Predicted genetic burden and frequency of phenotype-associated variants in the horse.

Disease-causing variants have been identified for less than 20% of suspected equine genetic diseases. Whole genome sequencing (WGS) allows rapid identification of rare disease causal variants. However, interpreting the clinical variant consequence is confounded by the number of predicted deleterious variants that healthy individuals carry (predicted genetic burden). Estimation of the predicted genetic burden and baseline frequencies of known deleterious or phenotype associated variants within and across the major horse breeds have not been performed. We used WGS of 605 horses across 48 breeds to identify 32,818,945 variants, demonstrate a high predicted genetic burden (median 730 variants/horse, interquartile range: 613-829), show breed differences in predicted genetic burden across 12 target breeds, and estimate the high frequencies of some previously reported disease variants. This large-scale variant catalog for a major and highly athletic domestic animal species will enhance its ability to serve as a model for human phenotypes and improves our ability to discover the bases for important equine phenotypes.

Clownfish in hypoxic anemones replenish host O2 at only localised scales.

The clownfish-anemone association exemplifies a symbiosis where both members benefit from nutrient exchange and protection from predators. Clownfish also perform aeration-like behaviour in their host anemones at night, but it is not yet known whether this is stimulated by the onset of hypoxia, and whether both members benefit from O2 replenishment. Oxygen at 3 distances above the sea anemone Entacmaea quadricolor (0.2, 1.2 and 2.2 cm) therefore was measured under 3 light levels (photon flux density = 0, 55 and 110 µmol m-2 s-1), with and without the anemonefish Amphiprion frenatus. Hypoxia (O2 < 50% air saturation) was recorded in the anemone, but only at 0.2 cm away from the anemone surface under dark conditions when A. frenatus was absent. This localised layer of hypoxia was eliminated by the presence of A. frenatus exhibiting aeration-like behaviour. Respirometry revealed that A. frenatus is extremely hypoxia tolerant (S crit = 14.3% at 25 °C), suggesting that aeration behaviour does not provide a major metabolic advantage to clownfish because they do not breathe water at 0.2 cm and are not metabolically constrained by O2 at distances ≥ 1.2 cm. That the aeration behaviour of A. frenatus facilitates only the metabolism of its O2-conforming host reveals a unique aspect of this symbiotic relationship.

Perceptual boundedness and perceptual support in conceptual development.

A theoretical framework for describing the role of perceptual information in early conceptual development is presented. In the main section of the article, a general operationalization of perceptual boundedness is introduced, 3 causes of this limitation are identified, the conditions under which infants and children seem to be perceptually bound are formulated, and the mechanisms by which this limitation declines are described. Traditional claims that young children are perceptually bound, as well as contemporary objections to these claims, are often based on the assumption that perceptual information is generally unveridical or insufficient. Recent doubts about this assumption are evaluated in the final section of the article. It is concluded that although realist arguments are untenable, there are limited forms of perceptual support for conceptual development.

Welfare state and infant mortality.

This article seeks to understand the effects of welfare-state spending on infant mortality rates. Infant mortality was chosen for its importance as a social indicator and its putative sensitivity to state action over a short time span. Country fixed-effects models are used to determine that public health spending does have a significant impact in lowering infant mortality rates, net of other factors, such as economic development, and that this effect is cumulative over a five-year time span. A net effect of health spending is also found, even when controlling for the level of spending in the year after which the outcome is measured (to account for spurious effects or reverse causation). State spending effects infant mortality both through social mechanisms and through medical ones. This article also shows that the impact of state spending may vary by the institutional structure of the welfare state. Finally, this study tests for structural breaks in the relationship between health spending and infant mortality and finds none over this time period.

The social geography of AIDS and hepatitis risk: qualitative approaches for assessing local differences in sterile-syringe access among injection drug users.

While significant gains have been achieved in understanding and reducing AIDS and hepatitis risks among injection drug users (IDUs), it is necessary to move beyond individual-level characteristics to gain a fuller understanding of the impact of social context on risk. In this study, 6 qualitative methods were used in combination with more traditional epidemiologic survey approaches and laboratory bioassay procedures to examine neighborhood differences in access to sterile syringes among IDUs in 3 northeastern cities. These methods consisted of (1) neighborhood-based IDU focus groups to construct social maps of local equipment acquisition and drug use sites; (2) ethnographic descriptions of target neighborhoods; (3) IDU diary keeping on drug use and injection equipment acquisition; (4) ethnographic day visits with IDUs in natural settings; (5) interviews with IDUs about syringe acquisition and collection of syringes for laboratory analysis; and (6) focused field observation and processual interviewing during drug injection. Preliminary findings from each of these methods are reported to illustrate the methods' value in elucidating the impact of local and regional social factors on sterile syringe access.

Accumulation of macrophages with dendritic cell characteristics in the pulmonary response to Listeria.

Pulmonary immunity reflects a balance between proinflammatory and immunosuppressive factors in the lung. To determine the immune activities of exudate macrophages in the pulmonary immune response, Lewis rats were injected intratracheally with heat-killed Listeria (HKL), labeled ex vivo with the lipophilic dye PKH-26. At 24 h, macrophages from bronchoalveolar lavage fluid were purified on the basis of their surface membrane expression of RMA, a macrophage-specific antigen, which is brightly expressed by resident alveolar macrophages but dimly expressed by monocytes. Pulmonary macrophages were analyzed for uptake of PKH-26-HKL, and RMA(bright/dim) macrophages sorted by FACS were compared for cytokine expression, nitric oxide (NO) release, and APC activities. RMA(bright) macrophages were OX-62(-), B7(-), and factor XIIIa(-); they were the dominant mediators of phagocytosis when low doses of HKL were administered intratracheally but did not support the proliferation of T lymphocytes. RMA(dim) exudate macrophages were OX-62(+), B7(+), and factor XIIIa(+). They expressed more IL-1 and TNF, but less nitric oxide, than did RMA(bright) macrophages; they were excellent APCs for T cell responses. We conclude that a subset of RMA(dim) exudate macrophages shows phenotypic and functional evidence of dendritic cell differentiation.

Syringe disposal options for injection drug users: a community-based perspective.

This study was a qualitative exploration of syringe disposal interventions for injection drug users (IDUs). Data were collected through in-depth interviews with 26 community members who injected drugs and 32 noninjecting community members in Atlanta, Georgia. Both groups supported syringe exchange programs as syringe disposal interventions, while noninjecting community members favored a one-way drop box. IDUs identified fear of arrest for possession of syringes as the most salient barrier to safe syringe disposal, revealing the negative consequences of drug paraphernalia laws.

Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR.

Binding of virus particles to specific host cell surface receptors is known to be an obligatory step in infection even though the molecular basis for these interactions is not well characterized. The crystal structure of the adenovirus fiber knob domain in complex with domain I of its human cellular receptor, coxsackie and adenovirus receptor (CAR), is presented here. Surface-exposed loops on knob contact one face of CAR, forming a high-affinity complex. Topology mismatches between interacting surfaces create interfacial solvent-filled cavities and channels that may be targets for antiviral drug therapy. The structure identifies key determinants of binding specificity, which may suggest ways to modify the tropism of adenovirus-based gene therapy vectors.

Glutathione S-transferase mu and theta polymorphisms and breast cancer susceptibility.

BACKGROUND: The enzymes encoded by the glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism (mainly inactivation, but activation is possible) of a wide range of carcinogens that are ubiquitous in the environment; the enzyme encoded by the GSTT1 gene may also be active in endogenous mutagenic processes. Homozygous deletions of the GSTM1 and GSTT1 genes are commonly found in the population and result in a lack of enzyme activity. This study was undertaken to evaluate the association between GSTM1 and GSTT1 gene polymorphisms and breast cancer risk. METHODS: Our study included 466 women with incident cases of breast cancer occurring from May 1989 through May 1994 and 466 matched control subjects. These individuals were part of a prospective cohort of U.S. women (i.e., the Nurses' Health Study). Odds ratios (ORs) and 95% confidence intervals (CIs) from conditional logistic regression models were used to estimate the association between genetic polymorphisms and breast cancer risk. RESULTS: The GSTM1 and GSTT1 null genotypes were not associated with an increased risk of breast cancer (OR = 1.05 [95% CI = 0.80-1.37] for GSTM1 null; OR = 0. 86 [95% CI = 0.61-1.21] for GSTT1 null). On the contrary, a suggestion of a decreased risk of breast cancer associated with the GSTT1 null genotype was observed among premenopausal women. When considered together, no combination of the GSTM1 and GSTT1 genotypes was associated with an increased risk of breast cancer. The relationship between GSTM1 and GSTT1 gene deletions and breast cancer risk was not substantially modified by cigarette smoking. CONCLUSIONS: Our data provide evidence against a substantially increased risk of breast cancer associated with GSTM1 and/or GSTT1 homozygous gene deletions.

Pulmonary immunity to Listeria is enhanced by elimination of alveolar macrophages.

To determine how resident alveolar macrophages (AM) regulate the antigen-presenting-cell (APC) activities of pulmonary dendritic cells (DC) in the response to particulate antigen, we pretreated Lewis rats intratracheally with liposomes containing clodronate (LIP-CLOD), which eliminated AM in vivo. Controls received saline encapsulated in liposomes (LIP-SAL) or saline alone intratracheally. At Day 3, rats were injected intratracheally with 1 x 10(7) heat-killed Listeria (HKL) and DC purified from lung were examined for their ability to stimulate HKL-immune T cells without added HKL. Only DC from LIP-CLOD-treated rats displayed enhanced APC activities for HKL. A second intratracheal HKL challenge at Day 14 yielded lymphocytic cuffing of the microvasculature in LIP-CLOD-treated lungs only. Intratracheal adoptive transfer of normal syngeneic AM into LIP-CLOD-treated rats suppressed APC activities of DC in vitro and the lymphocytic response in vivo. Bronchoalveolar macrophages from rats treated with LIP-CLOD and HKL showed decreased production of nitric oxide (NO), a potent suppressor of DC and T-helper 1 lymphocyte activities as compared with those of controls. We conclude that eliminating AM in vivo reduces local production of NO and promotes pulmonary cell-mediated immunity to HKL.

Providing mifepristone-misoprostol medical abortion: the view from the clinic.

In order to gather information about the practical aspects of offering medical abortion, we conducted focus group discussions at each of 17 sites participating in the first large-scale, multi-center trial of mifepristone-misoprostol abortion in the United States. The sites were chosen to represent diverse practice settings (Planned Parenthood affiliates, university research clinics, private practices, and feminist health centers) and geographical regions. Seventy-seven clinic staff members (including counselors, administrators, physicians and other health workers) participated. They discussed the impact of adding a medical method to their clinic structure, their own preferences about offering the method, and their perceptions of women's preferences. Staffing a medical abortion service requires different skills and temperament than those needed for a surgical service. Nearly all participants were eager to begin offering the medical method, and they perceived a strong demand for it on the part of women. They had mixed feelings about the type of provider who should offer the method, but nearly all felt that the regimen could be greatly simplified from the three-visit regimen tested in the trial.

Coxsackievirus and adenovirus receptor amino-terminal immunoglobulin V-related domain binds adenovirus type 2 and fiber knob from adenovirus type 12.

The extracellular region of the coxsackievirus and adenovirus receptor (CAR) is predicted to consist of two immunoglobulin (Ig)-related structural domains. We expressed the isolated CAR amino-terminal domain (D1) and a CAR fragment containing both extracellular Ig domains (D1/D2) in Escherichia coli. Both D1 and D1/D2 formed complexes in vitro with the recombinant knob domain of adenovirus type 12 (Ad12) fiber, and D1 inhibited adenovirus type 2 (Ad2) infection of HeLa cells. These results indicate that the adenovirus-binding activity of CAR is localized in the amino-terminal IgV-related domain and confirm our earlier observation that Ad2 and Ad12 bind to the same cellular receptor. Preliminary crystallization studies suggest that complexes of Ad12 knob bound to D1 will be suitable for structure determination.

Abortion, revised: participants in the U.S. clinical trials evaluate mifepristone.

This paper centers on the questions: How do non-surgical abortion methods affect private experiences of abortions? How might they influence public conceptions of abortion? Drawing on interviews with clients who participated in the 1994-95 U.S. clinical trials of mifepristone at one trial site (conducted during the trials), and focus group interviews conducted with health care workers at all 17 trial sites (after the trials were completed), we examine participants' evaluations of this method of abortion. Surgical abortion functioned as the reference point by which research participants assessed medical abortion. They discussed mifepristone abortion in terms of nature and invasion, privacy and bodily integrity, denial and agency. Clients frequently portrayed mifepristone abortion as a better moral choice than surgical abortion--in some cases even depicting it as not-really-an-abortion but rather as a miscarriage. Clients felt that mifepristone offered them a greater measure of control over their abortion experiences. Health care providers offered critical analysis of their clients' perceptions, yet affirmed the potential of medical abortion to offer women greater variety and latitude in procreative decision-making, and perhaps even to depoliticize the issue of abortion in the U.S. by thwarting the efforts of anti-abortionists to target providers and aborting women.

Community-based programs for safe disposal of used needles and syringes.

OBJECTIVES: To review issues related to discarded syringes in the community and to describe community-based programs for the safe disposal of used needles and syringes. METHODS: We used the medical literature and chain referral to identify community-based syringe disposal programs other than syringe exchange programs (SEPs). We held a workshop in June 1996 involving staff from disposal programs; manufacturers of syringes, sharps containers, and other disposal devices; solid waste companies; public health staff; and researchers. RESULTS: Fifteen programs for the safe disposal of syringes were identified in the United States, Canada, and Australia. Of these, 12 primarily served persons with diabetes who use insulin, and 3 primarily served injection drug users (IDUs). The programs used three major strategies: puncture-resistant containers discarded in trash, community drop boxes, and sharps containers turned in for biohazard disposal at community sites, hospitals, or pharmacies. Participants in the workshop described key points in developing syringe disposal programs. Programs should involve pharmacists, physicians, waste disposal companies, public health departments, hospitals, diabetes educators, persons with diabetes who use insulin, and IDUs. For IDUs, criminal penalties for possession of syringes are a substantial deterrent to participation in community efforts to safely dispose of used syringes. The multiple and sometimes conflicting local, state, and federal laws and regulations concerning medical waste hinder development of multistate or national approaches to the safe disposal of syringes. More information is needed on community-based syringe disposal programs. CONCLUSION: Communities in the United States, Canada, and Australia have developed different approaches to achieve safe disposal of used syringes.

Biomechanical evaluation of lateral patellar dislocations.

This investigation was undertaken to identify the structures torn within the medial retinaculum and localize the injury site anatomically following acute lateral dislocation of the patella in a cadaver model. The patellae of 10 fresh-frozen cadavers were translated laterally 135% of the patella width on a universal testing instrument. Magnetic resonance imaging (MRI) was performed on all specimens prior to testing and immediately following testing. Anatomical dissection also was performed on the medial retinaculum following testing. Dissection revealed avulsion fractures from the inferomedial border of the patella in 8 of the 10 knees. The medial patellofemoral ligament was injured in 8 of the 10 knees; the location of the injury varied. Tears of the medial patellofemoral ligament from the femur in 6, a midsubstance tear in 1, and stretch in 1 knee were noted. In a knee with a femoral-sided tear, an avulsion fracture of the medial patellofemoral ligament was identified. None of the cadaver knees demonstrated tears of the lateral retinaculum or medial patellotibial ligaments on dissection. Review of the MRIs revealed a medial retinaculum tear in 6 of the 10 knees. Two tears from the femur, 3 from the patella, and 1 tear from both the patella and femur were noted. An avulsion fracture was noted from the inferomedial patellar border in 3 of the 10 knees. No pathology was noted on 4 of the MRIs. When anatomically correlated, the 3 patellar retinacular tears and 3 avulsion fractures noted on MRI represented a tear of the medial patellomeniscal ligament from the patella. The femoral-sided tear represented a tear of the medial patellofemoral ligament from the femur. An appreciation of the spectrum of injury to the medial retinaculum may aid in the diagnosis of an acute dislocation of the patella and help establish the anatomical structures damaged. The pathology demonstrated in this study may explain the diversity of injury seen clinically. Whereas an avulsion fracture from the patella may represent the medial patellomeniscal ligament, a femoral-sided retinacular tear may represent the medial patellofemoral ligament. This may lead to future refinements of surgical options and anatomic restoration of the damaged structure.

Glutathione S-transferase class mu deletion polymorphism and breast cancer: results from prevalent versus incident cases.

A common deletion polymorphism in the gene coding for the glutathione S-transferase class mu (the GSTM1 gene) results in a decreased ability to detoxify carcinogenic epoxide intermediates and has been associated with increased breast cancer risk in some small studies. We studied the GSTM1 gene deletion polymorphism (conferring the null genotype) in 243 women who had prevalent breast cancer and 245 women without breast cancer, who were among the 32,826 women in the Nurses' Health Study who gave a blood sample in 1989-1990. In the prevalent case series, the null genotype was slightly more common among cases (58%) than among controls (51%; age-adjusted odds ratio = 1.30; 95% confidence interval, 0.91-1.86). Among cases, the prevalence of the GSTM1 deletion increased with duration of survival [68% for > or = 8 years since diagnosis; 57% for 4-8 years; 51% for < 4 years; P (trend) = 0.04]. In an incident case series of 240 women who were diagnosed with breast cancer following blood collection and prior to June of 1992 and compared with age-matched controls, the GSTM1 deletion was not associated with an elevation in risk (relative risk, 1.08; 95% confidence interval, 0.74-1.57). No significant interaction with cigarette smoking was evident. Thus, there was no significant increase in risk of incident breast cancer associated with the GSTM1 null genotype; however, the gene deletion polymorphism appeared to confer improved survival. These data suggest that odds ratios based upon prevalent cases in molecular epidemiologic studies may be biased due to differential survival. Further studies are required to determine whether this polymorphism is associated with improved breast cancer prognosis.

Buffered lidocaine decreases the pain of digital anesthesia in the foot.

The pain associated with injections for inducing digital anesthesia can be decreased by adding sodium bicarbonate to plain lidocaine. A randomized, double-blind study has demonstrated that 24 out of 30 participants indicated on a visual analogue scale that buffered lidocaine is less painful than plain lidocaine. The pain decreased by 50% or more for almost half of the participants. Practitioners can easily buffer lidocaine in the office by adding a small volume of sodium bicarbonate to plain lidocaine.

Concomitant syndactyly and polydactyly in a pediatric foot.

Syndactyly and polydactyly in a child may warrant surgical treatment to avert resultant emotional and psychologic problems. The authors present a unique case report of a bilateral polydactyly of the hallux and bilateral syndactyly of the second and third toes in a normal 6-year-old Hispanic female. The article will discuss the surgical management of these problems, using the skin harvested from resection of the extra hallux for the adjacent side of the lesser toes after desyndactyly.

Validation of reflectance pulse oximetry: an evaluation of a new sensor in piglets.

OBJECTIVE: A new reflectance pulse oximetry sensor, developed for intrapartum estimation of arterial oxygen saturation (SaO2), was calibrated and evaluated. The sensor contains two light emitting diodes of 735 and 890 nm, and a photodetector at a distance of 14 mm from both light emitting diodes. METHODS: In seven Yorkshire/Hampshire piglets, the reflectance sensor (Nellcor Puritan Bennett Inc.) was calibrated using blood sample SaO2 values. The resulting calibration line was evaluated in four Dutch piglets, by comparing pulse oximetry saturation readings (SpO2) with blood sample and intravascular fiberoptic oximetry SaO2 values. Several reflectance sensors were fixed on each animal. Desaturation levels were obtained by changing the gas mixture of oxygen/ nitrous oxide via a tracheal catheter. RESULTS: In the Yorkshire/ Hampshire piglets, the standard deviation of difference (SpO2-SaO2) was 4.7% (n = 364), over an SaO2 range of 17% to 100%. In the Dutch piglets, the mean difference (SpO2-SaO2) was -1.6% and the standard deviation of difference was 5.4%, over the same SaO2 range (n = 254). Comparisons of continuous recordings of reflectance SpO2 and fiberoptic SaO2 revealed variation in individual regression lines. CONCLUSIONS: This new 735/890 nm reflectance sensor demonstrates acceptable accuracy in piglets. A further evaluation during labor should assess its feasibility for fetal surveillance.