Biomedical subjects
J Bauer
Publications and source records attributed to J Bauer.
Intricate journey: the path of a manuscript from submission to publication.
This article traces the path of a manuscript that is submitted for publication consideration from the time of its receipt to its ultimate appearance in print. The peer review process is explained in detail. Though the process is similar for most journals, this article describes the process specific to the Journal of PeriAnesthesia Nursing.
Continuing education: burden or opportunity?
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Superior caval venous syndrome after atrial switch procedure: relief of complete venous obstruction by gradual angioplasty and placement of stents.
Superior caval venous syndrome is one of the late problems known to occur after Mustard repair of complete transposition. Reoperation may leave residual stenosis, and carries substantial risk for the patient. It is now feasible to use intravascular stents to overcome systemic venous baffle obstructions, and such an approach is probably more effective. The purpose of our study therefore, was to assess immediate and medium term results of inserting stents subsequent to gradual balloon enlargement of acquired atresia of the intraatrial baffle in patients who had undergone an atrial switch operation. We investigated five patients with complete obstruction of the superior caval venous pathway at perforation of the atretic segment was achieved using a guide wire technique. The procedure was successful in all patients. Gradual angioplasty was performed and intravascular stents were implanted. The pressure in the superior caval vein dropped to normal values, symptoms improved, and the patency of the newly created venoatrial communication was proven at mid-term follow-up. Thus critical obstructions at the superior caval venous pathway after the Mustard procedure can be reopened by interventional catheterization. Implantation of balloon-expandable intravascular stents is safe and effective in the acute relief of the obstructions, but careful long-term follow-up is mandatory.
Physiological characterisation of a pyruvate-carboxylase-negative Saccharomyces cerevisiae mutant in batch and chemostat cultures.
A prototrophic pyruvate-carboxylase-negative (Pyc-) mutant was constructed by deleting the PYC1 and PYC2 genes in a CEN.PK strain of Saccharomyces cerevisiae. Its maximum specific growth rate on ethanol was identical to that of the isogenic wild type but it was unable to grow in batch cultures in glucose-ammonia media. Consistent with earlier reports, growth on glucose could be restored by supplying aspartate as a sole nitrogen source. Ethanol could not replace aspartate as a source of oxaloacetate in batch cultures. To investigate whether alleviation of glucose repression allowed expression of alternative pathways for oxaloacetate synthesis, the Pyc- strain and an isogenic wild-type strain were grown in aerobic carbon-limited chemostat cultures at a dilution rate of 0.10 h-1 on mixtures of glucose and ethanol. In such mixed-substrate chemostat cultures of the Pyc- strain, steady-state growth could only be obtained when ethanol contributed 30% or more of the substrate carbon in the feed. Attempts to further decrease the ethanol content of the feed invariably resulted in washout. In Pyc- as well as in wild-type cultures, levels of isocitrate lyase, malate synthase and phospho-enol-pyruvate carboxykinase in cell extracts decreased with a decreasing ethanol content in the feed. Nevertheless, at the lowest ethanol fraction that supported growth of the Pyc- mutant, activities of the glyoxylate cycle enzymes in cell extracts were still sufficient to meet the requirement for C4-compounds in biomass synthesis. This suggests that factors other than glucose repression of alternative routes for oxaloacetate synthesis prevent growth of Pyc- mutants on glucose.
Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days.
BACKGROUND: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients. PATIENTS AND METHODS: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS). RESULTS: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities. CONCLUSIONS: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.
Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.
BACKGROUND: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. PATIENTS AND METHODS: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. RESULTS: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. CONCLUSIONS: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.
Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat.
Annexin-1, a calcium-dependent phospholipid binding protein, has been shown to act as an endogenous central neuroprotectant, notably against cerebral ischaemic damage. In the present study we extend these findings to an animal model of multiple sclerosis, EAE, and report that endogenous annexin-1 is expressed in ED1+ macrophages and resident astrocytes localized within the lesions in the central nervous system (CNS). Intracerebroventricular (i.c.v.) administration of an NH2-terminal fragment spanning amino acids 1-188 of annexin-1 after the onset of the clinical symptoms significantly reduced both the neurological severity as well as weight loss of mild EAE. Immunoneutralization of endogenous brain annexin-1 failed to exacerbate the clinical features of EAE. Thus, although the role of endogenous annexin-1 in the pathogenesis of EAE remains to be determined, our findings suggest that annexin-1 may be of therapeutic benefit to the treatment of multiple sclerosis.
Seizure occurrence during ovulatory and anovulatory cycles in patients with temporal lobe epilepsy: a prospective study.
We investigated the influence of ovulatory and anovulatory menstrual cycles on seizure occurrence in female patients with complex partial seizures. We prospectively documented seizures in relation to menstrual cycles (defined by measurement of basal body temperature and progesterone serum concentrations) in 39 female patients. One hundred and thirty-two cycles of 35 patients entered final analysis. Only eight patients had anovulatory cycles, in 18 patients all cycles were ovulatory. In the remaining nine patients anovulatory as well as ovulatory cycles were documented. In ovulatory cycles the mean frequency of seizures during the days of menstruation was significantly higher as compared to the periovulatory or the luteal phase of the cycles. During anovulatory cycles seizure frequency was significantly lower during menstruation than in the remaining days of the cycles. Since progesterone is known to exhibit anticonvulsant effects, seizure occurrence during menstruation seems to be related to ovulatory cycles, possibly due to the premenstrual decrease of progesterone. Therapeutic recommendations for the treatment of seizures related to the menstrual cycle (catamenial seizures) include the administration of hormones, as progesterone (recommended especially for women with catamenial epilepsy who have a documented inadequate luteal phase) or the suppression of the menstrual hormonal cycle by synthetic gonadotropin releasing hormone analogs.
Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6.
Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1beta, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1beta-induced IL-6 expression required the transcription factor nuclear factor-kappaB (NF-kappaB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-kappaB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved.
[Anticonvulsant combination therapy: rational concepts versus real effectiveness].
Primary drug treatment of epilepsies is usually a monotherapy with an antiepileptic drug. This procedure causes less side effects as polytherapy and probably shows the same efficacy. Two third of patients with focal epilepsies are sufficiently treated with a single antiepileptic drug: 60% of patients with Grand mal and 22-30% of patients with complex focal seizures remain seizures free. An alternative monotherapy will suppress seizures in another 30% of patients. With polytherapy this is achieved in only 12% of the remaining patients, furthermore, side effects increase in polytherapy. Generalized epilepsies are usually treated with valproate monotherapy. Patients remain seizure free from absence in 60-90%, from myoclonic-impulsive seizures in 75-97% and from Grand mal in about 85%. Alternative monotherapy is less common because of the limited efficacy and possible side effects of drugs: ethosuximide does not control Grand mal and phenobarbitone may cause sedation. Thus, polytherapy is commonly initiated when monotherapy fails to control seizures (lamotrigine is often chosen as comedication). Rational polypharmacy is a term suggesting rational concepts in planning antiepileptic polytherapy leading to a superior anticonvulsant effect. However, this consideration is not based on or supported by clinical data. Yet, a combination of drugs which have no or little pharmacokinetic interactions seems to be a clinically relevant recommendation. Thus, newly developed drugs such as vigabatrin, lamotrigine or gabapentin are more frequently used as comedication with standard antiepileptic drugs.
Life-threatening parvovirus B19-associated myocarditis and cardiac transplantation as possible therapy: two case reports.
Parvovirus B19 infection can cause a wide spectrum of disease syndromes. Two cases of parvovirus B19 infection were identified that resulted in life-threatening myocarditis shortly after acute infection in immunocompetent individuals. The diagnosis was made with serological and polymerase chain reaction techniques. One patient was successfully treated by heart transplantation. Sequence analysis showed that the parvovirus B19 cloned from the patients' sera had 99% homology with the prototype sequence. Clinicians should be alerted to the possible role of parvovirus B19 in myocarditis presenting in immunocompetent patients.
Serum sex hormones are altered in patients with chronic temporal lobe epilepsy receiving anticonvulsant medication.
PURPOSE: To evaluate the changes in serum sex hormones of gonadal or adrenal origin, the gonadotropic hormones, and sex hormone-binding globulin (SHBG) in men and women with chronic temporal lobe epilepsy (TLE), who are undergoing monotherapy with carbamazepine or receiving carbamazepine in combination with other anticonvulsant drugs. METHODS: Gonadal hormones (estradiol, testosterone, free testosterone, and inhibin B), adrenal hormones [cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and 17alpha-hydroxyprogesterone], and gonadotropic hormones (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) were measured in 22 women and 26 men with TLE. The study also measured prolactin; human growth hormone and its major mediator, insulin-like growth factor-I; thyroid hormones (free thyroxine and free triiodothyronine); thyroid-stimulating hormone (TSH); and SHBG. The results were compared with those obtained from 60 healthy women and 106 healthy men. RESULTS: In the female patients, TSH, DHEAS, follicular-phase LH, and luteal-phase estradiol were significantly lower than in the control groups, with prolactin and SHBG significantly higher. In the male patients, DHEAS, 17alpha-hydroxyprogesterone, free testosterone, inhibin B, and the testosterone/LH ratio were significantly lower than in the control group, with LH, FSH, and SHBG significantly higher. Increased FSH in 31% of the men indicates an impairment of spermatogenesis; lowered inhibin B in 12% indicates an impaired Sertoli's cell function; and the decreased testosterone/LH ratio in 50% indicates an impaired Leydig's cell function. CONCLUSIONS: The case patients had endocrine disorders, mainly concerning the gonadotropic and gonadal functions in both sexes; the adrenal function, with lowered DHEAS levels in both sexes; and lowered 17alpha-hydroxyprogesterone levels in the men. SHBG levels were increased in patients taking anticonvulsant medications.
Aggravation of focal epileptic seizures by antiepileptic drugs.
Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.
Results from 5 years of nationwide DNA fingerprinting of Mycobacterium tuberculosis complex isolates in a country with a low incidence of M. tuberculosis infection.
Results from DNA fingerprint analyses of Mycobacterium tuberculosis complex isolates from tuberculosis (TB) patients diagnosed during 5 years in Denmark are presented. The lack of success in eradicating TB in this low-incidence country may be explained by an unrecognized high frequency of active TB transmission (57%) among native Danes. Only two strains of M. tuberculosis are responsible for 40% of all clustered cases of TB among Danes.
IS1245 restriction fragment length polymorphism typing of Mycobacterium avium isolates: proposal for standardization.
Mycobacterium avium has become a major human pathogen, primarily due to the emergence of the AIDS epidemic. Restriction fragment length polymorphism (RFLP) typing, using insertion sequence IS1245 as a probe, provides a powerful tool in the molecular epidemiology of M. avium-related infections and will facilitate well-founded studies into the sources of M. avium infections in animal and environmental reservoirs. The standardization of this technique allows computerization of IS1245 RFLP patterns for comparison on a local level and the establishment of M. avium DNA fingerprint databases for interlaboratory comparison. Moreover, by combining international DNA typing results of M. avium complex isolates from a broad spectrum of sources, long-lasting questions on the epidemiology of this major agent of mycobacterial infections will be answered.
Longitudinal evaluation of salivary cortisol levels in full-term and preterm neonates.
The aim of the present study was to test the practicability of sequential cortisol determinations in saliva of low birth weight neonates and to evaluate the impact of systemic and inhaled glucocorticoid therapy on saliva concentrations of cortisol in preterm neonates with bronchopulmonary dysplasia (BPD). Salivary cortisol levels were measured by RIA in saliva samples from 10 full-term and 10 preterm healthy neonates and from 20 preterm neonates with BPD during systemic [dexamethasone (DEX); n = 10] or topical steroid therapy [budesonide (BUD); n = 10]. Saliva samples of each individual were collected on 3 consecutive days at 06.00, 12. 00, 18.00 and 24.00 h. Cortisol levels in saliva ranged from 0.8 to 60.6 nmol/l (median 6.5 nmol/l) in full-term neonates, from 0.6 to 52.1 nmol/l (median 5.5 nmol/l) in preterm neonates, from 0.4 to 14. 0 nmol/l (median 1.0 nmol/l) in preterm neonates treated with DEX and from 0.4 to 15.2 nmol/l (median 2.5 nmol/l) in preterm neonates treated with BUD. Autocorrelation analysis revealed a distinct endogenous cortisol rhythm in 2 of the 10 healthy full-term neonates and in 3 of the 10 healthy preterm neonates with a wavelength of 12-30 h. Salivary cortisol levels in preterm neonates treated with DEX or BUD were significantly lower than those measured in healthy preterm neonates. These results demonstrate that the measurement of salivary cortisol levels is a reliable and practicable way of assessing adrenal function in full-term and preterm neonates. This study also shows for the first time that some neonates display an endogenous cortisol rhythm which is not coupled to the exogenous day/night cycle. Furthermore, systemic and nebulized glucocorticoids suppress adrenal function in low-birth-weight neonates. After treatment these children should be closely monitored for potential adrenal insufficiency.