The genetics of aging

We present a case of a patient who is HIV positive and developed both thrombotic thrombocytopenia purpura and visceral Kaposi's sarcoma (KS) with hemorrhage. This case presents a difficult management problem in that the patient's bleeding originated from KS lesions and did not quickly abate with plasmapheresis therapy despite both clinical and laboratory improvement after 2-4 days. Chemotherapy was initiated on day 13 and the patient's condition improved markedly afterward. We believe the addition of chemotherapy to plasmapheresis hastened the improvement of our patient's thrombotic thrombocytopenic purpura (TTP) and KS-related bleeding. Therefore, under similar conditions, we recommend combining plasmapheresis and chemotherapy at the onset of therapy.     

Clinical and toxicological data in fenthion and omethoate acute poisoning

This study paper reports on two cases of poisoning with the organophosphorus insecticides, fenthion and omethoate. The two victims were admitted in the Intensive Care Unit (ICU) a few hours after ingestion of the two insecticides. They received appropriate treatment for organophosphorous poisoning (gastric lavage, activated charcoal, atropine and pralidoxime) and supportive care. Both patients survived. Organophosphate blood levels were determined on admission (fenthion 2.9 micrograms/ml, omethoate 1.6 micrograms/ml) and during the hospitalisation and proved to be considerably high. Slow elimination rate of the poison already distributed in the body was indicated for both pesticides. The patient with omethoate poisoning remained clinically well (Glasgow Coma Scale: 15) and was discharged three days later. The patient with fenthion poisoning, who had also ingested 30 mg of bromazepam and 720 mg of oxetoron, developed cholinergic crisis six hours after admission and was intubated for 24 days, with concomitant complications.     

Complex orofacial movements and the disappearance of cerebellar mutism: report of five cases

Intoxications with poisonous mushrooms, in particular toadstools, are still a serious medical problem. The author presents contemporary views on the etiopathogenesis of intoxications with Amanita phalloides, the clinical picture of the phalloid syndrome and its prognosis. He emphasizes the importance of a comprehensive therapeutic approach, incl. the administration of antidotes (penicillin G and silibinin) and extracorporeal haemoelimination treatment. Early sorption haemoperfusion, either alone or combined with haemodialysis or plasmapheresis, prevent the development of hepatic and renal failure and significantly reduce the mortality from mushroom poisoning. The results of amanitine sorption in in vitro experiments and in the treatment of human intoxications justify the use of biocompatible synthetic resin sorbents (Amberlite XAD-2) in the treatment of mushroom poisoning rather than active charcoal.     

Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen

STUDY OBJECTIVE: Carbon monoxide (CO) poisoning is a major clinical problem. The risk of morbidity and the most effective treatment have not been clearly established. We measured the incidence of delayed neurologic sequelae (DNS) in a group of patients acutely poisoned with CO and tested the null hypothesis that the incidence would not be affected by treatment with hyperbaric oxygen (HBO). DESIGN: We conducted a prospective, randomized study in patients with mild to moderate CO poisoning who presented within 6 hours. Patients had no history of loss of consciousness or cardiac instability. INTERVENTIONS: The incidence of DNS was compared between groups treated with ambient pressure 100% oxygen or HBO (2.8 ATA for 30 minutes followed by 2.0 ATA oxygen for 90 minutes). DNS were defined as development of new symptoms after oxygen treatment plus deterioration on one or more subtests of a standardized neuropsychologic screening battery. RESULTS: In 7 of 30 patients (23%), DNS developed after treatment with ambient-pressure oxygen, whereas no sequelae developed in 30 patients after HBO treatment (P < .05). DNS occurred 6 +/- 1 (mean +/- SE) days after poisoning and persisted 41 +/- 8 days. At follow-up 4 weeks after poisoning, patients who had been treated with ambient pressure oxygen and had not sustained DNS exhibited a worse mean score on one subtest, Trail Making, compared with the group treated with HBO and with a control group matched according to age and education level. There were no differences in scores between the control group and the hyperbaric oxygen group. CONCLUSION: DNS after CO poisoning cannot be predicted on the basis of a patient's clinical history or CO level. HBO treatment decreased the incidence of DNS after CO poisoning.     

In praise of alternative medicine: views of a healthcare consumer and college health employee

The blood flow property is one of the factors determining blood perfusion and oxygen supply. The viscosity of the blood is primarily related to the hematocrit, but also to the amount of fibrinogen and other macromolecules present in the blood. Patients with ischemic heart disease have shown a rapid and safe improvement in their hemorheological state when treated with heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP). In this study we used two extracorporeal hemapheresis methods, plasmapheresis (PP) and immunoadsorption (IA), in 15 patients (eight patients treated with PP and seven patients with IA) with various diseases. Hemorheological variables and plasma fibrinogen were measured before and after the first and before the third treatment performed at 3 consecutive days. The aim of our study was to investigate the immediate effects of these two treatment modalities on the flow properties of blood. Immediately after the first PP and IA session statistically significant declines in plasma fibrinogen concentration, plasma viscosity, whole blood viscosity, and erythrocyte aggregation tendency were found. These changes persisted before the third treatment session. The erythrocyte fluidity and hematocrit remained unchanged. We conclude that extracorporeal hemapheresis therapy, with plasmapheresis or immunoadsorption, affects the blood rheology by decreasing the plasma viscosity and erythrocyte aggregation tendency. The decrease in plasma fibrinogen is probably the main factor underlying that, but other factors such as a decrease in immunoglobulins may also be of importance.     

Microangiopathic hemolytic anemia associated with cancers. Symptomatic treatment by plasma exchange

OBJECTIVE: To determine the interest of plasmapheresis in the management of cancer-associated microangiopathic haemolytic anaemia (MHA) not due to cancer treatment. MATERIAL [corrected] AND METHODS: National retrospective study using the file of the French Hemapheresis Society. RESULTS: We isolated 6 patients (5 men and a woman aged 32 to 69-year-old) who had prostatic (4 cases) or breast carcinomas or Hodgkin's disease. Diagnosis of cancer preceeded MHA in 3 patients (from 2 to 4 years). Bone or bone marrow metastases were demonstrated in 5 patients. The clinical presentation included anuria (4 cases), bleeding (4 cases), and laboratory findings were consistent with microangiopathic haemolysis and thrombopenia in all cases and intravascular coagulation (2 cases) and/or renal failure (4 cases). MHA symptomatic treatment included 4 to 10 courses of plasmapheresis, extra-renal epuration (4 patients), anticoagulation (4 patients) and/or antiagregant (3 cases), haemodialysis (4 cases) and vincristine (2 cases). Cancer treatment consisted of antitumoural chemotherapy (2 cases) and/or hormonotherapy (5 cases). In all cases, haemolysis, thrombopenia and intravascular coagulation were controlled within 30 days. MHA treatment was effective alone in 3 patients. No relapse were observed in 3 patients whereas the course of cancer continued in 2 patients. Two patients relapsed and died from MHA after 4 and 36 months. Two patients relapsed and died from MHA within a few months and 1 was lost to follow-up. CONCLUSION: Symptomatic treatment of cancer-associated MHA including plasmapheresis may be useful while waiting for an aetiologic management of the tumour.     

Acute psychosis associated with abrupt withdrawal of carbamazepine following intoxication

Carbamazepine is regularly used in the treatment of trigeminal neuralgia. Although exacerbation of psychosis has been described following abrupt discontinuation of carbamazepine in chronic schizophrenics, a withdrawal syndrome has not been reported previously in patients treated for trigeminal neuralgia. The case presented here suggests that abrupt withdrawal of toxic concentrations of carbamazepine may precipitate a withdrawal reaction, which is manifest some days after discontinuation of the drug. Therefore it may be advisable to withdraw therapy slowly in these situations.     

Hippocampal damage induced by carbon monoxide poisoning and spreading depression is alleviated by chronic treatment with brain derived polypeptides

A model of acute carbon monoxide poisoning combined with spreading depression (SD) induced metabolic stress was used to examine the protective effects of cerebrolysin (CL) on the development of electrophysiological, behavioral and morphological signs of hypoxic damage. Capillary electrodes were implanted into the neocortex and hippocampus of anesthetized rats which were then exposed for 90 min to breathing of 0.8% to 0.5% CO, while 3 to 4 waves of cortical and hippocampal SD were elicited by microinjections of 5% KCl. Duration of SD-provoked depolarization of cerebral cortex and hippocampus was noted. Nine and 18 to 19 days later propagation of SD waves was recorded with the same electrodes and decrease of their amplitude was used as an index of brain damage which was significant in the hippocampus but not in the cortex. CL-treatment (2.5 ml/kg per day) started after CO administration and continued for 14 days significantly improved hippocampal recovery manifested by increased amplitude of SD waves. Behavioral tests performed 10 and 20 days after CO poisoning in the Morris water maze revealed better performance (escape latency 7 s) in the CL-treated than in untreated animals (14 s). Morphological analysis showed marked damage in the hippocampus consonant with electrophysiological and behavioral findings in the same animals. No apparent histological damage was found in rats exposed to CO inhalation alone without the additional SD-provoked depolarization. It is concluded that chronic CL-treatment enhances recovery of hippocampal tissue after hypoxic damage of intermediate severity.     

Extracellular neurofibrillary tangles are immunopositive for the 40 carboxy-terminal sequence of beta-amyloid protein

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption.     

Vascular rejection in heart transplantation: clinical correlation, treatment options, and future considerations

Vascular rejection injures the vascular endothelium in cardiac allografts in the absence of significant intramyocardial lymphocytic infiltration. When compared with cellular rejection, vascular rejection occurs earlier after transplantation, is more resistant to immunosuppressive augmentation, causes more allograft dysfunction, and is associated with a higher frequency of allograft loss. Between January 1990 and October 1992, acute hemodynamically significant vascular rejection developed in 13 of 170 patients (8%). Endomyocardial biopsy specimens revealed the typical findings of endothelial cell activation, immune complex deposition, and interstitial fibrin deposition in the absence of significant lymphocytic infiltration. All patients had clinical evidence of allograft dysfunction. In addition to high-dose corticosteroids, all patients received cyclophosphamide as an oral pulse for 4 days and underwent plasmapheresis for 3 consecutive days. Eight patients received OKT3 (n = 6) or antilymphoblast globulin (n = 2), and nine patients underwent systemic anticoagulation. Six patients required inotropic therapy for hemodynamic instability. Although one patient died during the initial episode, rejection resolved and left ventricular function returned to normal in 12 of 13 patients. However, vascular rejection recurred in three patients, two of whom subsequently died. Two other patients died during late follow-up because of noncompliance. Eight patients remain alive with normal allograft function and angiographically normal coronary arteries. Whereas the addition of cyclophosphamide and plasmapheresis may improve the outcome of vascular rejection, the results of treatment with currently available treatment modalities remain unacceptably poor.     

Positive panel reactive antibody titers in patients bridged to transplantation with a mechanical assist device: risk factors and treatment

Patients who are bridged-to-transplantation with mechanical support have a high incidence of pretransplant sensitization defined by panel reactive antibody (PRA) titers greater than 10. Risk factors for positive PRA in patients with assist devices were investigated. From 1993 to 1997, 17 patients underwent implant surgery with CardioWest C-70 total artificial hearts (TAHs; CardioWest Technologies, Inc., Tucson, AZ), and 13 with Novacor left ventricular assist systems (LVASs; Baxter Healthcare, Novacor Division, Oakland, CA) for bridge-to-transplantation at this institution. Two patients died during implantation of the assist devices. Of the remaining 28 patients, four (14%) were women (3 with TAHs and 1 with an LVAS). All four women (100%) had a positive PRA, whereas only two of the 24 men (8%) had positive PRA (p < 0.0001). The transfusion histories of these patients were reviewed. Using chi-squared analysis (alpha = 0.05), the PRA levels were independent of transfusion of packed red blood cells and fresh frozen plasma. There was an association, however, between platelet transfusions and PRA levels. The times on device awaiting cardiac transplantation were also compared between the PRA positive and PRA negative groups. The average time to transplantation for PRA positive patients was 116 days, whereas the average waiting time for the PRA negative patients was 55 days (p = 0.05). Based on these data, a female patient with consistently positive PRA (93%) after TAH implantation underwent a transplant on post implant day 25 despite a positive lymphocytotoxic crossmatch with the donor. She was treated with plasmapheresis during cardiopulmonary bypass at the time of transplantation, and with four further treatments post transplant. As of this writing, she is alive and well on our standard triple immunotherapy. Therefore, women who are bridged-to-transplantation with assist devices are at risk for positive PRA. It is recommended that patients who are bridged-to-transplantation with assist devices and have high PRA levels be treated with perioperative plasmapheresis. With this aggressive approach, it may no longer be necessary to keep patients on mechanical support for prolonged periods, but possible to perform transplants as soon as suitable donors become available.     

New trends in glass-ionomer chemistry

Carbamazepine (CBZ) is an effective anticonvulsant agent. Current literature reports describe several cases of seizure exacerbation and/or EEG worsening due to CBZ with a high prevalence in children and adolescents; we report 10 new cases. Nine patients had epilepsy; one showed delayed psychomotor development and frequent EEG paroxysmal abnormalities. Four patients were on monotherapy, six on polytherapy. All but one had therapeutic CBZ plasma concentrations. Seizures increased in frequency in nine, and in eight patients new seizure types appeared, mostly absences. Cognitive functions/behaviour worsened in eight; EEG recordings showed slowing background activity and increased paroxysmal abnormalities, in six cases diffuse/generalized spike waves were seen and in two continuous spike wave discharges. The mean time of clinical EEG worsening was 1-2 days after introduction of CBZ at therapeutic doses. After CBZ withdrawal clinical EEG improvement was evident in a few days. The underlying pathogenetic mechanism is not yet understood. However, the pathophysiology of seizure exacerbation might be related to the interaction between age-related alterations in the balance of excitation and inhibition in the developing thalamocortical circuitry and the essential activity of CBZ that tends to induce interictal discharges.     

Hydroxyl radical production in the brain after CO hypoxia in rats

Reactive oxygen species (ROS) have been implicated in the pathogenesis of neuronal injury after carbon monoxide (CO) poisoning. Severe CO poisoning is treated with hyperbaric oxygen (HBO), which eliminates CO quickly from hemoglobin and body tissue stores, but has a potential to increase ROS generation. In this study, the effects of HBO on generation of highly reactive hydroxyl radical (HO.) in the brain after CO poisoning in rats was investigated using nonenzymatic hydroxylation of salicylic acid to 2,3 dihydroxybenzoic acid (2,3-DHBA) as a probe. In control studies, the concentrations of 2,3-DHBA after HBO in brain mitochondria and postmitochondrial supernatant (cytosol) were similar to air-exposed animals. After CO poisoning, 2,3-DHBA concentration increased in brain mitochondria but not in the cytosol. After CO exposure and HBO administration at 1.5 atmospheres absolute (ATA), a decrease in 2,3-DHBA production was detected in brain mitochondria. After CO and HBO at 2.5 ATA, 2,3-DHBA concentration increased in both mitochondria and cytosol. The oxidant scavenger dimethylthiourea (DMTU) and the monoamine oxidase (MAO) inhibitor pargyline, administered to CO poisoned rats after HBO at 2.5 ATA, diminished 2,3-DHBA production in both subcellular compartments. These findings indicate that brain HO. production can be either diminished or accelerated after severe CO poisoning depending on the oxygen partial pressure employed during therapy.     

Xenobiotic metabolism in rat, dog, and human precision-cut liver slices, freshly isolated hepatocytes, and vitrified precision-cut liver slices

Human, rat, and dog phase I and phase II xenobiotic metabolism in precision-cut liver slices and freshly isolated hepatocytes was compared using a range of substrates. Carbamazepine (50 microM) and styrene (2 mM) were used as probes to study the maintenance of cytochrome P450 and epoxide hydrolase-mediated metabolism in male Sprague-Dawley rat, precision-cut liver slices and hepatocytes. Carbamazepine metabolism in both models resulted in the formation of the bioactive 10,11-epoxide (KM = 766 microM and Vmax = 2.5 pmol/min/mg protein in precision-cut slices). Epoxide formation was higher (2.4-fold) in hepatocytes than slices. Styrene was deactivated to styrene diol at a higher rate in hepatocytes (9.7-fold) than slices. The lower rate of metabolism in slices compared with hepatocytes confirms our previous observations using testosterone, 7-ethoxycoumarin, 1-chloro-2,4-dinitrobenzene and 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazolinone in the rat. Testosterone 6 beta-hydroxylation in human liver slices was similar to cultured hepatocytes, but lower than in freshly isolated hepatocytes. 7-Ethoxycoumarin O-deethylation was higher in freshly isolated human hepatocytes, as was the ratio of glucuronide to 7-hydroxycoumarin. Testosterone hydroxylations, 7-ethoxycoumarin O-deethylation, and 1-chloro-2,4-dinitrobenzene conjugation were also lower in male beagle dog slices, compared with freshly isolated hepatocytes. Attempts at long-term preservation of dog liver slices using vitrification and storage for up to 9 days at -196 degrees C resulted in the retention of phase I and phase II metabolism, although conjugation was lower than in freshly prepared slices. Xenobiotic metabolism in short-term incubations is consistently lower in dog and rat precision-cut slices than in freshly isolated hepatocytes; whereas, in humans, this quantitative difference is partly hidden by the large interindividual variation.     

Treatment of amiodarone iodine-induced thyrotoxicosis with plasmapheresis and methimazole

The present report illustrates the clinical and biochemical outcome in two amiodarone iodine-induced thyrotoxicosis (AIIT) patients submitted to plasmapheresis. Amiodarone was discontinued, and treatment with MMI (40 mg/day) was started. In addition, patients were submitted to two sessions of plasma-exchange, with a one-day interval between the two session. In both patients serum total T3 (TT3) and free T3 (FT3) concentrations decreased promptly but in contrast to the serum TT3, FT3 levels remained steadily above the normal range. A similar behaviour was observed for total T4 and free T4 plasma concentrations. Interestingly, a clearcut clinical amelioration was observed in both patients even before a reduction of circulating free thyroid hormone concentrations could be documented. In conclusion, our experience indicates that plasmapheresis may be useful in order to obtain a rapid amelioration of severe clinical picture of thyrotoxicosis, but cannot be considered as a definite therapy in AIIT. It should be considered that plasmapheresis is not devoid of risks and is also a very expensive procedure.     

Reversible pitch perception deficit due to carbamazepine

Carbamazepine (CBZ) is a drug frequently used to treat variety of neurological diseases or symptoms. Among its adverse effects, auditory disturbance is described rarely. In the present report, we describe an 18-year-old girl who noted false lowering of perceived pitch after starting CBZ treatment for epilepsy, and review the literature reporting CBZ-associated abnormal pitch perception.     

Treatment of hemorrhagic lupus pneumonitis with plasmapheresis

Pulmonary hemorrhage is a rare and often fatal complication of systemic lupus erythematosus (SLE). Treatment with high-dose steroids and cyclophosphamide has been of only modest value, with a reported mortality of up to 92%. We have recently seen three patients with active SLE who developed acute life-threatening pulmonary hemorrhage. Diagnostic evaluation of these patients showed negative sputum and blood cultures, negative glomerular basement membrane antibodies, and negative antineutrophilic cytoplasmic antibodies. In two patients, an open-lung biopsy was performed, and histological examination showed granular alveolar immunofluorescence staining for immunoglobulin and complement components. Treatment with plasmapheresis was initiated with prompt resolution of symptoms and clearing of chest radiograph. Two patients had recurrent bleeds despite treatment with cyclophosphamide and high-dose steroids and required repeated intubation. Plasmapheresis resulted in rapid radiographic and clinical improvement on each occasion. Two patients survived long-term and are presently without pulmonary problems; one patient died of sepsis after initial response to plasmapheresis. The dramatic improvement of the pulmonary disease in these patients leads us to conclude that rapid initiation of plasmapheresis should be strongly considered in SLE patients with severe, life-threatening pulmonary hemorrhage.     

The peak latency of orbital presaccadic spike potential with horizontal eye movements

A case of Macrozamia riedlei seed poisoning is described in a young Dachshund. Vomiting and depression commenced within 6 h of ingestion; other signs that developed included severe hepatopathy, jaundice, abdominal pain that was unresponsive to analgesics, severe gastro-intestinal haemorrhage and thrombocytopenia as well as crystalluria and marrow dyserythropoiesis. The dog was euthanased 6 days after ingestion of the seeds.     

Chondronecrosis of the cricoid cartilage after intubation. Two case reports

Chondronecrosis of the cricoid cartilage is a rare complication of intubation. The records of two children were reviewed. An 8-month-old girl with myelomonocytic leukaemia developed chondronecrosis 10 days after a 2-day period of ventilation. A 4-year-old girl comatose after poisoning by the histamine antagonist, alimemazine, developed chondronecrosis after a 2-day period of intubation. The complication was suspected when extubation led to dyspnoea owing to laryngeal stridor and was confirmed by direct laryngoscopy. We review the development of the condition, the causative factors, treatment and prevention.     

Influence of therapeutic plasmapheresis on elimination of ceftiaxone

To study the plasma elimination rate of ceftriaxone given to patients undergoing plasmapheresis, a single 2-g intravenous dose of ceftriaxone was given to 11 patients who underwent plasmapheresis 3 h (early group) or 15 h (late group) later. Even though the early patient group had twofold more ceftriaxone removed than the late group, all individual patients had 24-h ceftriaxone levels of 9 micrograms/ml or higher. We conclude that patients undergoing plasmapheresis lasting 150 min or less may safely be treated with 2 g of ceftriaxone once daily without risking periods of subtherapeutic plasma ceftriaxone levels.