Clinical report from the pilot USA Kernicterus Registry (1992 to 2004).

To identify antecedent clinical and health services events in infants (>/=35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants >/=35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels >20 mg per 100 ml (342 micromol l(-1); range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age 0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age 35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infant's care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.

Anti-inflammatory activity of parthenolide-depleted Feverfew (Tanacetum parthenium).

Extracts of Tanacetum parthenium (L.) Sch. Bip., a plant known under the common name "Feverfew", contains the sesquiterpene lactone parthenolide, a potent skin sensitizer. To eliminate the risk of skin sensitization from Feverfew, we developed a parthenolide-depleted extract of Feverfew (PD-Feverfew) and determined its effectiveness as an anti-inflammatory agent. We confirmed that PD-Feverfew was sufficiently depleted of parthenolide since PD-Feverfew did not inhibit TNF-alpha induced-NF-kappaB activity unlike parthenolide containing whole Feverfew. PD-Feverfew directly inhibited the activity of pro-inflammatory enzymes 5-lipoxygenase, phosphodiesterase-3 and phosphodiesterase-4. PD-Feverfew inhibited the release of pro-inflammatory mediators nitric oxide, PGE(2) and TNF-alpha from macrophages and TNF-alpha, IL-2, IFN-gamma and IL-4 from human peripheral blood mononuclear cells. Additionally, PD-Feverfew inhibited TPA-induced release of PGE(2) from human skin equivalents. In vivo, PD-Feverfew inhibited oxazolone-induced dermatitis, and was more potent than whole Feverfew in reducing TPA-induced dermatitis. Finally the efficacy of PD-Feverfew was confirmed clinically by a reduction in erythema in a methyl nicotinate-induced vasodilation model. In conclusion, our results indicate that PD-Feverfew extracts have potent anti-inflammatory activity suggesting that this botanical would be efficacious in relieving inflammation without inducing immune sensitization.

Efficacy of BAL5788, a prodrug of cephalosporin BAL9141, in a mouse model of acute pneumococcal pneumonia.

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.

An in vitro oral biofilm model for comparing the efficacy of antimicrobial mouthrinses.

The ability of commercial mouthrinses to reduce total viable counts of mixed microbial populations was examined using a previously developed in vitro model of supragingival plaque. Exploratory experiments aimed at fine-tuning the model indicated that optimal correspondence between in vitro and clinical results for chlorhexidine-containing formulations were obtained at a saliva:medium ratio of 70:30 (v/v); moreover, expanding the microbial population from 5 bacterial species to 5 bacterial species + Candida albicans had no noticeable impact on overall results. The efficacies of 12 different mouthrinse proprietary products containing chlorhexidine, hexetidine, octenidine, Triclosan, plant extracts, or aminefluoride/stannous fluoride vis-à-vis biofilm clearance were compared. All mouthrinses promoted a statistically significant reduction in microbial load compared to distilled water. The herbal- and phenolic-based products were substantially less effective than most chlorhexidine-containing mouthrinses, or mouthrinses containing hexetidine or octenidine. No significant difference between the plaque-clearing plaque-clearing abilities of Listerine and Meridol was observed. This polyspecies biofilm model can be a valuable tool for preclinical testing of antiplaque formulations, particularly during the product development stage.

Discovery of 4-[(Z)-(4-bromophenyl)- (ethoxyimino)methyl]-1'-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4'-methyl-1,4'- bipiperidine N-oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection.

Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K(i) = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.

An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.

The protease-activated receptor 2, expressed on keratinocytes but not on melanocytes, has been ascribed functional importance in the regulation of pigmentation by phagocytosis of melanosomes. Inhibition of protease-activated receptor 2 activation by synthetic serine protease inhibitors requires keratinocyte-melanocyte contact and results in depigmentation of the dark skinned Yucatan swine, suggesting a new class of depigmenting mechanism and agents. We therefore examined natural agents that could exert their effect via the protease-activated receptor 2 pathway. Here we show that soymilk and the soybean-derived serine protease inhibitors soybean trypsin inhibitor and Bowman-Birk inhibitor inhibit protease-activated receptor 2 cleavage, affect cytoskeletal and cell surface organization, and reduce keratinocyte phagocytosis. The depigmenting activity of these agents and their capability to prevent ultraviolet-induced pigmentation are demonstrated both in vitro and in vivo. These results imply that inhibition of the protease-activated receptor 2 pathway by soymilk may be used as a natural alternative to skin lightening.

Enhancing self-belief with EMDR: developing a sense of mastery in the early phase of treatment.

Deep inside each of us is a seed that holds our vision of truth, peace, and happiness. Our early childhood attachments, societal influences, and innate capacity determine how well that seed is nurtured and the deepest inner vision is set free. This article is about the ways that vision becomes clouded by attachment deficits, trauma, and subsequent symptoms. The deep inner wish to heal allows for transformation, and approaches like Eye Movement Desensitization and Reprocessing, and hypnotherapy can assist in creating a more rapid acceleration of trauma resolution and transformation of self.

Stress management in medical education: a review of the literature.

PURPOSE: To review systematically clinical studies providing empirical data on stress-management programs in medical training. METHOD: The authors searched Medline and PSYCHINFO from 1966 to 1999. Studies were included if they evaluated stress-management programs for medical trainees (medical students, interns, or residents); reported empirical data; and had been conducted at allopathic medical schools. RESULTS: Although the search yielded over 600 articles discussing the importance of addressing the stress of medical education, only 24 studies reported intervention programs, and only six of those used rigorous scientific method. Results revealed that medical trainees participating in stress-management programs demonstrated (1) improved immunologic functioning, (2) decreases in depression and anxiety, (3) increased spirituality and empathy, (4) enhanced knowledge of alternative therapies for future referrals, (5) improved knowledge of the effects of stress, (6) greater use of positive coping skills, and (7) the ability to resolve role conflicts. Despite these promising results, the studies had many limitations. CONCLUSION: The following considerations should be incorporated into future research: (1) rigorous study design, including randomization and control (comparison) groups, (2) measurement of moderator variables to determine which intervention works best for whom, (3) specificity of outcome measures, and (4) follow-up assessment, including effectiveness of future patient care.

Intentional systemic mindfulness: an integrative model for self-regulation and health.

Self-regulation is the process whereby systems maintain stability of functioning and adaptability to change. Self-regulation is based on feedback loops which can be enhanced through attention. All self-regulation techniques, therefore, involve the cultivation of attention. However, the intention with which attention is directed may be crucial. In this paper, we explore intentional systemic mindfulness a model that explicitly introduces intention into self-regulation theory and practice. Intention as defined by this model is composed of the context of attention-systemic perspectives - and the quality of attention - mindfulness qualities. Intentional systemic mindfulness addresses both "why" (systemic perspectives) and "how" (mindfulness qualities) one directs attention, which may promote healing on multiple levels. Directions for research and implications for multiple levels of integrative health are considered.

Multivitamin supplementation and risk of birth defects.

It is widely accepted that supplementation with folic acid, a B vitamin, reduces the risk of neural tube defects (NTDs). This case-control study tested the hypothesis that multivitamins reduce risks of selected birth defects other than NTDs. Infants with and without birth defects and aborted fetuses with birth defects were ascertained in the greater metropolitan areas of Boston, Philadelphia, and Toronto during 1993-1996. Mothers were interviewed within 6 months after delivery about a variety of factors, including details on vitamin use. Eight case groups were included: cleft lip with or without cleft palate, cleft palate only, conotruncal defects, ventricular septal defects, urinary tract defects, limb reduction defects, congenital hydrocephaly, and pyloric stenosis (n's ranged from 31 to 186). Controls were 521 infants without birth defects (nonmalformed controls) and 442 infants with defects other than those of the cases (malformed controls). Daily multivitamin supplementation was evaluated according to gestational timing categories, including periconceptional use (28 days before through 28 days after the last menstrual period). Odds ratios (ORs) below 1.0 were observed for all case groups except cardiac defects, regardless of control type. For periconceptional use, ORs with 95% confidence intervals that excluded 1.0 were estimated for limb reduction defects using both nonmalformed controls (OR = 0.3) and malformed controls (OR = 0.2) and for urinary tract defects using both nonmalformed controls (OR = 0.6) and malformed controls (OR = 0.5). Statistically significant ORs for use that began after the periconceptional period were observed for cleft palate only and urinary tract defects. These data support the hypothesis that periconceptional vitamin supplementation may extend benefits beyond a reduction in NTD risk. However, other than folic acid's protecting against NTDs, it is not clear what nutrient or combination of nutrients might affect risk of other specific defects.

Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects.

BACKGROUND: Platelets are integral to cardiac vegetations that evolve in infectious endocarditis. It has been postulated that the antiplatelet aggregation effect of aspirin (ASA) might diminish vegetation evolution and embolic rates. METHODS AND RESULTS: Rabbits with Staphylococcus aureus endocarditis were given either no ASA (controls) or ASA at 4, 8, or 12 mg. kg-1. d-1 IV for 3 days beginning 1 day after infection. Vegetation weights and serial echocardiographic vegetation size, vegetation and kidney bacterial densities, and extent of renal embolization were evaluated. In addition, the effect of ASA on early S aureus adherence to sterile vegetations was assessed. In vitro, bacterial adherence to platelets, fibrin matrices, or fibrin-platelet matrices was quantified with either platelets exposed to ASA or S aureus preexposed to salicylic acid (SAL). ASA at 8 mg. kg-1. d-1 (but not at 4 or 12 mg. kg-1. d-1) was associated with substantial decreases in vegetation weight (P<0.05), echocardiographic vegetation growth (P<0.001), vegetation (P<0.05) and renal bacterial densities and renal embolic lesions (P<0.05) versus controls. Diminished aggregation resulted when platelets were preexposed to ASA or when S aureus was preexposed to SAL (P<0.05). S aureus adherence to sterile vegetations (P<0.05) or to platelets in suspension (P<0.05), fibrin matrices (P<0.05), or fibrin-platelet matrices (P<0.05) was significantly reduced when bacteria were preexposed to SAL. CONCLUSIONS: ASA reduces several principal indicators of severity and metastatic events in experimental S aureus endocarditis. These benefits involve ASA effects on both the platelet and the microbe.

The construct of control in mind-body medicine: implications for healthcare.

Research suggests that one of the principal reasons patients are attracted to alternative medicine is that they find many of these therapies more congruent with their philosophical orientation toward health. Many mind-body approaches, which are some of the most frequently used classifications of complementary and alternative therapies, grow out of research demonstrating the important role of psychological factors in treating and preventing illness. This article reviews research on one such factor--control--and its importance in health. Studies demonstrating the following are highlighted: (1) illness frequently results in feelings of loss of control; (2) gaining a sense of control can help patients to cope with illness; (3) whereas control may influence physiological function and health outcomes, the amount of active control we can exercise over physical functioning and health is limited; and (4) it is important to match control strategies to patient control styles and preferences. The implications of mind-body studies are also discussed.

Effects of mindfulness-based stress reduction on medical and premedical students.

The inability to cope successfully with the enormous stress of medical education may lead to a cascade of consequences at both a personal and professional level. The present study examined the short-term effects of an 8-week meditation-based stress reduction intervention on premedical and medical students using a well-controlled statistical design. Findings indicate that participation in the intervention can effectively (1) reduce self-reported state and trait anxiety, (2) reduce reports of overall psychological distress including depression, (3) increase scores on overall empathy levels, and (4) increase scores on a measure of spiritual experiences assessed at termination of intervention. These results (5) replicated in the wait-list control group, (6) held across different experiments, and (7) were observed during the exam period. Future research should address potential long-term effects of mindfulness training for medical and premedical students.

Do trans fatty acids increase the risk of coronary artery disease? A critique of the epidemiologic evidence.

On the basis of metabolic and epidemiologic data it has been claimed that trans fatty acid intake causes coronary artery disease (CAD), with > or = 30,000 deaths/y in the United States and a considerably greater number of nonfatal cases. The metabolic evidence is still controversial; the epidemiologic evidence is reviewed here. In most studies the likelihood that CAD "caused" margarine use, rather than the reverse, was not excluded. Uncontrolled confounding (particularly confounding by indication) was ubiquitous. Selection bias conditional on margarine use was common. The projection of 30,000 deaths/y is not justified. If the metabolic evidence, when fully evaluated, is deemed to be suggestive, then the question of whether trans fatty acids are indeed harmful to human populations will be resolved only by means of a randomized controlled trial.

Coffee consumption and myocardial infarction in women.

Whether coffee consumption increases the risk of coronary heart disease has not yet been established. In a case-control study of nonfatal myocardial infarction among Massachusetts women aged 45-69 years in 1986-1990, 858 cases with first infarctions were compared with 858 community controls matched on age and town precinct. Detailed information on coffee drinking, cigarette smoking, and other factors was obtained by telephone interview. Relative risks (as estimated by odds ratios) and their 95% confidence intervals were computed from multiple logistic regression analyses that controlled for smoking and other risk factors. The risk of myocardial infarction increased with increasing number of cups per day among both drinkers of any type of coffee and drinkers of caffeine-containing coffee only: tests for trend, p = 0.002 and p = 0.0004, respectively. For consumption of caffeine-containing coffee alone, the relative risk estimates for 5-6 cups, 7-9 cups, and 10 or more cups per day relative to less than 1 cup per day were 1.4 (95% confidence interval (CI) 0.8-2.5), 2.1 (95% CI 0.9-4.9), and 2.5 (95% CI 1.0-6.5), respectively. No increase was observed for fewer than 5 cups per day. The positive association with heavy coffee drinking was present among nonsmokers as well as smokers. These findings and other recent studies suggest that heavy coffee consumption increases the risk of myocardial infarction.

The antimicrobial activity of essential oils and essential oil components towards oral bacteria.

A method for reproducibly determining minimal inhibitory concentrations and minimal bactericidal concentrations of plant extracts towards fastidiously and facultatively anaerobic oral bacteria, predicated upon measurements of optical densities in microtitre plate wells, was devised. The antimicrobial properties of some botanical oils were surveyed; of these, Australian tea tree oil, peppermint oil, and sage oil proved to be the most potent essential oils, whereas thymol and eugenol were potent essential oil components.

Periconceptional folic acid exposure and risk of occurrent neural tube defects.

OBJECTIVES: A recent controlled trial has established that use of a 4-mg folic acid supplement before and during early pregnancy reduces the risk of recurrent neural tube defects (NTDs) by 72%. The present study was designed to determine whether folic acid also reduces the risk of first (occurrent) NTDs. DESIGN: Case-control study. SETTING: Tertiary and birth hospitals in metropolitan areas of Boston, Mass, Philadelphia, Pa, and Toronto, Ontario. PARTICIPANTS: Mothers of 436 occurrent cases with NTDs and mothers of 2615 controls with other major malformations. MAIN OUTCOME MEASURES: The prevalence of use of multivitamins containing folic acid was compared between mothers of cases and controls. RESULTS: The mothers of 17% of cases and 3% of controls reported knowledge of the folic acid-NTD hypothesis and were excluded from further analysis. For daily use of a multivitamins containing folic acid in the periconceptional period (28 days before through 28 days after the last menstrual period), the relative risk (RR) (and 95% confidence interval) was 0.4 (0.2 to 0.6). The most commonly used dose of folic acid was 0.4 mg, and the RR estimate was 0.3 (95% confidence interval, 0.1 to 0.6). For dietary folate, there was a dose-related decline in risk according to the quintile of intake (P for trend = .02). CONCLUSION: These findings suggest that daily periconceptional intake of 0.4 mg of folic acid (the dose most commonly contained in over-the-counter multivitamin preparations) reduces the risk of occurrent NTDs by approximately 60%. A relatively high dietary intake of folate may also reduce the risk.

Relative effects of feeding saturated fats and cholesterol on fluidity of rabbit lipoproteins.

1. The effects of saturated fat and cholesterol on lipoprotein fluidity were tested in New Zealand white rabbits fed diets containing corn oil (CO) or cocoa butter (CB) with and without added 0.2% cholesterol. 2. Saturated fats had little effect on fluidity in any lipoprotein fraction. 3. Cholesterol feeding dramatically reduced fluidity in VLDL and LDL, but minimal change was noted in HDL. 4. Cholesterol-fed rabbits were hypercholesteroloemic throughout the 10-month study. 5. The rabbits became adapted to cholesterol feeding as VLDL became more fluid with time.