise to the mesoderm, have received renewed attention recently. In the frog, some of these mechanisms have begun to be elucidated, and several factors have been found to cause uncommitted ectoderm cells to differentiate into mesoderm. All of the factors identified to date are related either to fibroblast growth factor (FGF) or to transforming growth factor beta (TGF-beta). Do the mechanisms that generate the embryonic axis of amphibians also operate in chick and mouse embryos? Here I address how amphibian and amniote embryos might provide complementary pieces of a puzzle.


Molecular genetics of sex determination in C. elegans.

Sexual fate in the nematode Caenorhabditis elegans is controlled by a group of genetically well-characterized genes. Several of these sex-determining genes have now been analysed at the molecular level. Transcriptional regulation is likely to control both commitment to a single sexual fate and maintenance of that decision; in addition, intercellular signalling appears to coordinate the sexual fates of cells throughout the animal to adopt a single sexual fate.


X-chromosome inactivation and cell memory.

Mammalian X-chromosome inactivation is an excellent example of the faithful maintenance of a determined chromosomal state. As such, it may provide insight into the mechanisms for cell memory, defined as the faithful maintenance of a determined state in clonally derived progeny cells. We review here the aspects of X-chromosome inactivation that are relevant to cell memory and discuss the various molecular mechanisms that have been proposed to explain its occurrence, with emphasis on DNA methylation and a recently proposed mechanism that depends on the timing of replication.


Ustilago maydis, the delightful blight.

Recent studies of the corn smut fungus life cycle and its regulation by two mating type loci and other genes provide a cornucopia of challenges in cell biology, genetics and protein structure. The fungus can exist in two states: nonpathogenic and pathogenic. The change from one state to the other is accompanied by a change in morphology (yeast-like to filamentous) and growth properties (saprophytic to parasitic).


The retinoblastoma protein and cell cycle regulation.

Although the precise function of the retinoblastoma gene product, p110RB1, remains unknown, recent data suggest that it plays a role in the control of cellular proliferation by regulating transcription of genes required for a cell to enter or stay in a quiescent or G0 state, or for progression through the G1 phase of the cell cycle. However, it is difficult to rationalize the expression of p110RB1 in a wide range of tissues with the fact that mutations in the RB1 gene initiate cancers in a limited number of tissues.


[Combination of interferon-alpha with cytostatic drugs: a potentially successful therapeutic approach in metastatic melanoma].

Pharmacological treatment of disseminated melanoma is characterized by rather low objective response rates with mono- and combined chemotherapy and by significant toxicity. For these reasons, many centres do not now offer any systemic treatment to melanoma patients with distant metastases. Systemic treatment with interferons has not fulfilled all that was expected of it, but type-I interferons (-alpha, -beta) have proved to be effective in about 10-15% of patients treated. The antitumour activity of these substances seems to be related mainly to their antiproliferative effect, whereas no immunomodulatory effects have been substantiated in clinical trials. Combined therapy with interferons and cytostatic drugs was introduced into clinical trials only a few years ago, and the initial results are promising. Large studies with a total of over 200 patients have already been performed to evaluate the combination of interferon-alpha and dacarbazine. This treatment was effective in around 50% of the patients, complete or partial remission being achieved in 30% and stabilization of the disease, in 20%. Toxicity is significant, but still manageable; the new generation of antiemetic drugs (serotonin receptor blockers), in particular appears promising. Up to now, no improvement of efficacy has been found following addition of interferon-alpha to cisplatin in four clinical trials. In a study in our own department, however, the combined action of interferon alpha and vindesine was found to be superior to that of either used as a single agent, and the combination was well tolerated on an outpatient basis.(ABSTRACT TRUNCATED AT 250 WORDS)


[Patient information prior to sterilization].

The law in Denmark prescribes that the patient and the general practitioner to whom the patient directs his or her request for sterilization are obliged to confirm by their signatures that the patient has received information about sterilization, its risk and consequences. We asked 97 men and 96 women, if they had received this information prior to their sterilization. They were also asked about their knowledge about sterilization. 54% of the women and 35% of the men indicated that they had not received information. Only few of these wished further information by the hospital doctor. Knowledge about sterilization was good. It is concluded that the information to the patient prior to sterilization is far from optimal. The patients' signature confirming verbal information is not a sufficient safeguard. We recommend, among other things, that the patient should receive written information and that both the general practitioner and the hospital responsible for the operation should ensure that optimal information is received by the patient.


[Reproductive and developmental toxicity study of 6-amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187). (II)--Oral administration to rats during the period of fetal organogenesis (prenatal examination)

6-Amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187) was given orally to pregnant Crj : CD (Sprague-Dawley) rats from days 7 through 17 of gestation at dose levels of 50, 200 and 800 mg/kg/day. In the 800 mg/kg/day group, salivation just after dosing, suppression in body weight gain and decreased food consumption were observed. No external, visceral and skeletal anomalies attributable to FUT-187 were observed in fetuses. From the present result, it is considered that the no-effect dose level of FUT-187 for dams and fetuses are 200 mg/kg/day and 800 mg/kg/day respectively.


[Reproductive and developmental toxicity studies of 6-amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187). (IV)--Oral administration to New Zealand white rabbits during the period of fetal organogenesis.

Oral administration of 6-amidino-2-naphthyl 4(-)[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) at doses of 10, 30 and 100 mg/kg was given to New Zealand White rabbits on days 6 to 18 of gestation. The following results were obtained. Decreased food consumption and suppression of body weight gain in dams were observed and these changes contributed to the increase in aborted or prematured births and increased fetal mortality at the 100 mg/kg group. There were changes attributable to FUT-187 on external, skeletal and visceral examinations of fetuses. Based on the above, the no-effect dose level in dams and fetuses in the present study is 30 mg/kg/day.


Mechanisms of amplification, deactivation, and noise reduction in invertebrate photoreceptors.

In this review we have discussed the problem of deactivation at both the rhodopsin and G protein levels. Of particular interest is the novel observation that rhodopsin deactivation can be modulated by light. This modulation is likely to play an important role in light adaptation by reducing the gain of transduction. One interesting possibility is that this modulation involves the phosphorylation of an arrestin-like molecule, but this remains to be tested. One of the experimental advantages of Limulus photoreceptors is the large size of the single photon responses and the fact that even single G proteins produce a detectable response. This made possible the observation that nonhydrolyzable GTP analogues produce discrete transient events rather than the step-like events that would be predicted by previous models. This observation led us to a new view of how enzyme deactivation is coupled to GTP hydrolysis on G protein. According to this view, enzymes are activated by G protein, but can be deactivated by processes that are not dependent on G protein or the hydrolysis of GTP. We have conducted several types of experiments, including some on the vertebrate rod system, that strongly support this hypothesis. A second major theme of this review is transduction noise. The available biochemical evidence suggests that both G protein and G protein-activated enzymes are likely to become spontaneously active and generate undesirable noise. Our measurements indicate, however, that this noise is orders of magnitude smaller than would be predicted by simple models, suggesting that special mechanisms must exist for suppressing this noise. We have proposed a specific mechanism by which enzymes regulated allosterically by multiple subunits could act as coincidence detectors to reduce transduction noise. Finally, there is the fundamental question of which second messengers have a direct role in invertebrate phototransduction. After Fesenko et al. (1985) showed that the light-dependent conductance in vertebrate rods was modulated by cGMP and not by Ca2+, there was rapid progress in understanding the vertebrate photoreceptor transduction mechanism. Now that it has been established that invertebrate light-dependent channels are regulated by cGMP and not by Ca2+, we can expect rapid progress in understanding invertebrate phototransduction. A key question that needs to be answered is whether the InsP3-Ca2+ pathway somehow triggers changes in cGMP or whether there is an altogether different pathway by which cGMP metabolizing enzymes are affected by light.


The molecular basis of signal transduction in olfactory sensory neurons.

Contributions from a wide spectrum of experimental systems have resulted in a dramatic increase in our understanding of this old and most enigmatic of the sensory systems. Many of the components of the odorant-induced transduction cascade have now been cloned, and the biochemistry, pharmacology, and regulatory mechanisms are being addressed in a logical fashion. One of the first priorities is to establish that the large family of putative receptor proteins described by Buck and Axel (1991) do, in fact, bind odorants. The ability to express members of this receptor family at high levels in the mammalian expression system is a first step in this direction. Determining specific ligand-receptor relationships is an extremely challenging task given the diversity of odorants able to be perceived and the potentially large size of the family of receptors. The role of other proteins in odorant presentation and processing, such as odorant binding protein produced in the lateral nasal gland (Pevsner et al., 1988), can be explored. A fascinating issue to be resolved is that of the distribution of receptor molecules within the population of olfactory sensory neurons. Does one cell express only one receptor, a small repertoire of receptors, or indeed the entire family? These questions can now be answered using a combined approach with in situ hybridization, immunocytochemistry, and single cell PCR techniques. One model of receptor distribution would provide for discrimination of a particular odorant by higher order analysis of the pattern of receptor neuron firing within the neuroepithelium.(ABSTRACT TRUNCATED AT 250 WORDS)


[Focal nodular hyperplasia of the liver].

For several weeks a 27-year-old man had experienced a pressure sensation and noticed a spherical area of resistance in the epigastrium. On physical examination the firm, elastic tumour seemed most likely to be arising from the liver. Sonography recorded a 7.4 x 10.5 cm echo-poor structure. Computed tomography demonstrated in the tumour a central star-like, hypodense zone which filled with contrast medium, a finding typical of focal nodular hyperplasia. Functional hepatobiliary scintigraphy and histological examination of a fine-needle biopsy from the tumour (slightly enlarged hepatocytes, portal reticular fibrosis, ductular proliferation) confirmed the diagnosis. As there was no danger of rupture and no sign of local compression surgical intervention was not indicated, but regular ultrasound monitoring is planned.


[The cost of arterial hypertension in Spain].

High blood pressure has a high incidence and produces a high morbidity and mortality due to associated diseases: cerebrovascular disease, ischemic cardiopathy, and cardiac failure. The socioeconomic impact of high blood pressure in Spain was estimated during 1985 in primary, hospitalary and pharmaceutical health care, to provide a framework for decision making and to determine strategies for reducing the costs of this entity. The methodology of analysis of the cost of the disease was followed with the aim of quantifying the socioeconomic consequences of an entity, disease or risk factor with prevalence being the focus of the study. The socioeconomic impact estimated was situated between 95,000 and 124,000 millions of pesetas according to the different hypothesis adopted in the analysis of sensitivity. The direct health care costs represented between 2.6 and 3.9% of the global health care costs for Spain in 1985. Health care funding consumed by high blood pressure in primary health care was higher (between 4.5 and 6.7%) than hospital attendance (between 1.0 and 1.5%) and pharmaceutical care (between 2.3 and 3.5%), with respect to the total costs of each category. The reduction of the costs related with high blood pressure in Spain must be obtained from improvement of efficacy of interventions carried out in health care education and primary health care. The economic evaluation of the primary and secondary prevention programs may aid in determining more cost-effective strategies.


Maudie: the life and times of McGill's Maude Abbott.

This article is an account of the life of Dr. Maude Abbott, the turn-of-the-century Canadian pioneer physician who founded what is now the International Academy of Pathology. She developed a system for the classification of medical museum specimens, accumulated the world's largest collection of congenital heart disease cases, and published historical works outside the field of medicine. A protegée and friend of Sir William Osler, she was guided by his counsel and inspired by his example. With Osler and Banting, she was one of the giants of Canadian medicine in the first half of the 20th century.


Aneuploidy in nonneoplastic and benign melanocytic and breast lesions determined by DNA flow cytometry.

A total of ten of 60 nonneoplastic lesions and eight of 76 benign neoplasms of skin and breast showed an aneuploid peak in DNA flow cytometry profiles obtained from archival paraffin blocks. This confirms previous similar scattered reports and emphasizes that caution needs to be exercised in interpreting aneuploidy in DNA flow cytometry to mean preneoplasia, neoplasia, or malignancy.


Subcellular localization of HMFG2 in breast carcinomas: an immunohistochemical and immunoelectron microscopic study.

Malignant transformation of human cells is associated with morphological and biochemical alterations. We have studied the distribution and pattern of staining of HMFG2 (human milk fat globulin) in normal breast, benign breast lesions, and 137 primary and metastatic breast carcinomas. Immunohistochemical staining was performed with an antibody to HMFG2 using the indirect peroxidase technique. Three patterns of staining were noted: 1) secretion and luminal staining (in normal breast, most benign breast lesions and some breast carcinomas); 2) plasma membrane staining (in breast carcinomas); 3) intracytoplasmic staining (in breast carcinomas). Immunoelectron microscopy was also performed on normal breast, infiltrating duct, and lobular carcinomas. Immunoelectron microscopy showed localization of the gold particles on the electron dense granules of the HMFG2 protein. These were localized along the surface of the extracytoplasmic lumina in normal breast ducts/acini and breast carcinomas, whereas localization was also noted within the intracytoplasmic lumina in cancer cells only. These results show that there is altered localization of milk fat globulin in breast cancer cells associated with membrane internalization and formation of intracytoplasmic lumina. This contributes to the understanding of the phenotypic alterations associated with malignant transformation in breast cancer.


Appendiceal involvement in ulcerative colitis.

Little information has been published regarding appendiceal changes in ulcerative colitis of any extent. An early study has shown the appendix to be involved in over 50% of all cases of ulcerative colitis for which a proctocolectomy was performed, but the extent of the colitis was not always defined. While some investigators have found appendiceal involvement only in continuity with adjacent involved cecum, others believed it may occur as a skip lesion. In this study, the colons and nonobliterated appendices of 87 patients who underwent total proctocolectomy for ulcerative pancolitis were examined to determine the frequency of appendiceal involvement and to determine the frequency with which such involvement truly occurs as a skip lesion. All 87 cases had ulcerative pancolitis, and 66 (62%) had colitic changes in the appendix. In the remaining 21 cases, there was no appendiceal inflammation. In all cases in which the appendix was involved, the cecum was also involved. Cecal activity or lack of activity correlated with appendiceal activity in 52 of the 87 cases (60%). Of the 35 cases in which there was some discrepancy in disease activity between the appendix and cecum, nine had more active disease in the appendix, and 26 had greater activity in the cecum, but in none of the cases where the cecum was normal or near normal was the appendix more severely involved. These data suggest that appendiceal involvement in resected ulcerative pancolitis always occurs in continuity with adjacent involved cecum, although there may be differences in disease activity between the two sites.


Histologic changes in liver allograft biopsies associated with elevated whole blood and tissue cyclosporine concentrations.

Cyclosporine is used in the postoperative management of rejection in liver allograft recipients. Despite its efficacy in the treatment of allograft rejection, the drug exhibits toxicity at elevated whole blood concentrations including nephrotoxicity with associated histologic changes, and evidence of hepatotoxicity as determined by liver function studies. To date, there have been few published reports describing histologic changes in liver biopsies from patients with elevated blood cyclosporine levels. In the present study, we retrospectively examined biopsies from 16 liver allograft recipients, seven patients with elevated whole blood cyclosporine levels (> 1000 ng/ml) and nine control patients who had whole blood cyclosporine levels in the therapeutic range (558 to 993 ng/ml). In each case, frozen liver biopsy tissue was available to measure tissue levels of cyclosporine and metabolites. The blood and tissue drug levels were then correlated with the histologic changes present in the biopsy specimens. Patients with increased cyclosporine levels displayed histologic changes consisting of hypertrophy of the bile ductal epithelium with cytoplasmic vacuoles and the presence of "foamy" material within the hepatic sinusoids that were either absent or occurred less frequently in the control group. The histologic changes correlated best with cyclosporine metabolite levels rather than tissue levels of native drug. When liver function studies were correlated with cyclosporine levels, only gamma glutamyl transpeptidase (GGT) demonstrated a significant positive correlation with the histologic changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Nephrogenic adenomas of the urethra involving the prostate gland: a report of two cases of a lesion that may be confused with prostatic adenocarcinoma.

Two cases of urethral nephrogenic adenoma involving the prostate are described. A diagnosis of prostatic carcinoma was raised in both cases and was seriously entertained in one of them. The patients, who were 65 and 68 yr old, underwent transurethral resection because of difficulty voiding; both had had a prior similar procedure. Microscopic examination in each case showed small tubules and clusters of cells in the fibromuscular stroma of the prostate. In one case the lesional cells had abundant clear cytoplasm, and in both cases some of the nuclei had prominent nucleoli. In each case a minor component of the cystic pattern of nephrogenic adenoma was also present. Features pointing to a diagnosis of nephrogenic adenoma were a morphology that was diagnosis of nephrogenic adenoma were a morphology that was focally characteristic of that lesion, an origin from overlying prostatic urethra in both cases, and negative immunohistochemical staining of the lesional cells for prostate-specific antigen and prostate-specific acid phosphatase. These cases illustrate that nephrogenic adenoma occasionally involves the prostate and in these cases can potentially be confused with prostatic adenocarcinoma.


Immunocytochemical characterization of male breast cancer.

Biologic properties of breast cancer in men that might reflect alterations in pathogenesis from the disease in women were examined. We studied 22 tumors from males, 18 invasive carcinomas, three of which were papillary, and three in situ tumors of which one was papillary, and one papilloma. Our data support the previously reported high incidence of papillary carcinoma in men. Estrogen receptor status and the expression of cancer-associated antigens recognized by antibodies DF3, B73.2, SP-1, and c-erbB-2 were compared to matched tumors from females. Immunocytochemistry was performed on formalin-fixed, paraffin-embedded sections using standard avidin-biotin techniques; anti-PSA was used to exclude the possibility of metatastic prostate cancer, and 12 cases of gynecomastia were included as nonmalignant controls. The incidence of estrogen receptor positivity was higher in tumors from males (73%) than from females (54%), as has been reported previously. The range of expression of all breast cancer antigens tested in male tumors was similar to that observed in females, but some interesting differences were noted. With the exception of the anti-mucin DF3, all the antibodies reacted only with neoplastic tissues. Expression of the oncoprotein c-erbB-2 was lower (17%) in males than in females (33%), despite the preponderance in men of the large-cell type carcinomas that have been associated with c-erbB-2 expression. Unexpectedly, the pregnancy-associated hormone detected by SP-1 was expressed in 33% of tumors from males and, in contrast to females, was found in less differentiated tumors.


DNA ploidy analysis of pleural mesotheliomas: its usefulness for their distinction from lung adenocarcinomas.

The distinction of malignant mesotheliomas from adenocarcinomas with pleural involvement is often difficult, even with electron microscopic and state-of-the-art histochemical and immunologic studies. We evaluated the DNA ploidy and cell cycle of 45 clinically, morphologically, and immunohistochemically well-characterized malignant mesotheliomas to establish their ploidy profile and compared it with that of 41 pulmonary adenocarcinomas. All the cases were mucin negative and had been immunophenotyped with the following monoclonal antibodies: anti-keratin, anti-CEA, anti-Vimentin, anti-HMFG2, Leu M1 (CD15) and B72.3. Single cell suspensions from the paraffin blocks were prepared following Hedley's technique and were analyzed with a Coulter EPICS V flow cytometer. The resulting histograms were interpreted with the Multicycle software program. Five cases were excluded due to their high coefficients of variation. DNA aneuploidy was defined by the presence of more than one G0/G1 peak on the histograms obtained exclusively from the tumor sample. With this criterion, there is a possibility of missing aneuploid cases with a single aneuploid cycling population; however, fixatives and time of fixation produce such a remarkable variation in the fluorochrome uptake that any control, other than normal tissue present in the sample, was rendered unreliable. Five (14%) cases were DNA aneuploid with DNA indexes ranging from 1.2 to 1.9 (mean = 1.5). Three cases had increased S + G2/M values. Of the aneuploid cases, four were epithelial and one sarcomatous. In comparison, aneuploidy was found in 31 (75%) of the lung adenocarcinomas studied (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)


Mucinous (so-called colloid) carcinomas of lung.

We present 24 cases of primary mucinous (so-called colloid) carcinomas of the lung. The patients were between 33 and 81 yr old (median: 57 yr), including 15 men and nine women. The lesions were discovered incidentally on chest X-ray, where they presented in diverse forms. No predilection for a particular lobe or pulmonary segment was observed. The tumors varied from 0.5 to 10 cm in greatest diameter. Grossly, the tumors were poorly circumscribed, soft, tan-to-gray mucoid lesions. Microscopically, they showed intra-alveolar pools of mucin containing small clusters of atypical cells floating in the mucin, and foci of neoplastic columnar epithelium lining scattered alveoli. Seven cases showed areas of solid, well-differentiated malignant glands adjacent to pools of mucin. In two cases, lymph node metastases were found at surgery. Eleven (57%) of 19 patients were alive over a follow-up period ranging from 2 to 192 mo; one of them had metastases to bone and another had intrapulmonary recurrence. Eight patients died with/of their tumors, two of them with known metastases to bone and/or brain, and one with recurrence after 2 yr of initial diagnosis. No follow-up was obtained in five patients. Although the extent of clinical evaluation varied, no other primary neoplasms (i.e., breast, gastrointestinal tract, or other organs where primary mucinous carcinomas are known to occur) were observed. These tumors probably represent a variant of bronchioloalveolar carcinoma and share the prognosis of that neoplasm. However, because of their often bland cytologic features and paucity of malignant cells, they may be difficult to diagnose as neoplasms.


Giant cell fibroblastoma in childhood immunohistochemical and ultrastructural study.

Two cases of giant cell fibroblastoma in children are presented. Histologic features included a dense fibrous tissue stroma with multinucleated giant cells lining sinusoid-like spaces. Immunohistochemical stains and electron microscopy provide evidence of a fibroblastic origin of the tumor cells. Ultrastructure of the multinucleated cells revealed segmentation of the nuclei with multiple centrioles, suggesting that an abnormality in the division of the tumor cells may be the mechanism for the formation of the giant cells.


Expression of epidermal growth factor receptor and ERBB2 (HER-2/Neu) oncoprotein in prostatic carcinomas.

Expression of epidermal growth factor receptor (EGFR) and ERBB2 oncoprotein were studied in paraffin-embedded normal (n = 2), hyperplastic (n = 17), and malignant (n = 147) prostatic tissues by immunohistochemistry. Strong immunoreactivity was detected in the epithelial cells of all normal and hyperplastic prostates with a new EGFR antibody (Mab31G7). In prostatic carcinomas, the EGFR immunoreactivity was variable with 47% showing uniform, 39% partial, and 14% no staining. Tumors with partial or uniform EGFR immunoreactivity were locally more advanced and of higher histological grade than the EGFR-negative tumors. EGFR-positive tumors also had two to three times higher S-phase fraction, suggesting that EGFR expression conferred proliferative advantage. Patients who had either partially or uniformly EGFR-positive carcinomas had a worse 10-yr progression-free (p = 0.05), overall (p = 0.03), and prostatic carcinoma-specific (p = 0.007) survival than those with EGFR-negative carcinomas. However, according to a multivariate analysis, EGFR did not have independent prognostic value. None of the normal, hyperplastic, or malignant prostate tissues showed clearly positive ERBB2 immunoreactivity with MAb1 antibody.


The use of combined in situ hybridization and immunocytochemistry to identify HIV-infected cells in brain tissue.

It is frequently important to identify the types of cells that are infected with human immunodeficiency virus type-1 (HIV-1) in sections of formalin-fixed paraffin-embedded (FFPE) brain tissue. Currently, both immunocytochemical and in situ hybridization methods are used for this purpose. Combined in situ hybridization and immunocytochemistry results in simultaneous detection of HIV-1 nucleic acids and proteins and allow comparison of transcriptional and translational events of cells infected with HIV-1 in the same section. In addition, this technique allows morphologic and immunologic identification of the cells within which in situ hybridization occurs and confirmation of the identity of the cells that are not hybridized. Procedures are described for use with FFPE brain tissue.


Clonal Epstein-Barr virus in lymphoepithelioma-like carcinoma of the stomach: demonstration of viral genome by in situ hybridization and Southern blot analysis.

Lymphoepithelioma (LE), originally described in the nasopharynx, is an undifferentiated carcinoma with heavy lymphocytic infiltrate. The tumor is common in Southeast Asia, particularly in southern China, where the Epstein-Barr virus (EBV) association has been documented more consistently than in Western countries. Tumors histologically similar to LE have been described also in other anatomical sites, mostly of fore-gut origin, such as salivary gland, tonsil, lung, thymus, and more recently stomach. We are reporting a case of poorly differentiated gastric adenocarcinoma with marked lymphocytic infiltrate resembling LE (LE-like carcinoma) in a Chinese without evidence of nasopharyngeal carcinoma. In situ hybridization for EBV revealed that the tumor cells but not the lymphoid cells harbored the virus. Tumor cells both in syncytial and glandular areas were positive for EBV. By Southern blot analysis EBV was demonstrated in the DNA extracted from the tumor, while the adjacent normal gastric tissue was negative. Moreover, analysis of the EBV termini revealed a clonal episomal form of the virus. Our case further supports the hypothesis that EBV is associated with LE-like gastric carcinoma. It also strongly suggests that EBV infection has preceded, and thus most likely contributed to, the clonal expansion in this tumor.


Oncocytic differentiation in intrahepatic biliary cystadenocarcinoma.

An intrahepatic biliary cystadenocarcinoma in a 56-yr-old white man was characterized by pronounced oncocytic differentiation. Grossly the tumor was a well-demarcated cyst filled with numerous branching papillary fronds. Most tumor cells had abundant granular, intensely eosinophilic cytoplasm on light microscopic examination and large numbers of densely packed mitochondria by electron microscopy. Mucin-secreting cells were also present. The patient returned 20 mo after resection of the primary tumor with recurrent tumor in the liver and widely disseminated disease throughout the abdominal cavity, and he died 5 mo later. Although less differentiated, the recurrent tumor again contained greatly increased numbers of mitochondria. The partial loss of oncocytic differentiation in the evolution of the present case and the benign nature of purely oncocytic tumors suggest that in the presence of mixed histologic features the potential for tumor progression is primarily determined by the lesser differentiated or nononcocytic component. To the best of our knowledge, oncocytic differentiation has not been previously described in biliary neoplasia.


[Growth factors in hematology].

New experimental findings on the mutual regulation of growth, differentiation and function of human blood cells by growth factors offer the opportunity to use these factors in the treatment of haematological diseases. The hitherto known growth factors are divided into four basic groups: 1. haematopoietic growth factors proper [multi-CSF (IL-3), GM-CSF, G-CSF, M-CSF, erythropoietin, lymphopoietin (IL-7) and megakaryopoietin (IL-11)], 2. cytokines (IL-1 to IL-11, TFN)., 3. other growth factors (PDGF, FGF, MGF) and 4. so-called negative regulators of haematopoiesis (IFN, MIP, TGF beta and IL-10), some of which support the differentiation of stem cells. Before growth factors can be routinely used in clinical work, it is essential to acquire closer knowledge of their interrelations, the activity of their receptors and natural or acquired inhibitors in vivo.


[Hematopoietic growth factors. Biology and clinical applications].

The authors present an account of haematopoietic growth factors which include the stem cell factor (SCF), factors stimulating granulocytomacrophage colonies (GM-CSF), granulocyte (G-CSF), monocytomacrophage (M-CSF) factors, erythropoietin (EPO) and also interleukin (IL) 1 to 11. Their main action is described as well as the site of action in haematopoiesis. In many of them participation in the pathogenesis of some diseases, incl. malignant ones, is anticipated. The preparation of growth factors in a recombinant-form and knowledge of their effect made it possible to use them in clinical practice. The authors mention possible indications, although in many their administration still has the character of clinical studies.


[Inhibitory factors in hematopoiesis].

The author presents a short review of inhibitory factors which affect hemopoietic stem and progenitor cells. At present, the existence of naturally occurring inhibitory factors which take part in the control of hemopoiesis under pathological conditions in which they were detected, and probably even under physiological conditions, has been proved. Through their effects the inhibitory factors create a complex network of negative feed-back regulations. Their cooperation with stimulatory factors seems to be mechanism which ensures the balance in hemopoiesis and recovers it in the case of a disorder.


[Familial occurrence of malignant hematologic diseases].

The cases of first-degree relatives from five families with hematological malignancies are described in this study. The occurrence of non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphoblastic leukemia (B-CLL) in the first family, NHL and chronic myeloid leukemia (CML) in the second one, two cases of Hodgkin's disease (HD) in the third and the fifth one's NHL and acute myelomonocytic leukemia (AMML) in the fourth one observed. Several factors which are considered to be involved in etiopathogenesis of hematological malignancies (virus infection, immune defects, HL-A antigens, cytogenic features) were discussed. Our study confirm other previous findings, that the familial susceptibility results from a combination of genetic and environmental influences.


[Fatal poisoning by the rupture of intestinal bags of cocaine].

We report a case of rupture of bags filled with cocaine into the digestive apparatus in a young man. He carried into his digestive tract one hundred of small bags containing 40 g of cocaine each one. The initial clinical picture was characterized by sympathetic hyperactivity, rectorrhagia, and psychosis that evolved in 72 h to neurologic coma, convulsions, rhabdomyolysis, hyperthermia, hypocalcemia, hyperdynamic picture with negative blood cultures, arterial hypotension, syndrome of adult respiratory distress, and multiorgan failure. Treatment with propranolol, mechanic ventilation, barbiturates and inotropic agents was ineffective and the patient died 7 days after.


["A life threatening event" in infants. Results of polysomnography and examination of a group of 122 infants].

Survivors of an "apparent-life-threatening-event" subsequently more often die from sudden infant death syndrome than others. The aim of this study was to find out abnormal clinical symptoms and/or polysomnographic patterns in this group of patients. Between January 1989 and September 1990 122 infants (mean age 13.98 weeks) were examined after a life threatening event (mean age 9.3 weeks at the event). In total, 222 polysomnographic studies were performed. In 46 cases additional esophageal pH-metric measurements, and in 26 cases a Holter 24 hours monitoring were done. Seven infants were premature and had been ventilated, and 6 were siblings of sudden-infant-death-syndrome victims. Pulmonary problems were identified in 7 (6%), cardiac problems in 17 (14%), 18 (15%) had neurological problems, and 40 (33%) showed a gastroesophageal reflux. In 14 (11%) other diseases were found. Only 43 (35%) infants were without pathologic findings and were classified as having had an "idiopathic" event. The polysomnographic studies showed that obstructive apnea occurred significantly more often, the maximal duration of apnea was longer, and the number of sudden pO2 decreases was significantly higher than in a group of 188 normal infants. Thus, patients having had an "apparent-life-threatening-event" showed a broad spectrum of abnormal clinical symptoms and some respiration disturbances compared to a reference group of infants.


Post streptococcal glomerulonephritis co-existing with acute rheumatic fever--a case report.

A case of post streptococcal acute glomerulonephritis co-existing with acute rheumatic fever is reported. The relevant literature is briefly reviewed.


[Eosinophilia-myalgia: new syndrome].

The eosinophilia-myalgia syndrome is a newly recognized illness that has been associated with the consumption of tryptophan products. We describe the clinical and histopathological findings and the results of biochemical analyses of tryptophan metabolism in patients with this syndrome and the toxic-oil syndrome which took place in 1981 in Spain. Symptoms and laboratory findings are similar. Chronic phase of EMS is characterised by long-term disability, sclerodermatous skin thickening, sensorimotor polyneuropathy and severe episodic myalgias. The development of the syndrome may result from a confluence of several factors including the ingestion of tryptophan, exposure to agents that activate indoleamine-2,3-dioxygenase, and possibly, impaired function of the hypothalamic-pituitary-adrenal axis.


Promotion of murine marrow alloengraftment and hematopoietic recovery across the major histocompatibility barrier by administration of recombinant human interleukin-1 alpha.

Irradiated C57BL/6 (H-2b) recipients of T-cell-depleted (TCD) BALB/c (H-2d) bone marrow (BM) and recombinant interleukin-1 alpha (IL-1 alpha) (1 microgram/d) had a significantly (P less than or equal to .006) higher 100-day actuarial survival rate, accelerated hematopoietic recovery, and higher levels of alloengraftment than a group of transplanted control mice treated identically, but given phosphate-buffered saline (PBS). To elucidate the mechanisms involved with IL-1 alpha-induced promotion of alloengraftment and hematopoietic recovery, we performed sequential splenic FACS studies on transplanted mice and secondary transfer studies in syngeneic mice given IL-1 alpha or PBS. Splenic phenotyping showed that recipients of IL-1 alpha had a higher proportion of donor granulocytes (52% v 19%) as compared with PBS controls as early as 7 days after bone marrow transplantation (BMT). On day 11 post-BMT, recipients of IL-1 alpha had a more than fourfold increase in splenocyte number, which included a higher percentage (90% v 59%) of donor cells, especially donor granulocytes (52% vs 32%), and a sevenfold increase in donor T cells as compared with controls. Host T-cell numbers were not affected. Taken together, these data suggest that IL-1 alpha stimulated bipotential (myeloid and lymphoid) donor cell engraftment. In a syngeneic BMT system, administration of IL-1 alpha resulted in a higher incidence of survival when recipients were transplanted with BM cells, indicating that IL-1 alpha administration probably either expanded or potentiated engraftment of a committed progenitor cell pool. Secondary transfer experiments using marrow from IL-1 alpha-treated mice showed that the number of day 12 colony-forming unit-spleen (CFU-S) cells was unaltered compared with untreated control mice, suggesting that more primitive, albeit committed, hematopoietic progenitor cells were not affected. We also examined the potential additive effects of IL-1 alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) administered in combination (for 14 days). Mice receiving a suboptimal amount of IL-1 alpha along with GM-CSF had significantly higher levels of donor alloengraftment (92%) with superior hematopoietic recovery, as compared with mice receiving either IL-1 alpha (57%) or GM-CSF (18%) alone.


[Evaluation of changes in microcirculation dynamics of a free muscular flap submitted to many hours of ischemia. In vivo experiments].

The paper presents the influence of progressive ischemia on the rat cremaster muscle isolated on neurovascular pedicle. Direct in vivo microscopic observations revealed destructive changes of microvessels progressing from periphery to the base of the flap along with increasing in time ischemia. Since there was absolutely no return of circulation after 6 hours of ischemia this period was recognized as critical ischemia for survival of the free muscular flap.


[Observation of microcirculation in the free muscular flap during critical ischemic conditions. In vivo experiment].

The influence of 6 hours ischemia on the microcirculation in the rat cremaster muscle isolated on neurovascular pedicle is presented. Microscopic observations of the microcirculation revealed gradual destruction of microvessels beginning in the 4th hour of ischemia. The changes in condensation, structure and colour of the vessels were progressive in time and after 6 hours of ischemia no return of the circulation was possible. Additional 2 hours of observation revealed no reperfusion, so destructive changes after 6 hours proved to be irreversible.


[The relationship of radiologic bone structure image to mineral content and morphometric parameters of trabecular bone].

Radiographic, mineralogic and histomorphometric investigations of the distal radial metaphyses were performed in a group of 57 men who sustained sudden death. The radiographic image of bone structure was assessed by nude eye and with computerized analyses of the microdensitometric curves. Mineral in bone specimens content was estimated by Dulce method. Trabecular mineralized bone area (Vmin), osteoid area (Vos) and trabecular width (dt) were measured on undecalcified sections. Decrease of bone mineral content and Vmin were noted with the age of those investigated. This process affected the radiographic image of bone structure. The radiographic picture of bone structure depends mostly on the mineral content and to a smaller extent on histomorphometric parameters. Microdensitometric measurements make objective assessment of bone structure on the radiograph possible.


[Mineralization phenomena in the area of long bone fracture wound healing].

Mineralization changes in the area of fracture healing in experimental rabbits were monitored during 28 days of observation. The changes were evaluated with the aid of microscopy in the polarized light, scanning microscopy, infrared spectroscopy and roentgenographic microanalysis in 7, 14, 21, and 28th day of healing process. Mineralization was found to be parallel to the increase of collagen quantity. In the course of healing an arrangement of atom structure of the phoshate takes place. Increasing mineralization is indicated not only by growing values of Ca and P in newly formed bone but also by Ca/P ratio approaching normal values in the final stage of healing. Despite of clinical and radiological features of bony union the process of mineralization is not yet completed. By the 28th day of healing the mineral structure of bone is still remarkably porous resembling cancellous bone. Cortical bone formation occurs on the basis of cancellous bone by organization of the osseous trabeculae.


[Index of the diaphyseal cortex and mechanical strength of the femur in experimental studies].

The mechanical strength at bending was examined in 26 femoral bones prepared from human corpses. The obtained data was compared with the cortical index (CI). The study demonstrates high correlation between CI and mechanical strength of the corpus as well as the collum of the examined bone, which means that CI is a good criterion in assessing biological age of the bone. Our study confirms previously made observations that revealed a considerable usefulness of CI determined in X-rays, for the estimation of osteoporosis advancement in long bones and their mechanical strength.


[Developmental anomalies of the cranio-cervical region].

The paper presents in compact form some anomalies of craniovertebral region; 77 cases of minor and 30 cases of major anomalies were reported. The aim of this paper is to indicate morphological heterogeneity of these anomalies and necessity of differentiation in cases of cranio-cervical injuries.


[Usefulness of reduction and fusion in the management of spondylolisthesis].

The results of treatment of spondylolisthesis in 72 patients by reduction with the use of Harrington rods and circumferential fusion were reported. In dysplastic spondylolisthesis 75% satisfactory results and 83.4% spinal fusions were achieved, in stenotic spondylolistheses 80% and 85% respectively. The influence of operation on sacral bone position against lumbar spine could not be accurately traced with the aid of Wiltse radiological criteria. The authors consider arthrodesis "in situ" as insufficient procedure, especially in dysplastic type of spondylolisthesis. They recommend addition of anterior fusion that retains and stabilizes reduction being limited to single motoric unit of the spine.


[Epidemiologic analysis of spinal injuries resulting from high falls].

A series of 1365 patients treated between 1965 and 1987 because of spine injury resulting from the fall from the height was analysed. A fall from the height may cause hyperflexion, axial loading or hyperextension type of injury. Hyperflexion injury occurs usually after fall from horsedrawn wagon, scaffold, roof or pillar. Axial loading injuries dominate in falls from the ladder, tree, suicidal jumps and falls from lower height. There is remarkable correlation among the height of the fall, degree of nervous system injury and results of management.


[Open injuries of the spinal cord].

A series of 26 patients with stab, gun shot or other injury was presented. Good prognosis in partial spinal cord injury due to the stab wound was pointed out. Gun shot wounds usually resulted in total paresis even with little damage to the bony structures.


[Gunshot wound of the lumbar spine].

A case of 20 years old patient with the gunshot injury of the spine was presented. The bullet has stuck in the spinal canal at L3-L4 level causing no neurological disturbances. It was removed in our department gunshot wounds to do this in district hospital. No complication occurred in the postoperative course.


[Stabilization of the fractured odontoid process with a compression screw].

The surgical technique for fractured dens stabilization with the use of compression screws was discussed. This method suggested by Böhler, in certain modification due to the equipment shortage, was applied in 8 patients operated shortly after injury has occurred. Relatively simple operative technique, good results, possibility to avoid head movements restrictions usually associated with posterior approach procedures makes this method valuable in certain cases especially in centers experienced in anterior approach spine surgery.


[Avascular necrosis of the hip in radiologic images during treatment using the Freyka pillow for congenital hip dislocation].

Radiological picture of 823 hips in 636 children treated with the use of Freyka pillow between 1972 and 1976 was assessed. Avascular necrosis of the proximal end of the femur was found in 113 cases. The older the child was at the beginning of treatment the highest were the chances for developing avascular necrosis, but more serious changes were found in younger children. In the hips with greater initial dislocation changes were more frequent. A comparison between hips treated with Freyka pillow and those treated with different methods as to frequency of avascular necrosis was difficult due to the lack of uniformity in criteria for both diagnosis and assessment of the results.


[Late assessment of the hip joint treated with the Freyka pillow without complications for congenital dysplasia and dislocation].

Clinical and radiological assessment of 504 hips in 389 patients of 10 to 21 years of age (13 years 10 month on average) has been carried out. The patients were treated by Freyka pillow in the childhood. Those with no reduction achieved primarily and operated on because of residual dysplasia as well as patients with severe avascular necrosis were excluded from this study. In 99% of the hips no clinical abnormality was found except for the change of rotation range--decreased external rotation. Radiographic assessment revealed 60% excellent results and 35% good ones with dominant residual feature of increased anteversion of the femoral neck. Remaining 5% were rated as fair--these were the cases that should have been operated on at a suitable time.


[Transient synovitis of the hip joint in children].

Etiology, pathology, clinical and radiological symptoms, and course of transient synovitis of the hip was discussed on the basis of authors observation of 144 children as well as on literature. It was found that unloading the joint by staying in bed with slightly flexed hip led to subsidence of pain and return of full range of movement in 10 to 21 days. Only in older children the symptoms may persist 4 to 5 weeks. Permanent consequences of transient synovitis of the hip as elongation of the extremity and coxa magna in X-ray pictures are rarely observed. Transient synovitis of the hip seems not to have etiological links with Perthes disease.


[Nonspecific arthritis of the hip in children].

Clinical and radiological picture as well as pathological classification of non specific hip arthritis in children were presented after reviewing 100 cases and on the base of literature. Different course and sequel of different pathological types of hip arthritis were pointed out with emphasis on suppurative arthritis of the hip. The management of all types of hip arthritis was discussed. The necessity of surgical drainage of the joint in the first 5-7 days of suppurative arthritis as the only measure to prevent irreversible hip destruction was underlined. The method should become popular among pediatric surgeons and pediatricians who are the first ones to take care of a child in the early stage of disease.


[Consideration of the legitimacy for connecting the opposite femoral head and neck in juvenile slipped capital femoral epiphysis].

Forty seven patients were treated because of slipping of the capital femoral epiphysis, in 23 patients (48.9%) both hips were involved. In one third of these cases both hips were diagnosed at the same time, in one third second hip was diagnosed from 6 to 24 months later, in one third only late diagnosis of juvenile symptom free--thus the late diagnosis. In 18 hips slipping was less than 30 degrees, in 5 hips more than 30 degrees. On the basis of authors own experience and review of literature the conclusion was made to fix with K--wires epiphysis of the opposite hip as a prophylaxis against slipping.


[Long term results of total hip arthroplasty in patients with ankylosing spondylitis].

The results of total hip arthroplasty with the use of 5 different types of prostheses in 63 hips of 38 patients were presented. The range of follow up was from 7 to 14 years. The evaluation was done with the aid of M. d'Aubigné--Postel criteria and radiological assessment. Patients opinion and his ability to work was taken into consideration. The pain was reduced most significantly. Remarkable improvement was found in the gait and in the range of hip motion. In 24.5% of patients possible, probable or evident radiographic loosening was found. Ectopic ossifications of different degree were found in 38.8% of patients, mostly in hips previously operated on or severely destroyed. Ankylosing hips improved in movement to lesser extent. No deep infection was observed in early or late follow up.


[Should trochanteric osteotomy be performed during total hip replacement?].

Advantages and disadvantages of trochanteric osteotomy were discussed. 716 total hip arthroplasties were performed in 594 patients. Trochanteric osteotomy was done in 79 hips (11%) of 68 patients: 39 cases of rheumatoid arthritis, 17 cases of ankylosing spondylitis, 9 cases of osteoarthritis and 3 cases of various conditions. In 73 hips the trochanter was reattached by Charnley, Coventry or Amstutz method; in remaining cases an original method was used. 42 hips in 36 patients were followed up. The results were evaluated on the basis of clinical, radiographic assessment and opinion of the patient. Trochanteric non-union was found in 3 hips (7.1%), delayed union in 2 cases (4.7%), the wire loop was broken in 6 hips (14.2%) with no disturbance of trochanteric union. The authors recommend Trochanteric osteotomy only in cases of difficult access to the joint or in order to prevent soft tissue damage in instances of difficult anatomic conditions.


[Evaluation of the hip joint after Kee-Farrar total hip arthroplasty from the aspect of certain clinical biomechanical criteria].

Hundred hips in 84 arthritic patients after Mc Kee-Farrar total hip arthroplasty were reviewed. Biomechanical measurements in operated, arthritic non-operated and normal hips were compared. The moment of adductive forces, adductive forces, the strength of abductors, Hamacher-Roesler index and Woźny coefficient were determined. In nonoperated arthritic hips these measurements were abnormal. They were close to normal values in operated hips with negative Trendelenburg sign.