Immune tolerance: a synopsis of the international experience

Summary. Because of the increased morbidity and cost of care associated with inhibitor development, immune tolerance therapy (ITT) is of crucial value in the care of haemophilia. The 24-year experience with this modality, primarily in the treatment of factor VIII inhibitors, has included the use of both high and low doses of clotting factor, with and without immune modulation. Overall success rates for ITT in haemophilia A have been similar (63–83%), while median time to IT has been variable (1.2–24 months). The role of type and purity of clotting factor used remains unclear. Three immune tolerance registries have suggested the potential importance of treatment parameters such as pre-induction inhibitor titer and daily factor dose in the prediction of successful outcome. Ultimately, prospective randomized studies of ITT are required to definitively compare therapeutic regimens with respect to efficacy, safety, and cost effectiveness.     

X‐linked hereditary motor sensory neuropathy (type 1) presenting with a stroke‐like episode

X‐linked hereditary motor sensory neuropathy type 1 (CMTX 1) is caused by mutation in the GJB1 gene that codes for the connexin 32 protein. Central nervous system involvement with or without white matter changes on magnetic resonance imaging (MRI) has rarely been reported in this condition. We report the case of a 7‐year‐old, previously well male who presented with a stroke‐like episode that manifested as left hemiparesis and dysphasia. An initial brain MRI showed white matter signal changes affecting the corpus callosum and periventricular areas with a posterior predominance. Our patient made a complete clinical recovery in 36 hours. Clinical examination at this stage showed no evidence of a peripheral neuropathy. A repeat brain MRI 6 weeks later showed almost complete resolution of the changes seen initially. Subsequent investigations showed a Val177Ala mutation in the GJB1 gene. This mutation has so far not been described in the Caucasian population and has been only described once before. Electrophysiological studies showed a mixed demyelinating and axonal sensorimotor neuropathy in keeping with CMTX 1. Five months after the initial presentation our patient developed clinical evidence of a peripheral neuropathy in the form of absent ankle reflexes, weak dorsiflexors, and evertors of both feet.     

Developing Actionable Dietary Guidance Messages: Dietary Fat as a Case Study

Although consumers say they are concerned about nutrition and are aware that eating a healthful diet is important for good health, this knowledge does not always translate into healthful diet behaviors or motivate behavior change. In an effort to better understand consumer attitudes about nutrition and to explore alternatives for communicating dietary advice in language that is meaningful and motivates behavior change, the International Food Information Council (IFIC) conducted qualitative research with consumers (using focus groups) and registered dietitians (using telephone interviews) in 1998 and 1999. Results of the research are presented using dietary fat as a case study. Findings from the IFIC research were reported to the Dietary Guidelines Advisory Committee to assist the Committee in developing meaningful and action-oriented dietary advice related to dietary fat for inclusion in the 2000 Dietary Guidelines for Americans that would be motivating and easy for consumers to implement. The recommendation to moderate fat intake in the new dietary guideline, "Choose a diet that is low in saturated fat and cholesterol and moderate in total fat" is consistent with communication recommendations in the IFIC research. Further, the moderate fat message is empowering because it suggests an achievable dietary regimen and reduces guilt and worry about foods. It allows flexibility to enjoy desired foods and promotes using common sense when it comes to diet. Several issues emerged from the IFIC research that apply to general nutrition communications with consumers, whether it be through national nutrition recommendations or in one-on-one counseling situations: to be effective, messages to consumers about nutrition, and specifically dietary fat, must address sources of discomfort about dietary choices; they must engender a sense of empowerment; and they should motivate both by providing clear information that propels toward taking action and appeals to the need to make personal choices.     

Disposition and Metabolism of [14C]Dibenzo[c,g]carbazole Aerosols in Rats after Inhalation

Disposition and Metabolism of [^l4C]Dibenzo[c,g]carbazole Aerosolsin Rats after Inhalation. Bond, J. A. Ayres, P. H., Medinsky,M. A., Cheng, Y. S., Hirshfield, D., and McClellan, R. O. (1986).Fundam Appl Toxicol. 7, 76-85. Dibenzo[c.£]carbazole (DBC)is a nitrogen-containing polycyclic aromatic hydrocarbon thathas been detected in tobacco tars, industrial oils, and dieselengine exhaust fumes. DBC is carcinogenic in respiratory tracttissue of hamsters and in lungs, kidneys, and livers of mice.The purpose of this research was to determine the respiratorytract deposition, distribution in tissues, metabolism, and excretionof DBC in rats after inhalation. Rats were exposed nose-onlyto 1.1 or 13 Mg [¹⁴C]DBC/liter air for 60 min. Activity medianaerodynamic diameters for the two concentrations of DBC rangedfrom 0.7 to 0.8 pm. Unne. feces, and selected tissues were collectedfor various times after exposure. The fractional depositionfor the 1.1 and 13 ug/liter exposure concentrations was similar,13 and 16%, respectively. The dominant route of excretion of¹⁴C following exposure to either concentration of DBC was thefeces, accounting for approximately 95% of the total 14C eliminated.Half-time for fecal excretion was 20 ± 6 hr (x ±SE). Gastrointestinal absorption of [I4C]DBC was 43%. Radioactivitywas widely distributed to all tissues examined, with the respiratorytract (lung, trachea, larynx, and nasal turbinates), upper gastrointestinaltract (stomach and small intestine), the liver, and the adrenalscontaining the highest concentrations of [I4C]DBC equivalentswithin 1 hr after exposure. At both concentrations of DBC tested,clearance of I4C from tissues was rapid, with approximately60 to 98% of the initial tissue burden being cleared with half-timesranging from 1 to 16 hr. The remaining 2 to 40% in the tissueswas cleared with half-times that ranged from 1.5 to 14 days.Several metabolites were detected in the urine and feces, noneof which appeared to be either glucuronide or sulfate conjugates.Small quantities of [I4C]DBC were detected in the urine, althoughquantities were less than 1% of the initial respiratory tractburden of [I4C]DBC. The results from this research indicatethat DBC was rapidly absorbed from the lungs and translocatedto many tissues. Prior to elimination, primarily in the feces,DBC was extensively metabolized There appeared to be no effectof exposure concentration on the toxicokinetics of inhaled DBC.     

Spontaneous Occurrence of the Induced Cardioinhibitory Vasovagal Reflex

ECG recording of spontaneous, neurally-mediated syncope is rare. We have observed ten patients who sustained 70 syncopal episodes in whom: (1) ECG monitoring recorded syncope caused by ventricular asystole (AV block, three patients; sinus arrest; seven patients); (2) syncope and the spontaneously observed arrhythmias were reproducible by carotid sinus massage, upright tilt test, or eyeball pressure; and (3) no discernable cause of precipitating factors were detected. Two patients had a history of cardiac disease and four patients had only mild nonclinical ECG or echocardiographic abnormalities. Syncopal episodes recorded during Holter monitoring were of sudden onset in four patients and preceded by prodromal symptoms in six patients. The maximum RR pause was 9.4 +/- 3.7 seconds (range 4.5-15). Electrophysiological evaluation was normal in seven patients. Slight sinus node dysfunction or atrioventricular conduction abnormalities were noted in three others. The clinical characteristics of spontaneous and induced episodes strongly suggest that increased vagal tone played a role in causing the spontaneous events. Vagal stimulation tests are useful for the diagnosis of syncope of unknown origin.     

Anomalous "VVI" Pacing of a Dual Chamber Pacemaker When Programmed in DDI(R) Mode

We describe the case of a dual chamber rate responsive pacemaker (Relay, model 294-03, Intermedics, Angleton, TX, USA) implanted in a 68-year-old male for sick sinus syndrome, which was not working properly when programmed in the DDIR mode, thus determining occasionally a sort of "VVI" pacing. However, the pacemaker performed well when programmed in the DDDR mode. We discovered that this was not a malfunction of a single device but rather a general behavior of this family of Intermedics dual chamber pacemakers (also not rate responsive), caused by a software problem.     

Ventricular and Dual Chamber Pacing for Treatment of Carotid Sinus Syndrome

Thirty-nine consecutive patients with recurrent syncope and either cardioinhibitory or mixed type carotid sinus syndrome were studied to determine the efficacy of ventricular (VVI) pacing in 16, and dual chamber (DDD/DVI) in 23 patients. Only those patients affected by the isolated vasodepressor form were excluded. Follow-up lasted 12 ± 5 months. Symptoms were totally eliminated in 67% of patients and ameliorated with persistence of minor symptoms in 33%. All patients underwent an initial 2-month follow-up in the VVI mode. Evaluation of the 19 patients who remained symptomatic and the 20 who became asymptomatic with VVI pacing demonstrated that factors observed prior to pacemaker implant were related to failure of the VVI mode. These included symptomatic pacemaker effect (42% vs 0%), mixed carotid sinus syndrome (95% vs 65%), orthostatic hypotension (47% vs 15%), or ventriculoatrial conduction (68% vs 38%). In the 23 patients with dual chamber pacing, random 2 month comparisons were performed between VVI and DVI/DDD pacing. The dual chamber mode was preferred by 14 patients, none preferred the VVI mode and nine noted no difference. Comparison of the two groups found that the factors linked to DVI/DDD preference were symptomatic pacemaker effect (50% vs 0%), ventriculoatrial conduction (78% vs 44%), or orthostatic hypotension (50% vs 11 %). VVI pacing is efficacious in a high proportion of patients affected by cardioinhibitory or mixed carotid sinus syndrome. The identification of causes of VVI pacing failure allows determination of those who will benefit from VVI pacing and those who should have DVI/DDD. VVI pacing is suggested for the cardioinhihitory type with no symptomatic pacemaker effect and for the mixed type with no symptomatic pacemaker effect or orthostatic hypotension or ventriculoatrial conduction. Dual chamber pacing should be used in all other instances.