Atrioventricular Node Ablation for Optimization of Pacemaker Treatment in Hypertrophic Obstructive Cardiomyopathy

Dual chamber pacing is a new indication for the treatment of drug resistant hypertrophic obstructive cardiontyopathy (HOCM) in patients with normal atrioventricular (AV) conduction. In sinus rhythm, the efficacy of the treatment is mainly related to the ability to bypass the normal AV conduction system in order to obtain a complete and permanent right ventricular (RV) capture. This is achieved by programming short AV delays. On the other hand, patients with HOCM frequently have co-existing left ventricular diastolic dysfunction, and the atrial contribution to left ventricular filling is critical. The lack of improvement, rarely encountered, is probably due to incomplete RV capture andlor to the deleterious effect of short AV delay. Instrumental AV node prolongation may he indicated in this situation. This procedure should be undertaken when previous drug-induced AV prolongation has failed. In theory, AV node modulation (i.e., creating a I ± AV block) seems ideal. However, this technique remains difficult, with disappointing chronic results. Most authors hence perform "conventional" AV node ablation. Particular attention is taken in order to perform a proximal node ablation, resulting in a complete AV block with narrow QRS escape rhythm. The reported incidence of AV node prolongation ranges from 7.5%-37.5%. The efficacy of the procedure on symptoms is explained by improved left ventricular filling and/or a further reduction in the systolic gradient evoked by complete RV capture. Another indication for AV node ablation in HOCM is the occurrence of atrial fibrillation, in order to restore adequate and permanent RV capture .     

Trypsin-mediated semisynthesis of salmon calcitonin

Salmon calcitonin, CT(1-32)·NH₂, was synthesised by the trypsin-mediated coupling of the peptide fragments CT(1-24) and CT(25-32)·NH₂, prepared by conventional Fmoc solid-phase chemistry. Optimal conditions regarding reaction time course, pH, proportion of catalyst, substrate concentration and composition of the reaction medium were determined from initial studies on the coupling of CT(1-11) to CT(12-24) and of CT(12-24) to CT(25-32)·NH₂. For the final successful semisynthesis, we found that it was unnecessary to protect lysine residues not involved in the coupling, and that secondary hydrolysis at these sites could be prevented by increasing the pH of the reaction medium. The reaction achieved equilibrium after 30-45 min, with overall conversion of around 30% of the initial amount of CT(1-24) substrate into product. Yields were depressed due to cyclisation of the CT(1-24) substrate via air-oxidation of the Cys¹ and Cys⁷ residues.     

Effect of oral and inhaled cetirizine in allergen induced bronchoconstriction

Cetirizine is a potent, selective H₁ histamine receptor antagonist. The effect of oral and inhaled eetirizine was assessed on the early bronchoconstrictor response to inhaled allergen in 10 mild atopie asthmatic patients in a double-blind, randomized, plaeebo controlled trial. All were sensitive to Dermatophagoides pleronyssinus and this was used as the provoking allergen. The geometric mean PD20 FEV] values obtained at allergen challenge were measured as cumulative breath units (c.b.u.) and following oral cetirizine, inhaled cetirizine and placebo were 124–5, 75–7 and 76–7 c.b.u. respectively. These did not differ significantly. We conclude that neither oral nor inhaled cetirizine significantly attenuates the early response to inhaled allergen in atopie asthmatic subjects. However, the method of repeated allergen challenge is likely to be relatively insensitive. Clinical and Experimental Allergy, [o]. 23, pp. 528–531.     

The influence of anaesthetic techniques and type of delivery on peripartum serum interleukin-6 concentrations

Background: Interleukin-6 is a pleiotropic cytokine with a wide range of physiological activities. It plays an important role in the immuno-neuro-humoral axis during stress and surgery.
Methods: Serum interleukin-6 in parturients was measured on hospital admission, immediately after birth and 12 and 24 hours later. All parturients had uncomplicated pregnancies, and delivered vaginally without (n=31) or with (n=20) epidural analgesia, or underwent Caesarean section under epidural (n=20) or general (n=10) anaesthesia.
Results: Serum interleukin-6 assayed immediately following Caesarean section was low, but peaked 12 hours later, irrespective of the anaesthetic technique or other foetomaternal characteristics. Patients who delivered vaginally showed the highest interleukin-6 levels immediately after delivery. These were positively correlated with serum interleukin-6 on admission and duration of labour. Serum interleukin-6 was significantly higher in parturients who had epidural analgesia, and was significantly lower in those receiving intravaginal prostaglandins compared to those without prostaglandins.
Conclusion: The interleukin-6 response after Caesarean section can be explained by a generalized acute phase response to surgery, with no anaesthetic, maternal or neonatal interference. The rapid increase in peripartum serum interleukin-6 levels after vaginal delivery reflects, in part, cervical ripening or labour, their physiological triggers and psychological or physical stress. Regional anaesthesia, duration of labour and exogenous prostaglandin administration can modulate the peripartum interleukin-6 response and subsequently the physiological effects of this cytokine.     

Is Electric Arc Welding Linked to Manganism or Parkinson’s Disease?

Manganese and its inorganic compounds are widely used in many industries and have been accepted as occupational neurotoxins that have caused a distinct and disabling clinical entity, manganism, in several types of work, notably where exposure is by way of dust. There is inconclusive and inconsistent evidence that, in these occupations, subclinical neurological effects, detectable only by neurobehavioural studies, may be caused by low doses. This has prompted a re-evaluation of occupational exposure limits. Some countries, including the UK, already demand much higher levels of protection against exposure than 5 years ago. Welding is the most common source of occupational exposure as manganese is an essential component of steel and so its compounds are inevitable components of fume emitted from steel welding processes. There it is found in respirable particles, often as complex oxides (spinels), sometimes within a core protected by a silicon oxide shell — as distinct from the much simpler form of particle formed by disintegration in processes such as mining and ore milling where manganism has been diagnosed convincingly. Millions of workers are at risk of exposure to manganese-containing compounds in fumes from electric arc welding of steel. In recent years it has been asserted that neurological and neurobehavioural disorders may develop consequent to exposure to steel welding fumes and that employment as a welder is associated with the unusually early onset of Parkinson’s disease. Causal relationships have been postulated. Welders have been recorded as having been exposed to high levels of manganese-containing fume, especially where they have worked in confined, unventilated spaces, although this appears from limited data to be the exception rather than the rule. Even then the dose received is generally less than in mining or ore crushing. When care is taken to exclude exposures from hardfacing and burning and cutting arc processes, where manganese may form a high percentage of the fume, manganese compounds usually form a relatively low percentage of the composition of welding fume particles, <2.0%, much outweighed by iron. Although these manganese-compound-containing welding fume particles are insoluble in water, the manganese compounds in particles that are retained in the alveoli may be absorbed, at least in part. Manganese concentrations in biological material samples in some exposed groups reflect this relative to unexposed workers. Some of the transfer systems for absorption and transport, including across the blood-brain barrier, are used in competition with iron which is present in abundance in welding fume. This may reduce absorption of manganese in welders and thus reduce the opportunity for sufficient doses to cause neurotoxicological consequences. Scrutiny of the literature covering the last 40 years has revealed only five cases that meet sufficient criteria for manganism to just cross the diagnostic threshold, and even then they carry a degree of doubt with them. This low incidence alone gives notice that welders have not been and are not at high risk of clinically apparent damage from exposure to manganese. If this needs to be further emphasised, there is the fact that the literature contains no confirmed cases of manganism in welders. Assertions of abnormal results in neurobehavioural studies of welders have raised the possibility of there being a subclinical form of manganism with loss of fine motor control as one of its features. While observations of such changes in workers in other industries have caused regulators in some countries to apply more stringent controls of exposure, as yet the results lack convincing consistency and there is no indication of any dose-effect relationship. If welding fume can have these motor effects it would be a heavy and perhaps career-ending blow to those affected. It would not be prudent to dismiss the warnings sounded by the results of studies of welders, no matter how flawed these investigations are, but wiser and better to act with vigour to reduce exposure and monitor the effectiveness of this additional protection whilst conducting high quality research to allow sound conclusions to be drawn as to whether there actually is a subclinical disorder. Idiopathic Parkinson’s disease is a common disorder affecting 1–2% of those in the general population aged >65 years. It has been suggested, on flawed and contested evidence, not that welding causes the disease but rather that employment as a welder carries with it the risk of developing this disease at a younger age than if that trade had not been followed. Manganese in welding fume has been nominated as the neurotoxin. This may be biologically feasible if manganese destroys insufficient receptor cells to produce clinical manganism but sufficient to enhance the effects of a reduced supply of dopamine to give the manifestations of already developing idiopathic Parkinson’s disease earlier in the course of destruction of the substantia nigra than if all receptors were intact.     

Hereditary spherocytosis. Recent experience and current concepts of pathophysiology.

Hereditary spherocytosis is a clinically heterogeneous, genetically determined red blood cell membrane disorder resulting in hemolytic anemia. A deficiency of spectrin, the largest and most abundant structural protein of the erythrocyte membrane skeleton, results in the formation of spherocytes which lack the strength, durability, and flexibility to withstand the stresses of the circulation. Clinical manifestations of the disease are primarily dependent on the severity of hemolysis, which additionally results in an increased incidence of pigment gallstones. The likelihood of cholelithiasis is directly related to patient age and is uncommon before 10 years of age. Splenectomy is indicated in virtually every patient. When the disease is diagnosed in early childhood, the risk of overwhelming postsplenectomy sepsis makes it advisable to delay splenectomy until after 6 years of age if possible. At the time of splenectomy, it is important to identify and remove any accessory spleens. If gallstones are present, cholecystectomy should be performed. Although spherocytosis persists following splenectomy, hemolysis is alleviated and clinical cure of the anemia is achieved for most patients. Patients with recessively inherited spherocytosis are exceptions. Although they are significantly benefited by splenectomy, their anemia is not completely corrected. Splenectomy reduces hemolysis in all patients and thereby decreases the risk for development of pigment gallstones. Excision of an enlarged spleen removes the danger of traumatic rupture.     

A new fluorescent mitochondrial antibody: Disease association

The case notes of 34 patients whose sera contained an antibody giving an unusual immunofluorescent staining pattern were reviewed. This antibody designated M2(1) gave a slightly different pattern of staining on composite sections of rat liver, kidney and stomach from the primary biliary cirrhosis associated M2 antimitochondrial antibody. Anaemia was present in 10 patients, endocrine disease in 7 patients and autoimmune liver disease in 6 patients. We did not find the presence of M2(l) antibody to be of specific diagnostic significance. Although the M2(l) antibody is rare, caution is required in order to avoid confusion between this antibody and the M2 antimitochondrial antibody of primary biliary cirrhosis.     

Studies on the relationship between transaldolase activity and testosterone synthesis in Leydig cells of pubertalmice

Objective: To study the relationship between transaldolase activity, protein expression and testosterone synthesis in Leydig cells of pubertal mice. Methods: Leydig cells were cultured for 2 hours and 8 hours, to the Stimulation Group, hCG was added and to the Controls, only the vehicle. The testosterone concentration was then determined by enzyme-linked immunoadsordent assay (ELISA) and the transaldolase activity and protein expression by Western blot. Results: (1) Both the testosterone concentration and the transaldolase activity in both Stimulation Groups were significantly higher than those in the corresponding Controls (2 h: p<0.05-0.01; 8 h: P<0.001); (2) The ratios of the A isoform, the B isoform and the total transaldolase protein to β-actin between the Stimulation and Control Groups did not differ signifi-cantly. Conclusion: hCG stimulates the transaldolase activity as well as the testosterone synthesis in the Leydig cells of pubertal mice, indicating a positive relationship between them.     

Scintigraphic visualization of intrathecal liposome biodistribution

Background: Liposomes containing local anaesthetics have been administered intrathecally and in the epidural space. Poor attention has been given to the pharmacokinetics of liposomes as drug carriers. Therefore, we observed the biodistribution of liposomes after intrathecal injection in rats by scintigraphic imaging during 24 h.
Methods: We administered ⁹⁹Tc-labeled multilamellar (MLV) and small unilamellar vesicles (SUV) of defined size and volume dispersities into the cerebrospinal fluid at the lumbar level. Those vesicles were free of contamination by radiolabeled colloids as visualized by light and electron microscopy and of neurotoxic products from phosphatidylcholine hydrolysis and peroxidation, both during the preparation process and after 24 h incubation in cerebrospinal fluid at 37°C in vitro.
Results: SUV immediately diffused from the lumbar site of injection to the head and were cleared between 1 and 24 h after injection. MLV were cleared more slowly from the spinal space and appeared in the head region 1 h after injection where they accumulated up to 24 h. These differences were explained in terms of vesicle sizes and volumes. SUV with 0.05 μm diameters were rapidly absorbed into the blood through the arachnoid granulations. In contrast, particles larger than the upper size limit of the arachnoid granulations permeability (±8 μm) could accumulate in the head with a slow elimination rate.
Conclusion: This difference in clearance from the intrathecal space outlines the importance of defining the size of the liposomes, the distribution of a tracer or a drug inside the liposomal preparation, the chemical stability and the absence of toxic degradation products of liposome formulations before clinical use.