Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study.

Despite rather strict recommendations for antibiotic treatment of disseminated Lyme borreliosis (LB), evidence-based studies on the duration of antibiotic treatment are scarce. The aim of this multicenter study was to determine whether initial treatment with intravenous ceftriaxone (CRO) for 3 weeks should be extended with a period of adjunct oral antibiotic therapy. A total of 152 consecutive patients with LB were randomized in a double-blind fashion to receive either amoxicillin (AMOX) 1 g or placebo (PBO) twice daily for 100 days. Both groups received an initial treatment of intravenous CRO 2 g daily for 3 weeks, followed by the randomized drug or PBO. The outcome was evaluated using the visual analogue scale at the follow-up visits. The final analysis included 145 patients, of whom 73 received AMOX and 72 PBO. Diagnoses of LB were categorized as either definite or possible, on the basis of symptoms, signs, and laboratory results. The diagnosis was definite in 52 of the 73 (71.2%) AMOX-treated patients and in 54 of the 72 (75%) PBO patients. Of the patients with definite diagnoses, 62 had neuroborreliosis, 45 arthritis or other musculoskeletal manifestations, and 4 other manifestations of LB. As judged by the visual analogue scale and patient records, the outcome after a 1-year follow-up period was excellent or good in 114 (78.6%) patients, controversial in 14 (9.7%) patients, and poor in 17 (11.7%) patients. In patients with definite LB, the outcome was excellent or good in 49 (92.5%) AMOX-treated patients and 47 (87.0%) PBO patients and poor in 3 (5.7%) AMOX-treated patients and 6 (11.1%) PBO patients (difference nonsignificant, p = 0.49). Twelve months after the end of intravenous antibiotic therapy, the levels of antibodies against Borrelia burgdorferi were markedly decreased in 50% of the patients with definite LB in both groups. The results indicate that oral adjunct antibiotics are not justified in the treatment of patients with disseminated LB who initially receive intravenous CRO for 3 weeks. The clinical outcome cannot be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. In patients with chronic post-treatment symptoms, persistent positive levels of antibodies do not seem to provide any useful information for further care of the patient.

Analysis of Borrelia burgdorferi IgG antibodies with a combination of IgG ELISA and VlsE C6 peptide ELISA.

Enzyme-linked immunosorbent assays (ELISAs) were used to detect antibodies to the C6 peptide of the Borrelia burgdorferi VlsE protein and a selection of B. burgdorferi IgG antigens, separately and as a combination, in 355 serum specimens from blood donors and patients. Western immunoblotting was used as the reference method. The sensitivity of the combined analysis of IgG antigen and C6 peptide analysis was markedly superior to those of the separate analyses. When the C6 peptide and IgG results were concordant, the customary confirmatory Western immunoblotting assay could be omitted, thus reducing the time and cost of analysis.

Culturing precision-cut human prostate slices as an in vitro model of prostate pathobiology.

Due to the complex morphology of the prostate, it was hypothesized that precision-cut tissue slices from human prostate would provide a unique in vitro model. Precision-cut slices were generated from zones of human prostate and their viability was assessed under conditions of different media for up to 120 h. Slices were also exposed to several concentrations of CdCI2, which was used as a model toxicant. Maintenance of both stromal and epithelial cells was noted; however, there was a gradual loss of luminal epithelial cells when the medium was not supplemented with dihydrotestosterone (DHT). Minimal leakage of lactate dehydrogenase occurred throughout the incubation. Prostate-specific antigen (PSA) was detected in the medium at all time points, although the rates of secretion fell over time. There was a loss of PSA-positive cells when the medium was not supplemented with DHT, consistent with a loss of luminal cells, whereas PSA-positive cells were maintained in the DHT-supplemented media. A proliferation of basal cells was observed in the presence of media containing 10% fetal bovine serum. Exposure of slices to CdCl2 demonstrated a dose-response effect ranging from proliferation to complete cellular necrosis. Given the retention of stromal-epithelial interactions and the use of acquired human tissue, prostate slices represent a unique in vitro model for investigating human prostate pathobiology.

End-of-life decision making in the intensive care unit.

Physicians are increasingly involved in how their critically ill patients die [72]. The more this happens, the more physicians will have to understand not only how their own backgrounds and biases influence their medical management, but also the cultural and religious backgrounds of the patient and surrogate [72, 73]. The medical profession must realise that, despite tremendous advances in medical knowledge and technology, not everyone can be saved all the time, even in the area of intensive care. Physicians must understand that "doing everything" that is best for the patient may not mean starting epinephrine or performing CPR, but rather may imply moving from a process of curing to caring with palliative care [10]. This process should be initiated by discussions with the patient or surrogate, and should include knowledge of the patients' wishes as demonstrated by advance directives and durable power of attorney. The patient's code status and the intention of forgoing life-sustaining treatment should be discussed with other members of staff together with the patient and/or family in a compassionate and humane manner. The wishes of the patient and family should be taken into consideration and the physician must try to make an impartial decision by doing what is medically and ethically correct and best for this specific patient. Hopefully, in this way, a more ethical and compassionate approach to end-of-life decisions in the ICU will be obtained.

Gene mapping in isolated populations: new roles for old friends?

Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from 'New Finland' and 'Old Finland' do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Aland Islands, Finland, and a collection of outbred Centre d'Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.

Evaluation of treatment responses in late Lyme borreliosis on the basis of antibody decrease during the follow-up period.

The purpose of this study was to identify a serological marker of successful treatment as distinct from treatment failure in late Lyme borreliosis. Consecutive serum samples from 68 treated patients with late Lyme borreliosis were analyzed during a 1-2 year follow-up period after the start of treatment. End-point enzyme immunoassay titres of IgG1, IgG2, IgG3, and combined IgG1+3 subclasses against a sonicate antigen of Borrelia burgdorferi were determined and compared to the IgG antibody response against Borrelia burgdorferi flagella. Individual half-lives of the antibody levels were calculated for each patient. The half-life values were compared to the patients' clinical outcome in order to find a serological marker of remaining disease activity or relapse. The levels of combined IgG1+3 subclass antibodies against the sonicate antigen and the individual levels of IgG1, IgG2, and IgG3 antibodies did not change significantly after treatment. In contrast, antibodies to flagella decreased markedly after successful treatment, with a half-life of 112+/-92 days (arithmetic mean value +/- SD). This was significantly shorter than the half-life after unsuccessful treatment (271+/-151 days), (P<0.0001). The decrease was observed mainly in IgG1 and IgG4 responses to flagella, less so for IgG2 or IgG3. The results suggest that a rapid decrease in flagella antibodies can serve as a marker for a successful treatment of Lyme borreliosis.

IgG seroprevalence of Lyme borreliosis in the population of the Aland Islands in Finland.

This is a study of people living in Aland, a group of islands in the Baltic Sea between Finland and Sweden. 500 blood donors and 3,248 health service clients who did not have Lyme borreliosis were examined for Borrelia burgdorferi IgG antibodies. The method used was an ELISA containing a selection of diagnostic antigens to a Borrelia burgdorferi PKo strain. It was found that the distribution according to sex, age and titre values was identical in the 2 groups, which were therefore treated as one. 19.7% of all the sera was positive. The prevalence in men was 23.6%, and in women 16.7%. The prevalence rises with age, the highest prevalence being seen in men (44.7%) and women (37.0%) over 70 y of age. The data show that the Aland islands are strongly endemic for Lyme borreliosis compared with international levels of infection.

International perspectives on ethics in critical care.

Differences in culture, resources, demand, level of development, and cultural and religious differences may alter ethical approaches around the world. The principles of medical ethics are beneficence, nonmaleficence, autonomy, disclosure of information, and social justice. Difficult decisions as to whom to admit and whom to exclude are faced by physicians internationally. Differences between countries are seen in the withdrawal and withholding of treatments and in the obtaining of informed consent in emergency circumstances.

Euthanasia.

This article provides a brief review of the history of euthanasia. The problems involved in withholding or withdrawing treatment, physician-assisted suicide, and arguments for or against euthanasia are discussed. Changes in both societal and physician attitudes and practices are presented.

Treatment of late Lyme borreliosis.

The aim of this study was to develop a treatment for late Lyme borreliosis and to compare the clinical results with serological findings before and after treatment. It was done in the Aland Islands (population 25,000), a region endemic for Lyme borreliosis. The patients were the first consecutive 100 patients from the Aland Islands with late Lyme borreliosis. They were followed for at least 1 year after treatment. The clinical results of treatment were compared with results of analyses of flagellar IgG antibodies to Borrelia burgdorferi done at the time of diagnosis before treatment and up to 12 months afterwards. Short periods of treatment were not generally effective. The outcome was successful in four of 13 treatments with 14 days of intravenous ceftriaxone alone, in 50 of 56 assessable treatments with ceftriaxone followed by 100 days of amoxycillin plus probenecid, and in 19 of 23 completed treatments with ceftriaxone followed by 100 days of cephadroxil. Titres of IgG antibodies to B. burgdorferi flagella declined significantly after 6 and 12 months in the patients who had successful treatments. All patients whose final titres were less than 30% of the initial titre were in the successful group. Their titres usually remained above the upper limit of normal for a long time but a decline to a value of less than 30% of that before treatment was always a sign of cure.

Linkage disequilibrium patterns vary with chromosomal location: a case study from the von Willebrand factor region.

Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughout a population's history. As a result, disequilibrium mapping may be useful in genomic regions of < 1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, we have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotyped for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (rm = -.76; P < .05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres.

Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands.

Patients with von Willebrand disease in four families in the Aland Islands, including the original family that was described in 1926 by the Finnish physician von Willebrand, were screened for mutations in the Swedish "hot-spot" regions (exons 18, 28, 32, 43, and 45) of the von Willebrand factor gene. One cytosine deletion in exon 18 was detected in each of these families. Linkage analysis and genealogical studies suggest that the deletion present in these four families probably has an origin in common with the mutations in the Swedish patients. Apart from the deletion in exon 18, two close transitions (G-->A at S1263 and C-->T at P1266) in exon 28 on the same chromosome were identified in one individual who married into the original family and in his two children. The transitions could be due to a recombination between the von Willebrand factor gene and its pseudogene.

Late Lyme borreliosis: epidemiology, diagnosis and clinical features.

Lyme borreliosis is endemic in the Aland Islands. Exposure of the inhabitants to bites of the tick Ixodes ricinus is heavy. The purpose of this study was to describe symptoms and signs of patients with late Lyme borreliosis in this area, and to correlate the findings with the epidemiological setting. The first 100 consecutive patients with late Lyme borreliosis found in the region since 1984 are included in this study. Neurological, articular and muscular symptoms and signs dominate. General screening for Lyme disease is not recommended in the area due to uncertainty about how to deal with seropositive healthy persons in this heavily exposed population. The recognition and prompt treatment of erythema migrans and other manifestations of primary Lyme borreliosis is important in order to avoid the late stages of the disease. Treatment of all those suffering tick-bites with an antibiotic would be an option in view of the incidence of infected ticks, but cannot be considered because tick-bites are extremely common among the inhabitants. The region would be suitable for general immunization against Borrelia burgdorferi if the means for doing this becomes available in the future.

Assessment of earthquake vulnerability of critical industrial facilities in the Central and Eastern United States

Critical industrial facilities can be defined as those facilities that could, if damaged release substances harmful to the public or to the environment. From a engineering point of view, critical industries facilities require more stringent critica than general use facilities such as office buildings, but shoult not require critica as stringent as that required for nuclear power plants (AU)