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Biomedical subjects

J A Koziol

Publications and source records attributed to J A Koziol.

At least 19 recordsLinked to original sources
PubMed1992

A less costly regimen of alglucerase to treat Gaucher's disease.

BACKGROUND: Alglucerase (Ceredase) provides effective enzyme-replacement treatment for patients with Gaucher's disease, but at the usually recommended dose of 60 U per kilogram of body weight every two weeks (130 U per kilogram per month), it costs $382,200 per year for a 70-kg patient. Theoretical considerations suggest that more frequent administration would be more efficient. METHODS: Fourteen patients with type 1 Gaucher's disease that was moderately severe to severe were given 30 U of alglucerase per kilogram per month, in divided doses given either daily or three times weekly, or 120 U given three times weekly. The effect of the treatment on the size of the liver and spleen and on blood counts was compared with published data on patients who received a total dose four to five times as large as the lower dose we used and who received treatment every two weeks. RESULTS: The response to 30 U of alglucerase per kilogram per month, fractionated into three or seven doses weekly, was approximately the same as that reported after the administration every two weeks of a dose four or five times as large, given in the large infusions usually recommended. A fourfold increase in the dose given three times weekly, from 2.3 to 9.2 U per kilogram, did not substantially increase the rate of improvement. CONCLUSIONS: The treatment of Gaucher's disease with smaller total doses of alglucerase given more frequently yields satisfactory results. A dose of 2.3 U per kilogram three times weekly yields major financial benefits with no sacrifice of therapeutic effect. Even taking into account the increased ancillary costs of more frequent administration, this method of administering alglucerase reduces the annual cost of the drug for a 70-kg patient to about $100,000.

Administration, Oral↗
PubMed1992

Tumour necrosis factor alpha antibody protects against lethal meningococcaemia.

Tumour necrosis factor alpha (TNF-alpha) has been shown to be the principal mediator of Gram-negative bacterial endotoxin-induced shock. Nevertheless, evidence suggests that TNF-alpha plays a beneficial role in controlling bacterial infections when multiplication of the microorganism is required to kill the host. Using an infant rat model of Neisseria meningitidis infection, we found that blood TNF-alpha concentration reaches a peak three hours after intraperitoneal injection of 3 x 10(6) bacteria. Thereafter, the level of TNF-alpha decreased and was undetectable six to eight hours after infection. A correlation was observed between the magnitude of initial TNF-alpha response and a fatal outcome. Pretreatment of the animals with polyclonal anti-TNF antiserum significantly reduced mortality relative to animals pretreated with control serum. However, pretreatment of animals with anti-TNF antibody did not alter the bacterial invasion of the cerebrospinal fluid. Injection of heat-killed bacteria did not cause death and induced lower TNF-alpha levels than the same number of live bacteria. This excludes the possibility that the role of TNF-alpha is to mediate a shock induced by the endotoxin component of the bacterial inoculum. These results indicate that TNF-alpha has a deleterious effect in this model of bacteraemia. Identification of the critical factors that determine the action of TNF-alpha during lethal bacteraemia will lead to a better understanding of these diseases and the development of appropriate therapeutic intervention.

Animals↗
PubMed1992

Serum interleukin-6 levels in patients with thrombocytosis.

Interleukin-6 (IL-6) has been shown to increase platelet counts in several animal models and to enhance megakaryocytopoiesis in vitro. In order to investigate the possible relationship between IL-6 and thrombocytosis, serum IL-6 levels in patients with platelet counts > or = 6 x 10(5)/microliters were measured using an IL-6-responsive bioassay. A cohort of healthy volunteers with normal platelet counts was used to establish a control mean serum IL-6 level [2.19 U/ml +/- 1.08 SD (range 0-5.5)]. Patients with primary thrombocytosis had a mean serum IL-6 level not significantly different from controls. In comparison, serum IL-6 levels of patients with reactive thrombocytosis were significantly greater than controls (38.3 U/ml +/- 94.6; range 0-933; P < 0.001). Although no significant correlation was observed between the degree of serum IL-6 elevation and the height of the platelet count in any individual, elevated serum IL-6 was highly correlated with reactive thrombocytosis.

Hematopoiesis↗
PubMed1992

CHAT analysis of the influence of specific risk factors on late results after carotid endarterectomy.

The CHAT classification separates various current and historical presentations of cerebrovascular disease in an effort to determine important prognostic clues for management and prognosis. To evaluate known risk factors for late stroke and death, we followed up for an average of 44 months 633 patients who had undergone 714 carotid operations. We analyzed the indication for surgery (by CHAT) and the effect of preoperative risk factors (age, hypertension, cardiac disease, tobacco use, diabetes, hyperlipidemia, renal disease, pulmonary disease, and total risk factor score) on the end points of late stroke and death. Ipsilateral stroke was uncommon after carotid endarterectomy: with life-table analysis, the probability of late stroke at 5 years after carotid endarterectomy was 3%. Among the 127 patients with amaurosis fugax, the incidence of late stroke and of mortality was a combined total of 1% per year, and the 17 patients who had been first seen with permanent ocular stroke (blindness) fared equally well. The 28 patients who were first seen with vertebrobasilar symptoms and were treated by carotid endarterectomy also fared particularly well, with no late strokes or deaths within the first 5 years. Logistic regression analyses revealed that the various indications for carotid endarterectomy were associated with differing patterns of risk factors as significant predictors of late stroke or death. For patients first seen with asymptomatic lesions, only diabetes was an important predictor for late stroke (p = 0.05) and renal disease was the only marker for early death (p = 0.05). On the other hand, those factors were not significant risk factors for patients first seen with amaurosis fugax, for whom tobacco use was a negative predictor for stroke (p = 0.06) and male gender a negative predictor for early death (p = 0.03). After cortical transient ischemic attacks and carotid endarterectomy, there were no risk factors predictive of late stroke or of death. For patients with prior stroke, age was a very strong predictor of stroke (p = 0.01) and both age and a history of cardiac disease were significant risk factors for early death (p = 0.007). In contrast to the results in reports of patients treated medically for transient ischemic attacks and stroke, we found that several risk factors appeared to play relatively minor roles. In conclusion, stroke after carotid endarterectomy was uncommon, least common after ocular symptoms, and most likely after permanent cortical stroke. Specific risk factors were less important for patients after carotid endarterectomy than for the medically treated stroke patient.

Analysis of Variance↗
PubMed1992

Phase I cancer trials: limitations and implications.

The goal of Phase I clinical trials is to establish a maximum tolerated dose (MTD) and a tolerable dose range for future efficacy testing. Various issues include schedule of drug delivery, starting dose, number of patients to be tested, pitfalls in the selection of MTD, risk:benefit ethical issues, and the problems introduced by patient heterogeneity. Statistical evaluation of various Phase I strategies illustrate the limitations of various approaches in terms of patient expectations regarding efficacy and the scientific goals of such trials. Patients should be given the opportunity to receive the drug at more than one single dose level.

Animals↗
PubMed1991

On the prevalence of transcriptional regions in human genomic DNA.

The dinucleotide sequences TpA and CpG are differentially expressed in transcribed vs. non-transcribed portions of the human genome (Beutler et al., 1989, Proc. natn. Acad. Sci. U.S.A. 86, 192-196). This fact is exploited here to estimate the total number of transcriptional regions in human genomic DNA.

DNA↗
PubMed1991

The expression of the Ig H chain repertoire in developing bone marrow B lineage cells.

Analyses of rearranged Ig H chain V region genes of bone marrow pre-B cells demonstrate extensive sequence diversity, particularly within the third hypervariable region (HCDR3). This diversity is constrained, however, through preferential utilization of certain D gene segments and possibly VH gene segments and a preponderance of productive rearrangements, primarily those expressing D gene segments in a preferred reading frame. The predominance of productively rearranged V genes with D regions translated in a preferred frame, is, at least in part, the consequence of selective clonal expansion encompassing at least five to six divisions subsequent to VH-D-JH rearrangement. Selection for clonal expansion appears to be dependent on recognition of the nascent H chain product of certain productively rearranged genes.

Antibody Diversity↗
PubMed1991

A note on efficient estimation of mutation rates using Luria-Delbrück fluctuation analysis.

The maximum likelihood and Luria-Delbrück P0 methods for the estimation of spontaneous mutation rates are compared. The maximum likelihood method is fully efficient, utilizing all available information in a fluctuation experiment, but can be numerically cumbersome. Under certain conditions, there is little loss of efficiency using the P0 method, which is readily implemented numerically. Design considerations should aid investigators in minimizing statistical errors associated with the statistical analysis of fluctuation experiments.

Mathematics↗
PubMed1991

A bivariate version of Andrews plots.

A bivariate version of Andrews plots is introduced for naturally paired multivariate data. The bivariate Andrews plots are space curves, and are particularly effective for revealing patterns and clusters when depicted dynamically. Projections of the bivariate Andrews plots recover the familiar univariate Andrews plots.

Animals↗
PubMed1991

Elevated serum interleukin-6 levels in patients with reactive thrombocytosis.

Interleukin-6 (IL-6) is known to promote megakaryocytopoiesis in vitro and raise platelet counts in vivo. To determine if there is a relationship between circulating IL-6 and thrombocytosis in man, we measured bioactive IL-6 in the serum of 13 patients with myeloproliferative disorders and 143 patients with reactive thrombocytosis having platelet counts greater than or equal to 600 x 10(9)/l. IL-6 activity was assayed using the IL-6-responsive B9 cell line. Seventy-one controls with normal platelet counts had a mean IL-6 level of 2.19 U/ml +/- 1.08 (SD). None of the 13 patients with myeloproliferative disorders had elevated IL-6 levels (1.56 U/ml +/- 1.2). In contrast, serum IL-6 levels of 143 patients (158 samples) with reactive thrombocytosis were significantly greater than controls (38.3 U/ml +/- 94.6; P less than 0.001), with 83% of the samples showing elevated serum IL-6. No significant correlation was observed between serum IL-6 levels and platelet counts in the reactive thrombocytosis group. We conclude that elevated IL-6 is associated with reactive thrombocytosis, and hypothesize that the increased platelet count in many cases is causally related to elevated IL-6.

Humans↗
PubMed1990

Multivariate data reduction by principal components, with application to neurological scoring instruments.

Principal components analysis is widely used as a practical tool for the analysis of multivariate data. The aim of this analysis is to reduce the dimensionality of a multivariate data set to the smallest number of meaningful and independent dimensions. The analysis can also provide interpretable linear functions of the original measured variables that may serve as valuable indices of variation. A brief introduction to principal components analysis is given herein, followed by an examination of a particular set of multivariate data accruing from a study of acute brain injuries in a pediatric population, in which severity of brain injury had been assessed with the Glasgow Coma Scale (CGS). Principal components analysis reveals that the GCS sum score is a particularly inefficient summarizer of information in this cohort. The determination of an objective weighting of measured variables, as provided through principal components analysis, is essential in the construction of meaningful neurological scoring instruments.

Coma↗
PubMed1990

Narcolepsy.

Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextroamphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence.

Adult↗
PubMed1990

Hemorrhagic transformation following tissue plasminogen activator in experimental cerebral infarction.

The effect of an intravenous infusion of recombinant tissue plasminogen activator on hemorrhagic transformation early after middle cerebral artery territory ischemia was studied in an established awake nonhuman primate (baboon) model. Following 3 hours' occlusion of the middle cerebral artery and 30 minutes' reperfusion in each of 30 baboons, a 60-minute infusion of recombinant tissue plasminogen activator (at three doses: Group A, 0.3 mg/kg, n = 6; Group B, 1.5 mg/kg, n = 6; Group C, 10 mg/kg, n = 6) or normal saline (n = 12) was undertaken. The frequency and volume of intracerebral hemorrhage, the volume of infarction, and clinical alterations were determined by computed tomography at 24 hours and 10 days, neuropathology at 14 days, and serial daily neurologic evaluations, respectively. Peripheral (nonintracranial) hemorrhage (Group A, p = 0.46; Group B, p = 0.015; Group C, p = 0.002) and peak plasma tissue plasminogen activator levels varied directly with the dose of recombinant tissue plasminogen activator. Petechial hemorrhagic infarction was a common finding among the 30 baboons. No significant differences in the incidences or volumes of infarction-related hemorrhage were apparent in any group compared with the respective saline-treated baboons. In pooled data, no significant relation between the volume of hemorrhage and the volume of infarction could be established. We conclude that the incidence and severity of hemorrhagic transformation are not related to infarction size and that recombinant tissue plasminogen activator does not increase the incidence or severity (volume) of hemorrhage when given early (less than or equal to 3.5 hours) after the onset of focal cerebral ischemia in this model.

Animals↗
PubMed1989

Evolution of the genome and the genetic code: selection at the dinucleotide level by methylation and polyribonucleotide cleavage.

Noting the scarcity of CpG dinucleotide in total genomic DNA derived from higher organisms and the scarcity of TpA dinucleotide in total genomic DNA derived from most life forms, we examined the distribution of these dinucleotides in sequences derived from functionally distinct types of human DNA, including mitochondrial DNA, intergenic DNA, intron DNA, and DNA destined to be represented in the cytoplasm as mRNA, tRNA, or rRNA. While CpG frequency has fallen to its lowest levels in DNA that is transcriptionally silent, TpA is most stringently excluded in DNA destined to be expressed as mRNA in the cytosol. This observation suggests that the selective pressures leading to the removal of CpG and TpA operate at different levels. With respect to TpA, dinucleotide scarcity may reflect a requirement for mRNA stability and may indicate the action of UpA-selective ribonucleases. We propose that, by reason of its instability, UpA must have been very rare in primordial RNA. Therefore, tRNA with the anticodon for this dinucleotide may have failed to evolve, making UpA the primordial doublet "stop" codon. The modern triplet code has faithfully conserved this arrangement in the two universal stop codons, UAA and UAG.

Base Sequence↗
PubMed1989

Adverse reactions to iopamidol and iohexol myelography with special attention to headache: role of myelographic technique.

In order to identify those myelographic risk factors associated with a higher incidence of adverse effects, myelographic technique, patient variables and post-myelographic symptoms were prospectively recorded in a group of 152 patients studied with iopamidol and in a second group of 28 patients studied with iohexol. None of the technical factors studied were identified to have a statistically significant relationship with the incidence of adverse reactions. Older patients fared better than younger patients in both groups. Overall, there was a lower incidence of side effects in the iopamidol group (29%) than in the iohexol group (50%). Headache, nausea, and vomiting were the most frequent reactions seen.

Aged↗