Cognitive function in post-treatment Lyme disease: do additional antibiotics help?

BACKGROUND: It is controversial whether additional antibiotic treatment will improve cognitive function in patients with post-treatment chronic Lyme disease (PTCLD). OBJECTIVE: To determine whether antibiotic therapy improves cognitive function in two randomized double-blind placebo-controlled studies of patients with PTCLD. METHODS: A total of 129 patients with a physician-documented history of Lyme disease from three study sites in the northeast United States were studied. Seventy-eight were seropositive for IgG antibodies against Borrelia burgdorferi, and 51 were seronegative. Patients in each group were randomly assigned to receive IV ceftriaxone 2 g daily for 30 days followed by oral doxycycline 200 mg daily for 60 days or matching IV and oral placebos. Assessments were made at 90 and 180 days after treatment. Symptom severity was measured from the cognitive functioning, pain, and role functioning scales of the Medical Outcomes Study (MOS). Memory, attention, and executive functioning were assessed using objective tests. Mood was assessed using the Beck Depression Inventory and Minnesota Multiphasic Personality Inventory. RESULTS: There were no significant baseline differences between seropositive and seronegative groups. Both groups reported a high frequency of MOS symptoms, depression, and somatic complaints but had normal baseline neuropsychological test scores. The combined groups showed significant decreases in MOS symptoms, higher objective test scores, and improved mood between baseline and 90 days. However, there were no significant differences between those receiving antibiotics and placebo. CONCLUSION: Patients with post-treatment chronic Lyme disease who have symptoms but show no evidence of persisting Borrelia infection do not show objective evidence of cognitive impairment. Additional antibiotic therapy was not more beneficial than administering placebo.

Assessment of adherence with medications in human immunodeficiency virus-infected children.

The purpose of this study was to determine the reliability of screening for medication adherence in HIV-infected children. The results suggest that caregivers who are unable to describe the medication regimen or who are nonadherent with appointments are unlikely to adhere to the medication regimen. Adherence with at least 90% of medication doses was associated with a virologic response.

Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.

BACKGROUND: It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease. METHODS: We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study. RESULTS: After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients. CONCLUSIONS: There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

Bax accelerates tumorigenesis in p53-deficient mice.

Bax is a Bcl-2 family member that promotes apoptosis and counters the protective effect of Bcl-2. Bax is a downstream effector of p53-induced apoptosis and is transcriptionally regulated by p53. Moreover, the introduction of Bax deficiency accelerates the onset of tumors in transgenic mice expressing truncated large T antigen. These results implicate Bax as a tumor suppressor. Consequently, we asked whether the levels of Bax expression would influence tumor development by comparing Bax-deficient and Bax transgenic mice in the presence or absence of p53. We found that Bax-deficient mice did not display an increased incidence of spontaneous cancers when followed for > 1.5 years. In addition, Bax-deficiency did not further accelerate oncogenesis in mice also deficient in p53. We generated Lck(pr)-Bax transgenic mice to examine the effects of overexpressed BAX on T-cell development and tumorigenesis. Lck(pr)-Bax mice show increased apoptosis consistent with the pro-apoptotic function of Bax. The introduction of p53-deficiency did not interfere with BAX-induced apoptosis; this is consistent with BAX operating downstream or independent of p53. However, we found that Lck(pr)-Bax/p53-deficient mice have an increased incidence of T-cell lymphomas when compared with p53-deficient mice. The Lck(pr)-Bax transgenic mice have an increased percentage of cells in cycle. These findings extend previous work suggesting that Bcl-2 family proteins regulate proliferation as well as cell death. We conclude that BAX-induced proliferation is synergistic with a defect in apoptosis contributed by p53-deficiency. Thus, the dual roles of BAX can either accelerate or inhibit tumorigenesis depending on the genetic context.

Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1.

BACKGROUND: Combination therapy including protease inhibitors has been shown to be effective in treating adults infected with human immunodeficiency virus type 1 (HIV-1), but there are only limited data regarding the treatment of children and adolescents. METHODS: A cohort of 1028 HIV-1-infected children and adolescents, from birth through 20 years of age, who were enrolled in research clinics in the United States before 1996 was followed prospectively through 1999. We used proportional-hazards regression models to estimate the effect on mortality of combination therapy including protease inhibitors. RESULTS: Seven percent of the subjects were receiving combination therapy including protease inhibitors in 1996; by 1999, 73 percent were receiving such therapy. In univariate analyses, a higher base-line percentage of lymphocytes that were CD4-positive, a higher weight for age, a higher height for age, black race, Hispanic ethnic background, younger age, and perinatally acquired infection were associated with a longer median time to the initiation of this type of therapy (P<0.001). After adjustment for covariates, the differences among racial and ethnic groups in the time to initiation were not statistically significant. Mortality declined from 5.3 percent in 1996 to 2.1 percent in 1997, 0.9 percent in 1998, and 0.7 percent in 1999 (P for trend <0.001). There were reductions in mortality in all subgroups defined according to age, sex, percentage of CD4+ lymphocytes, educational level of the parent or guardian, and race or ethnic background. In adjusted analyses, the initiation of combination therapy including protease inhibitors was independently associated with reduced mortality (hazard ratio for death, 0.33; 95 percent confidence interval, 0.19 to 0.58; P<0.001). CONCLUSIONS: The use of combination therapy including protease inhibitors has markedly reduced mortality among children and adolescents infected with HIV-1.

Developmental antecedents of sexual coercion in juvenile sexual offenders.

Previous research has linked adult sex offending behavior to a multiplicity of variables, including juvenile delinquency and the experience of childhood abuse. The purpose of this study was to explore developmental pathways among childhood abuse, juvenile delinquency, and personality dimensions possibly conducive to adolescent sexual coercion. Using a retrospective self-report inventory, we measured the extent to which juvenile sexual offenders experienced childhood trauma, engaged in adolescent delinquency, and exhibited particular dispositions and cognitive biases. The effects of childhood and adolescent antecedents on sexual coerciveness were then analyzed through simultaneous multiple regression path analyses. Results suggest that sexual compulsivity and hypermasculinity, through misogynistic fantasy behavior, significantly discriminate verbally and physically coercive juvenile offenders from those offenders who do not report using force in their offenses. Results also suggest that alcohol abuse may play a more salient role in the expression of coercive juvenile sexual coercion than previously hypothesized.

The fine connective tissue architecture of the human ligamentum nuchae.

STUDY DESIGN: An anatomic study of the posterior midline structures of the cervical spine was performed using a new sheet-plastination (E12) technique in conjunction with gross anatomic dissection. OBJECTIVES: To clarify the structural status of the human ligamentum nuchae. SUMMARY OF BACKGROUND DATA: Little is known about the arrangement of connective tissue attachments of the neighboring neck muscles to the ligamentum nuchae. In addition, it is not clear whether the cervical supraspinous ligaments form part of the ligamentum nuchae. METHODS: This study used a combined approach of a detailed gross anatomic study on eight cadavers and a macroscopic and microscopic study of the connective tissue organization of the posterior midline structures on serial horizontal thin (2.5 mm) plastinated slices of the cervical spine (occiput-T1) from an adult female cadaver. RESULTS: The dorsal and ventral portions of the ligamentum nuchae are a single entity formed by the aponeurotic fibers of the trapezius, splenius capitis, rhomboideus minor, and serratus posterior superior muscles. CONCLUSIONS: The regional differences in the connective tissue organization of the ligamentum nuchae and its well-defined attachments to the C6 and C7 vertebrae suggest that it is designed to function in the lower cervical spine.

Flavobacterium meningosepticum sepsis in an infant with a diarrheal prodrome.

A full term, previously normal 2 1/2-month-old black boy was transferred to our hospital from an outlying facility on hospital day 5 for failure to thrive. Three weeks before transfer, the infant was hospitalized for a diarrheal illness with fever. The baby received 3 days of ceftriaxone empirically and was discharged home after the sepsis evaluation was negative. Mild diarrhea and steady weight loss continued and the baby was readmitted. Blood culture done on admission grew Flavobacterium meningosepticum, an organism previously described as an uncommon cause of sepsis in neonates and immunocompromised individuals. As it is water-borne, it has been associated with infection via contaminated water. This organism is usually resistant to antibiotics commonly used for empiric treatment. To our knowledge, this is the first reported case of Flavobacterium bacteremia associated with a prodromal and concurrent diarrheal illness.

A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team.

OBJECTIVE: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 300 assessed the clinical efficacy and safety of combination zidovudine/lamivudine (ZDV/3TC) compared with either didanosine (ddI) alone or combination ZDV/ddI. STUDY DESIGN: Children with symptomatic human immunodeficiency virus (HIV) infection, 6 weeks through 15 years of age, were stratified according to age and randomly assigned to receive ddI, ZDV/3TC, or ZDV/ddI. The primary endpoint was time to first progression of HIV disease or death. Enrollment in the ZDV/ddI arm stopped after 11 months on the basis of results of PACTG Protocol 152, but blinded follow-up continued. RESULTS: For the 471 children who could be evaluated, the median age was 2.7 years, median CD4 cell count was 699 cells/mm3, and median log10 HIV RNA was 5.1/mL. Median follow-up was 9.4 months. Patients receiving ZDV/3TC had a lower risk of HIV disease progression or death than those receiving ddI alone (15 vs 38 failures, P = .0006) and a lower risk of death (3 vs 15 deaths, P = .0039). Weight and height growth rates, CD4+ cell counts, and RNA concentrations showed results favoring ZDV/3TC. For patients concurrently randomized to all 3 treatment arms, both ZDV/3TC and ZDV/ddI recipients had lower risk of HIV disease progression than those who received ddI alone (P = .0026 and P = .0045). CONCLUSIONS: Combination therapy with either ZDV/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI.

The correlation between surface measurement of head and neck posture and the anatomic position of the upper cervical vertebrae.

STUDY DESIGN: Repeated measurements were made of surface postural angles registering the relative positions of the head and neck in photographs and of angles of the upper cervical vertebrae recorded in lateral cephalometric radiographs in the same subjects. For all registrations, subjects assumed the natural head rest position. OBJECTIVES: To examine the correlation between external measurement of head and neck posture and the anatomic positions of the upper four cervical vertebrae. SUMMARY OF BACKGROUND DATA: Interpretation of surface cervical posture measurement is confounded by lack of knowledge about the extent of the underlying compensatory adjustments among the upper cervical vertebrae that may accompany variation in head and neck posture. The correlation between surface measurement and postural characteristics of the upper cervical spine has not been reported to date. METHODS: The association between a set of angles describing the anatomic position of the four upper cervical vertebrae on lateral cephalometric radiographs and a surface measurement of head and neck posture, the craniovertebral angle, was studied in 34 young adult women aged between 17.2 and 30.5 years, mean age, 24.5 years. Anatomic positions of the upper four cervical vertebrae were expressed by angles relative to the true vertical or horizontal. Surface angles registering head and neck position for each subject were obtained from photographs recorded on two occasions. RESULTS: No strong correlation could be established between the angles taken from the lateral cephalometric radiographs measuring the extent of upper cervical lordosis, orientation of the atlas, vertebral inclination, or odontoid process tilt and surface angles recording head and neck position. This finding was attributed principally to the much greater positional variability demonstrated within the upper cervical spine when compared with the surface measurements of head and neck position. CONCLUSION: Anatomic alignment of the upper cervical vertebrae cannot be inferred from variation in surface measurement of head and neck posture. This is the case even in those people identified with more extreme head and neck postural tendencies.

Heterobifunctional cross-linkers containing 4,9-dioxa-1,12-dodecanediamine spacers.

A series of heterobifunctional linker arms has been prepared by functionalization of (tert-butoxycarbonyl)-4,9-dioxa-1,12-dodecanediamine [tBOC-HN(CH2)3 O(CH2)4 O(CH2)3 NH2] with anhydrides or acid chloride.

Chromogenic lactate-leukocyte esterase substrates.

The first successful reported use of lactate-based chromogenic, colorimetric substrates for a serine protease-based enzyme is described. A series of hydroxy-protected 5-phenyl-3-hydroxypyrrolyl L-lactate substrates of the general formula RO-Lac-OPP were prepared and formulated into reagents for the determination of leukocytes in dry phase formats.

Effect of nitrogen dioxide and other combustion products on asthmatic subjects in a home-like environment.

Nitrogen dioxide (NO2) is one of a number of nitrogen compounds that are by-products of combustion and occur in domestic environments following the use of gas or other fuels for heating and cooking. In this study, we examined the effect of two levels of NO2 on symptoms, lung function and airway hyperresponsiveness (AHR) in asthmatic adults and children. In addition, in the same subjects, we examined the effects of the same levels of NO2 mixed with combustion by-products from a gas space heater. The subjects were nine adults, aged 19-65 yrs, and 11 children, aged 7-15 yrs, with diagnosed asthma which was severe enough to require daily medication. All subjects had demonstrable AHR to histamine. Exposures were for 1 h on five separate occasions, 1 week apart, to: 1) ambient air, drawn from outside the building; 2) 0.3 parts per million (ppm) NO2 in ambient air; 3) 0.6 ppm NO2 in ambient air; 4) ambient air+combustion by-products+NO2 to give a total of 0.3 ppm; and 5) ambient air+combustion by-products+NO2 to give a total of 0.6 ppm. Effects were measured as changes in lung function and symptoms during and 1 h after exposure, in AHR 1 h and 1 week after exposure, and in lung function and symptoms during the week following exposure. Exposure to NO2 either in ambient air or mixed with combustion by-products from a gas heater, had no significant effect on symptoms or lung function in adults or in children. There was a small, but statistically significant, increase in AHR after exposure to 0.6 ppm NO2 in ambient air. However, there was no effect of 0.6 ppm NO2 on AHR when the combustion by-products were included in the test atmosphere nor of 0.3 ppm NO2 under either exposure condition. We conclude that a 1 h exposure to 0.3 or 0.6 ppm NO2 has no clinically important effect on the airways of asthmatic adults or children, but that 0.6 ppm may cause a slight increase in airway hyperresponsiveness.

Vaccination update. Hib, hepatitis, polio, varicella, influenza, pneumococcal and meningococcal disease.

Immunization of infants and children is the most effective strategy for decreasing the incidence of some infectious diseases. Most invasive disease due to Haemophilus influenzae type b occurs before age 5 years, and routine vaccination of infants for hepatitis B is currently recommended because selective immunization of high-risk persons has not been feasible. Decades of use of poliovirus vaccine has effectively eliminated cases of wild-virus infection, although some vaccine-related cases still occur. The newly approved varicella vaccine appears to be a cost-effective way to decrease infection rates in children. Improved immunization rates for influenza and pneumococcal and meningococcal diseases could help decrease excess mortality in elderly persons and those with chronic illness.

Vaccination update. Diphtheria, tetanus, pertussis, mumps, rubella, measles.

Despite the availability of many effective vaccines, some vaccine-preventable diseases still cause significant morbidity and mortality. Increased prevention should be attainable through proper education about the efficacy and safety of vaccines, improved immunization rates, and adherence to recommended vaccination guidelines from the Advisory Committee on Immunization Practices. Childhood immunization should include a complete diphtheria, tetanus, and pertussis series and a measles, mumps, and rubella series. Booster doses for tetanus should be given every 10 years throughout life.