Human pharmacokinetics of molsidomine

Molsidomine is well absorbed by the gastro-intestinal tract and is taken up by the liver during the first passage. Its bioavailability is 60 per cent. Digestive or sublingual absorption is rapid: maximal plasma concentrations are obtained 0.5 to 1.0 hours after administration. Molsidomine is minimally bound by plasma proteins and is distributed in a volume of 1 litre/kg. The excretion is essentially extrarenal: less than 2 per cent of the administered dose is excreted in the form of unchanged molsidomine. Molsidomine is metabolized in the liver to two pharmacologically active metabolites which spontaneously and rapidly breakdown into inactive metabolites which are excreted by the kidneys. The plasma half-life of molsidomine is 1 to 2 hours: it is not modified in patients with renal failure, but it is prolonged in patients with hepatic failure. The kinetics are linear and independent of the route of administration and the dose. There is a correlation between the plasma concentration and the pharmacological effect: the minimal effective concentration is about 5 ng/ml. At the usual dose of 2 mg three times a day, there is no accumulation of the drug.     

Improvement of the method of collection of blood flowing from the adrenal glands in the experiment on dogs

Blood from the adrenal gland can flow in two directions--into the caudal vena cava and by anastomoses into the portal vein. A method of multiple blood procuring from these vessels in dogs for the purpose of studying the adrenal gland function is suggested. Polyethylene catheters, 0.9 mm in diameter and 35--40 mm in length glued to capron plates, mandrins, Gordeev's needles and blood-drawing needles are necessary. Transperitoneal surgical approach to the caudal and mesenteric veins is to be provided. Purse-string suture is applied on the wall of the mesenteric vein. The catheter is washed with heparin, the mandrin is introduced into it and it is inserted into the Gordeev's needle. A puncture is made in the centre of the purse-string suture with this needle, which is introduced into the vein together with the catheter. Gordeev's needle is withdrawn and the catheter is pushed through to the portal vein. The purse-string suture is tightened, and the capron plate is fixed in the wall of the vein. The mandrin is recovered from the catheter, heparin is administered into its canal, polyethylene plug is inserted and withdrawn through the abdominal wall outside with the aid of the blood-drawing needle. The catheter is introduced into the caudal vena cava in the same way. Blood samples can be obtained on the 14th postoperative day.     

Intermittent chemotherapy of experimental leprosy in mice

In this study we assess the degree of prolonged bacteriostasis of Mycobacterium leprae after temporary exposure to ehtionamide or thiacetazone, and relate this to their efficacy when administered intermittently to mice with experimental leprosy infections. The results show that temporary exposure of M. leprae to either of these drugs results in a prolonged bacteriostatic effect, but that efficacy is rapidly lost as the interval between doses is increased. Using the mouse foot pad system, growth of M. leprae is not inhibited by thiacetazone when the frequency of administration is less than three times weekly. When ethionamide is administered once weekly, growth of M. leprae is inhibited but bactericidal activity is lost. When ethionamide is administered in combination with continuous dapsone therapy, either continuously or three times weekly, the bactericidal activity of the drug combination is greater than when either drug is administered alone. However, when ethionamide is administered once weekly in combination with continuous dapsone treatment, the bactericidal effect is identical to that when dapsone is given alone: that is, ethionamide makes no contribution to the combination.     

Effect of overall phenotypic selection on genetic change at individual loci.

The selective advantage of an allele Gi (relative to the mean of alleles at this locus) is given by (formula: see text) in which Ai is the average excess of the allele on the character, X; W(X) is the fitness function; F(X) is the frequency function; W is the mean fitness; and the prime denotes differentiation. With truncation selection si = AaF(C)/w in which F(C) is the ordinate at the culling level and w is the proportion saved; this does not depend on any assumption about the distribution of F(X). If the character is normally distributed, si = AiI/sigma2, in which I is the selection differential and sigma2 is the variance of the character distribution. Finally, if the logarithm of the fitness is proportional to the squared deviation from the optimum and the character is distributed normally, si = AiK(Xop--m), in which Xop is the optimum value of the character, m is the mean value, and K is a constant determined by the variances of the fitness function and the frequency function. Truncation is the most efficient form of directional selection in the sense of producing the maximum gene frequency change for a given effect of the gene on the character, but fitness functions can depart considerably from sharp truncation without greatly reducing the efficiency.     

MRI diagnosis of cavernous sinus invasion by pituitary adenomas

Several MRI signs are helpful for the preoperative MRI diagnosis of cavernous sinus invasion by an adenoma. The first step is to analyse the percentage of encasement of the intracavernous ICA by the adenoma. If this percentage is greater than or equal to 66%, the cavernous sinus is invaded. If the percentage of encasement of intracavernous CA is less than 25%, the cavernous sinus is not invaded. If the percentage of encasement is between 25 and 66%, the analysis of the cavernous venous compartment, the drawing of intercarotid lines and the analysis of the shape and venous compartments of the cavernous sinus are necessary. The cavernous sinus invasion remains very likely if the carotid sulcus venous compartment is obliterated, or if the lateral intercarotid line is crossed. Conversely, if the median intercarotid line is uncrossed, the superior venous compartment is visible, the cavernous sinus is of normal size, or there is no bulging of its lateral dural wall, invasion of the cavernous sinus space can reliably be excluded.     

Hemoglobin Volga, β27 (B9) Ala→Asp: Functional and Clinical Correlations of an Unstable Hemoglobin

Hb Volga (β27 Ala→Asp) on the basis of physical tests is only a mildly unstable hemoglobin yet it is associated with a gross re-ticulocytosis. This is partly explicable by an increased oxygen affinity with a compensating erythrocytosis but there is also brisk hemolysis. It is not certain that this hemolysis is due to precipitation of the hemoglobin as in vitro inclusion body formation is not remarkable and there is no evidence of preferential proteolysis of the abnormal subunits, at least in the reticulocytes. There is increased autoxidation and it may be the consequence of this that is the prime cause of hemolysis.     

Demonstration of a new analytical grading system for the determination of pheochromocytoma within the scope of hypertension control

The problems of the phaeochromocytoma are in its rareness, its appearance--every patient with hypertension can be a carrier of a phaeochromocytoma--, its localisation--10% are situated outside the adrenal glands--, its operability with following permanent normalisation of the pressure. As hypertension is very frequent and the diagnostics is very expensive the finding of carriers of phaeochromocytomas is possible only by means of screening methods. Thus cases with an urgent suspicion are found. Such a method is described, the basis of which is a semiquantitative determination of the vanillic amygdalic acid. Instead of the usually used diazocolour-reagent in connection with a non-optimal buffer a complete nitrophenylantiazotate with a buffer of high ionic strength is taken. The pH-value 10 of the urine which is to be demanded for the colour reaction is thus reached in every case. In order to avoid falsely normal results with every urinary test a preparation with added vanillic amygdalic acid is performed and thus the presence of colour inhibitors is recognized. If the result is pathological a quantitative determination is necessary.     

Limited venous access and pacemaker insertion in a haemodialysis patient: case report

The population of haemodialysis patients is increasing as is their age. There is a higher risk of cardiac comorbidities in these patients. Pacing is increasingly common in this group. We present a case highlighting the difficult issues and exemplifies the need for careful planning preprocedure. Haemodialysis patients often have difficult and limited vascular access. Insertion of pacing leads is associated with subclavian vein stenosis. If this is on the side of an AV fistula there is significant risk of losing the fistula with obvious consequences to the patient. Careful consideration of site and route of access needs to be made prior to pacing. The need for involvement of renal and vascular teams before starting the procedure is essential as it is paramount that the best route of access for pacing wires is selected.     

The influence of the flow of the reacting gas on the conditions for a thermal explosion

The classical problem of thermal explosion is modified so that the chemically active gas is not at rest but is flowing in a long cylindrical pipe. Up to a certain section the heat-conducting walls of the pipe are held at low temperature so that the reaction rate is small and there is no heat release; at that section the ambient temperature is increased and an exothermic reaction begins. The question is whether a slow reaction regime will be established or a thermal explosion will occur. The mathematical formulation of the problem is presented. It is shown that when the pipe radius is larger than a critical value, the solution of the new problem exists only up to a certain distance along the axis. The critical radius is determined by conditions in a problem with a uniform axial temperature. The loss of existence is interpreted as a thermal explosion; the critical distance is the safe reactor's length. Both laminar and developed turbulent flow regimes are considered. In a computational experiment the loss of the existence appears as a divergence of a numerical procedure; numerical calculations reveal asymptotic scaling laws with simple powers for the critical distance.     

THE NEGATIVE CONTROL MECHANISM FOR E. coli DNA REPLICATION

Evidence is presented to show that the initiation of DNA replication in E. coli 555-7 requires synthesis of a protein whose production is correlated with total protein synthesis. Once replication is initiated, however, reinitiation will occur if all further protein synthesis is prevented; a small amount of protein synthesis is sufficient to prevent this unregulated reinitiation. This shows that the initiation of DNA replication is under negative control. A mechanism for the control of DNA replication is proposed; in this mechanism a replication repressor is synthesized periodically, while an antirepressor protein is synthesized continuously. Derepression of initiation results after sufficient accumulation of the antirepressor protein, and repression is re-established by repressor synthesis after the initiation of replication.     

Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]

How exocrine pancreatic secretion is regulated is only partly known. It is assumed that interaction of several neural and hormonal mechanisms is involved. In man, the intestinal component of these control mechanisms is very important while extra-intestinal mechanisms (such as the cephalic and the gastric phase) play lesser roles. Regulation of pancreatic secretion by the intestine is composed of three main mechanisms. 1. The proximal intestinal (duodenal) phase of the secretory response to a meal is elicited by nutrients within the proximal intestinal lumen. It is mediated mainly by interactions between cholinergic reflexes and release of the peptide hormone cholecystokinin (CCK). Recent data suggest that part of the action of CCK is not exerted directly on the acinar cellular level, but rather by modulation of cholinergic inputs. 2. The distal intestinal (ileal) phase is elicited by contact of the distal intestinal mucosa with nutrients that pass through the ileal lumen due to physiological malabsorption. The ileum (in contrast to the duodenum) induces net-inhibition of pancreatic secretion. The mediation is unknown, candidate mediators are PYY and GLP-1. 3. Intestinal feedback-regulation of pancreatic secretion in humans is controlled by intraluminal protease activity; this mechanism is not covered in the present paper.     

Benign ulceration of the gecum presenting with massive hemorrhage

Massive gastrointestinal hemorrhage secondary to benign cecal ulceration is a rare occurrence. The diagnosis of bleeding from this benign condition is rerely entertained and is often a finding on a pathologic examination. A case of massive hemorrhage from a cecal ulcer is presented, and the literature is reviewed. The role of angiographic demonstration of the lesion, if angiography is readily available, is emphasized, but surgery is the definitive therapy.     

The Decay of Genetic Variability in Geographically Structured Populations

The geographical structure of a population distributed continuously and homogeneously along an infinite linear habitat is explored. The analysis is restricted to a single locus in the absence of selection, and every mutant is assumed to be new to the population. An explicit formula is derived for the probability that two homologous genes separated by a given distance at any time t are the same allele. The ultimate rate of approach to equilibrium is shown to be t(-3/2)e(-2ut), where u is the mutation rate. An approximation is given for the stationary probability of allelism in an infinite two-dimensional population, which, unlike previous expressions, is finite everywhere. For a finite habitat of arbitrary shape and any number of dimensions, it is proved that if the population density is very high, then asymptotically the transient part of the probability of allelism is spatially uniform and decays at the rate e(-[2u+1/(2N)]t), where N is the total population size. Thus, in this respect the population behaves as if it were panmictic. The dependence of the amount of local gene frequency differentiation on population density and habitat size and dimensionality is discussed.     

Leiomyosarcoma of the inferior vena cava

A case of leiomyosarcoma of the inferior vena cava in a 74 year old woman is reported. The clinical and pathological features are described and the outcome and response to treatment analysed. This is a very rare form of malignant disease (less than 100 published cases) which mainly affects elderly women. The diagnosis is often made at a late stage because the symptomatology is not specific and because the tumour is so rare. Treatment is mainly surgical and is only possible in the infrarenal part of the inferior vena cava. It is very difficult or impossible to operate on the upper part of the vessel. The prognostic is poor. There are no reports of survival after 5 years.     

Retroperitoneal cystic lymphangioma]

The lymphangioma is a rare disease, more frequently reported in children and just occasionally in the adult patient. The lymphangioma is considered a benign neoplasm of embryonic origin of the lymphatic vessels. Its habitual location is in the cervical and axillary area; it is rarely found in the abdominal cavity and exceptionally in the retroperitonio. In this latter location, the lesion habitually is asymptomatic. The clinical diagnosis of the retroperitoneal cystic lymphangioma is not often due to its rarity and the absence of clinical expression. The size of the lesion is more important than its location to the symptomatology development. The findings of the abdominal ultrasonography and computerized tomography of the abdomen usually show a cystic lesion and its location. The treatment is surgical and it consists of the resection of the cyst or group of cysts once the liquid accumulation in its interior may be responsible for the development of some important complications of this disease. The cure is obtained when the lesion is completely resected also with the resection of eventual adhesive structures. The relapse may take place when the resection is incomplete. A case of retroperitoneal lymphangioma in a female adult patient as incidental finding of abdominal ultra-sonography is described. It is discussed the clinical picture, the radiologic diagnosis, the treatment and the prognostic of this unusual disease.     

Pathogenicity of entamoeba histolytica

The pathogenicity of Entamoeba histolytica is discussed from an immunologic point of view. The evidence that there is some "trigger" mechanism which converts a commensal dwelling organism into a tissue invasive pathogen is rejected as inadequate. The number of liver abscess cases in comparison with the number of intestinal amebic infections in a population is so low that this in itself suggests that tissue invasion is a rare event in the life history of the ameba. A review is made of the experimental evidence that some type of sensitization is necessary before ameba can invade tissue. In postulating an immunologic basis for the pathogenicity of ameba, a parallel between the behavior of malignant cells in the body and an amebic infection in the gut is made. An appealing hypothesis which deserves further research effort is that an altered immune response is the basis for the pathogenic mechanism in the host.     

Antithrombotics in pre-hospital phase of acute coronary syndromes

Antithrombotic therapies are the corner stone of acute coronary syndrome management. We have the proof that many of them should be initiated during the prehospital care because their clinical benefit is time-dependent. The hypothesis that anticoagulation therapy is an effective treatment of STEMI, which benefit is time-dependent, is now validated. It is also fair to affirm that GP lIb/IIIa receptor inhibitors are the adjuvant therapy of choice for primary PCI. Indeed, these medications reduce short-term and long-term mortality. This clinical benefit is time dependent. Clopidogrel therapy is probably also a medication of the prehospital phase. It is well established now that the biological efficacy of this pro drug is loading dose dependent. It is also demonstrated that its clinical efficacy depends on the time delay between symptom onset and initiation of the therapy. However, the clinical benefit of prehospital administration remains to be established.     

Treatment of intracoronary thrombus in the catheterisation laboratory in acute coronary syndrome patients

Treatment of intracoronary thrombus is well documented. Three situations should be differentiated Primary percutaneous coronary intervention for early STEMI presenters is the most frequent one. Glycoprotein IIb/IIIa inhibitors are the gold standard antithrombotic treatment with a clear mortality benefit with abciximab. Thrombectomy with simple to use devices is another attractive option for interventionalists, although there is no clear established clinical benefit. Rescue PCI following failed thrombolysis is a more complicated situation given the underlying bleeding risk that is difficult to evaluate. The second situation is when a thrombus appears during an elective PCI. Although much less frequent than primary PCI, it is more often related to a lack of identification of the risk, to an inappropriate choice of the materials or to a non-optimal upstream antithrombotic treatment. A careful identification of all potential relevant causes is the key point of the management strategy. Post-PCI rethrombosis is the third situation and probably the less frequent. However, it is the most difficult to deal with.     

Primary hypertrophic pyloric stenosis in the adult

A case is reported of a 55 year old male patient with primary hypertrophic pyloric stenosis who was subjected to distal gastrectomy. Adult hypertrophic pyloric stenosis is an uncommon condition which is usually misdiagnosed as carcinoma of the antrum. It is a benign disease resulting from hypertrophy of the circular fibres of the pyloric canal and is recognizable radiologically by narrowing and elongation of the pyloric canal and endoscopically by appearances resembling those of the cervix. This condition is probably congenital although aetiology has not been established. In the absence of symptoms, no clinical treatment is required. However, surgical intervention is advocated, when stenosis gives rise to symptoms, there is a suspicion of malignancy, or the ulceration due to the disease. Distal gastrectomy with gastroduodenostomy is the treatment of choice.     

Intradural extramedullary tuberculoma of the spinal cord: a review of reported cases

Intradural extramedullary tuberculoma of the spinal cord (IETSC) is a rare modality of tuberculosis, with only a few cases described so far. Here we review 22 reports of the disease found in the literature of the last 25 years. IETSC is closely associated with tuberculous meningitis (TM). Both conditions may occur simultaneously, but more frequently IETSC is preceded by TM. IETSC has been described in a predominantly young population of both genders. The pathogenesis is unknown, although a paradoxical reaction to antituberculous medication is a reasonable possibility. The disease presents insidiously with paraparesis, hypoesthesia with a sensory level, and bladder dysfunction, due to cord involvement or compression by the inflammatory process. Permanent paraparesis is a common sequela. MRI is the diagnostic technique of choice in IETSC. Prompt surgical excision of the tuberculoma is the cornerstone of therapy. Antituberculous treatment is also indicated; unless resistance is present, conventional chemotherapy is probably enough. Corticosteroids are also generally recommended. In conclusion, IETSC is a rare complication of TM, which presents insidiously, despite adequate antituberculous treatment. To avoid the permanent disability that this condition may provoke, an early diagnosis and prompt treatment is critical.