Porcine sperm zona binding ability as an indicator of fertility.

The escalated use of artificial insemination in swine has increased the importance of determining fertility of a semen sample before it is used. Multiple laboratory assays have been developed to assess fertilizing potential but they have yielded inconsistent results. This experiment sought to determine the relationship between in vitro competitive zona binding ability and in vivo fertility based on heterospermic inseminations and paternity testing. The zona pellucida binding ability and fertility of sperm from 15 boars was assessed by comparing sperm from one boar with sperm from other individual boars in a pairwise fashion using four ejaculates. The relationship of zona binding ability to the mean number of piglets sired per litter for each boar as well as historic fertility data (litter size and farrowing rate) was assessed. The in vitro competition assay consisted of labeling sperm from each boar of the pair with a different fluorophore and incubating an equal number of sperm from each boar in the same droplet with porcine oocytes. The competitive assay was highly effective in ranking boars by zona binding ability (R2=0.94). Paternity testing using microsatellite markers was used to determine the mean number of piglets sired per litter for each boar during heterospermic inseminations. The pairwise heterospermic insemination assay was effective in ranking boar fertility (R2=0.59). Using historical data from these boars, average litter size and farrowing rate were correlated (r=0.81, p<0.001). However, zona binding ability was not significantly correlated with historic farrowing rate data or historic average litter size. Boar sperm zona binding ability was also not correlated significantly with the mean number of piglets sired per litter following heterospermic insemination. But the number of piglets sired by each boar was related to a combination of zona binding ability, sperm motility, normal morphology, acrosomal integrity, and the presence of distal droplets (R2=0.70). These results suggest that zona binding ability is not an accurate predictor of fertilizing ability when used alone; however, when coupled with other sperm assessments, fertility may be predicted successfully.

The health burden of breast hypertrophy.

Women seeking consultation for the surgical relief of symptoms associated with breast hypertrophy have been the focus of many studies. In contrast, little is known about those women with breast hypertrophy who do not seek symptomatic relief. The purpose of this study was to describe the health burden of breast hypertrophy by using a set of validated questionnaires and to compare women with breast hypertrophy who seek surgical treatment with those who do not. In addition, this latter group was compared with a group of control women without breast hypertrophy. Women seeking consultation for surgery were recruited from 14 plastic-surgery practices. Control subjects were recruited by advertisements in primary-care offices and newspapers. Women were asked to complete a self-report questionnaire that included the European Quality of Life (EuroQol) questionnaire, McGill Pain Questionnaire, Multidimensional Body Self Relations Questionnaire (MBSRQ), the Short Form-36 (SF-36) questionnaire, and questions regarding breast-related symptoms, comorbidities, and bra size. Descriptive statistics were compiled for three groups of women: (1) hypertrophy patients seeking surgical care, (2) hypertrophy control subjects (those whose reported bra-cup size was a D or larger), and (3) normal control subjects (those whose reported bra-cup size was an A, B, or C). The multiple linear regression method was used to compare the health burdens across groups while adjusting for other variables. Two hundred ninety-one women seeking surgical care and 195 control subjects were enrolled in the study. The 184 control subjects with bra-cup information available were further separated into 88 hypertrophy control subjects and 96 normal control subjects. In the control group, bra-cup size was correlated with health-burden measures, whereas in the surgical candidates, it was not. When scores were compared across the three groups, significant differences were found in all health-burden measures. The surgical candidates scored more poorly on the EuroQol utility, McGill pain rating index, MBSRQ appearance evaluation, physical component scale of the SF-36, and on breast symptoms than did the two control groups. In addition, the hypertrophy control subjects scored more poorly than the normal control subjects. With multiple linear regression analysis incorporating important potential confounders, the poorer scores in the surgical candidates remained statistically significant. It was concluded that breast hypertrophy in those seeking surgical care and those not seeking surgery has a significant impact on women's quality of life as measured by validated and widely used self-report instruments including the EuroQol, MBSRQ, McGill Pain Questionnaire, and the SF-36. Likewise, a new assessment instrument for breast-related symptoms also demonstrated greater symptomatology in women with breast hypertrophy.

An Internet-based utility assessment of breast hypertrophy.

The Internet has changed the way people shop, do business, and communicate with one another. Even those who try to avoid computers are bombarded with Web advertisements on television and in newspapers and magazines. The Internet also has excellent, but still largely underused, potential for conducting research studies. A Web-based questionnaire essentially combines the power and graphic flexibility of a computer with the freedom of a mail survey. The specific goals of this study were (1) to develop a Web-based utility assessment tool and (2) to use this tool to measure the health burden of breast hypertrophy by using the Internet to sample a population. An open-enrollment, Internet-based survey was developed to assess societal preferences for mild and severe breast hypertrophy using three established assessment techniques: visual analogue scale, time trade-off, and standard gamble. Subjects were recruited from a Web-based clinical trial listing service. Demographics, subjects' utility for their current health, and responses to a comorbidity index were also recorded. Data were recorded from August 1, 1999, to January 31, 2000. There were 480 unique responses, and 356 (74 percent) met the inclusion criteria. The respondents were predominantly female (81 percent), Caucasian (83 percent), and in the middle income brackets. Their mean age was 32.9. The average score for capacity of understanding was 4.99 out of 5 (5 = excellent). The median utility score for severe breast hypertrophy (visual analogue scale, 0.70; time trade-off, 0.85; standard gamble, 0.88) differed significantly from the median utility score for mild breast hypertrophy (visual analogue scale, 0.93; time trade-off, 1.0; standard gamble, 0.98) for each method. The results showed that the construction of a Web-based questionnaire for utility assessment is feasible and can be used to capture the utility of health states. The authors were able to enroll a large number of subjects with excellent capacity to understand the study, resulting in a high rate of usable responses. The applicability of these data to cost-effectiveness studies is limited by the extent to which the sampled population of this study is representative of society in general. The demographics of this study sample also differed from those of the Internet population. The study was piloted by measuring the values for breast hypertrophy, but the procedure could be used to assess the burden on quality of life of any disease and, potentially, the efficacy of surgical interventions. The study method is recommended as an accurate and cost-effective alternative for measuring quality of life.

Buprenorphine sublingual tablets: effects on IV heroin self-administration by humans.

RATIONALE: Studies have shown that buprenorphine, a partial mu opioid agonist, effectively reduces heroin taking. While previous research with buprenorphine utilized a liquid formulation, a tablet formulation is proposed for clinical use. However, because recent research suggests that the liquid and tablet differ in bio-availability, it is unclear what dose of the buprenorphine tablet effectively antagonizes the reinforcing effects of heroin. OBJECTIVE: The present study was designed to compare the effects of two sublingual doses of buprenorphine maintenance on heroin self-administration. METHODS: Eight heroin-dependent men participated in a 6-week, double-blind, placebo-controlled inpatient study to evaluate the reinforcing effects of intravenous heroin (0, 6.25, 12.5, 25 mg) during maintenance on 8 or 16 mg sublingual buprenorphine. Participants first sampled the available dose of heroin, and then were allowed to respond under a progressive ratio schedule for either heroin or $20. For each heroin dose, one sample session and three choice sessions occurred. Two sessions per day were conducted. A sample session was followed by the first choice session on one day, and the second and third choice sessions occurred on the following day. These sessions were conducted while participants were maintained on daily doses of 8 or 16 mg buprenorphine (3 weeks each). RESULTS: Relative to placebo, 12.5 and 25 mg heroin produced significant increases in break point values under both maintenance dose conditions. The mean break point value for 12.5 mg heroin was significantly lower under 16 mg buprenorphine, compared to 8 mg. CONCLUSIONS: These results demonstrate that the reinforcing effects of heroin were not fully antagonized by these doses of the tablet formulation of buprenorphine, and that 16 mg buprenorphine reduced heroin self-administration relative to 8 mg.

Measuring health state preferences in women with breast hypertrophy.

The purpose of this article is to introduce the measurement of utilities, or patient preferences, to the plastic surgery community. Specifically, the study demonstrated the development and validation of a utility measure for estimating the health-related quality of life in women with breast hypertrophy. Two self-administered instruments were developed, a Wheel and a Table. All subjects completed the utility assessments for their "current health" and again for "breast-related symptoms." The reliability of the instruments was assessed in repeat (test-retest) interviews of 47 women within 10 to 18 days. Utilities obtained with the new instruments were also compared with the performance of other validated utility assessment instruments, including a visual analogue scale, a computer-based instrument (U-Titer), and a preference classification system (EuroQol). Of the 47 women in the test-retest reliability study, 21 had experienced breast hypertrophy (13 had not had reduction surgery and 8 had undergone reduction mammaplasty). Mean utility values for breast-related symptoms among women with breast hypertrophy (n = 13) were: Table, 0.85; Wheel, 0.90; and U-Titer, 0.66. Current health utility scores were significantly lower for women with breast hypertrophy (n = 13), as measured by all instruments except the Wheel. The Table had good reliability and distinguished women with breast hypertrophy from those without. Although the Table provided higher utility values for the same health state compared with the computer-based interview (U-Titer), it is much less costly to implement. The Table is recommended as a reasonable alternative for use in multicenter studies of women with breast hypertrophy. The reported utility value for breast hypertrophy of 0.86 is much lower than predicted. It is comparable with the reported burden of living with other health conditions, such as moderate angina (0.90) and a kidney transplant (0.84).

Reliability of the Lichtman classification of Kienböck's disease.

The purpose of this study was to establish the interobserver reliability and intraobserver reproducibility of the staging of Kienböck's disease according to Lichtman's classification. Posteroanterior and lateral wrist radiographs of 64 patients with a diagnosis of Kienböck's disease and 10 control subjects were reviewed independently by 4 observers on 2 separate occasions. The reviewers included 3 hand fellowship-trained surgeons and 1 orthopedist who was not fellowship-trained in hand surgery. A stage was assigned to each set of radiographs according to the Lichtman classification. Paired comparisons for reliability among the 4 observers showed an average absolute percentage agreement of 74% and an average paired weighted kappa coefficient of 0.71. Furthermore, all the controls were correctly classified as stage I, which is in accordance with the Lichtman system. With regard to reproducibility, observers duplicated their initial readings 79% of the time with an average weighted kappa coefficient of 0.77. These results indicate substantial reliability and reproducibility of the Lichtman classification for Kienböck's disease.

Surgical treatment of early breast cancer: what would surgeons choose for themselves?

CONTEXT: Although breast-conserving surgery (BCS) is less invasive than mastectomy and results in similar survival, many women eligible for BCS continue to undergo mastectomy. Whether the persistent use of mastectomy means that women do not understand their options or reflects an informed preference is unknown. OBJECTIVE: To learn which treatment surgeons would choose when asked to imagine that they themselves had early-stage breast cancer. DESIGN: Cross-sectional survey. SAMPLE: Convenience sample of 40 staff and resident surgeons attending surgical grand rounds at Dartmouth-Hitchcock Medical Center in 1998. MAIN OUTCOME MEASURE: Choice of BCS or mastectomy for the treatment of stage I breast cancer. RESULTS: Twenty-six male and 14 female surgeons participated in the survey. Half chose BCS and half chose mastectomy for treatment of their hypothetical early-stage breast cancer. Results did not differ by the sex of the surgeon. CONCLUSION: Even after being reminded of the equivalent 10-year survival statistics, half of the surgeons surveyed said that they would choose mastectomy over BCS for themselves. The assumption that BCS is the "right" choice for early-stage breast cancer may be unwarranted because many patients may have an informed preference for mastectomy.

Three-dimensional model of the ligand binding domain of the nuclear receptor for 1alpha,25-dihydroxy-vitamin D(3).

A three-dimensional model for residues 142-427 of the ligand binding domain (LBD) of the human nuclear receptor for 1alpha, 25-dihydroxy-vitamin D(3) [VDR] has been generated based on the X-ray crystallographic atomic coordinates of the LBD of the rat alpha1 thyroid receptor (TR). The VDR LBD model is an elongated globular shape comprised of an antiparallel alpha-helical triple sandwich topology, made up of 12 alpha-helical elements linked by short loop structures; collectively these structural features are similar to the characteristic secondary and tertiary structures for six nuclear receptors with known X-ray structures. The model has been used to describe the interaction of the conformationally flexible natural hormone, 1alpha,25-dihydroxy-vitamin D(3) [1alpha, 25(OH)(2)D(3)], and a number of related analogs with the VDR LBD. The optimal orientation of the 1alpha,25(OH)(2)D(3) in the LBD is with its A-ring directed towards the interior and its flexible side chain pointing towards and interacting with helix-12, site of the activation function-2 domain (AF-2) of the VDR. Mapping of four natural and one experimental point mutations of the VDR LBD, which result in ligand-related receptor dysfunction, indicates the close proximity of these amino acids to the bound ligand.

Sensitive and selective liquid chromatographic assay of memantine in plasma with fluorescence detection after pre-column derivatization.

A procedure was developed for the determination of memantine in plasma using liquid chromatography with fluorescence detection. Following a liquid-liquid extraction from 1 ml of plasma containing the internal standard amantadine, the extract was derivatized at room temperature with dansyl chloride, and the highly fluorescent derivatives were chromatographed with a reversed-phase C18 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated memantine and amantadine were eluted in less than 13 min with no interference from endogenous material. The calibration curve was linear over the concentration range of 3-400 ng/ml with inter- and intra-assay imprecision (C.V.) of less than 10%. The limit of quantitation was 3 ng/ml, and no major antidepressant, neuroleptic or their respective metabolites interfered with the quantitation of memantine. This method could also be applied to the quantitation of amantadine.

Comparison of intravenous and intranasal heroin self-administration by morphine-maintained humans.

Eight heroin-dependent individuals, maintained on divided daily doses of oral morphine, participated in a 2.5-week inpatient study comparing the effects of intranasal (IN) (placebo, 12.5, 25, 50, 100 mg) and intravenous (IV) (placebo, 6.25, 12.5, 25, 50 mg) heroin. Each morning, participants received $20 and a sample dose of heroin, and each afternoon they had the opportunity to self-administer all or part of the morning heroin dose or money amount. Participants responded under a modified progressive-ratio schedule (PR 50, 100, 200, 400, 800, 1200, 1600, 2000, 2400, 2800) during a ten-trial self-administration task. During each trial, participants could respond for 1/10th of the heroin dose or 1/10th of the money amount. The total amount of heroin and/or money chosen during the self-administration task was given at the end of the task. Thus, participants received drug and/or money twice each day: once during the morning sample session and once during the afternoon self-administration session. Participants received IV solution and IN powder simultaneously during each dosing; only one route contained active drug. Heroin produced dose-related increases in break point values by both routes of administration. Although IV heroin was approximately four-fold more potent than IN heroin, the maximal break point values for both routes were not significantly different. A similar difference in potency between the IV and IN routes was found for several ratings of subjective effects (e.g., "I feel a good drug effect," "I feel high"), but maximal subjective ratings were lower for IN compared to IV heroin. These results suggest that the reinforcing efficacy of heroin is similar by the two routes of administration, but that IN heroin is less potent than IV heroin. The results also underscore the importance of evaluating drug self-administration in the evaluation of the abuse liability of drugs.

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans.

RATIONALE: Data in laboratory animals suggest that D1 receptor agonists may have potential utility for the treatment of cocaine abuse. OBJECTIVE: The effects of ABT-431, a selective agonist at the dopamine D1 receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. METHOD: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg i.v.) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. RESULTS: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of "High," "Stimulated," dose liking, estimates of dose value, "Quality," and "Potency." Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. CONCLUSIONS: These data suggest that D1 agonists may have potential utility for the treatment of cocaine abuse.

Blockade of cocaine-induced increases in adrenocorticotrophic hormone and cortisol does not attenuate the subjective effects of smoked cocaine in humans.

Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of cocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective effects of smoked cocaine in humans. To examine whether attenuation of HPA function at the pituitary level reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced order under each pre-treatment condition. Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocorticotrophic hormone and cortisol release. Maximal heart rate following cocaine administration was significantly increased by dexamethasone. However, the subjective effects of cocaine were not affected by dexamethasone pre-treatment. These results extend our earlier findings with humans, indicating that the role of the HPA axis in mediating the effects of cocaine is limited. These data are concordant with findings in non-human primates, but contrast with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans.

Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

Flupenthixol treatment for cocaine abusers with schizophrenia: a pilot study.

Cocaine use is common among individuals with schizophrenia and schizoaffective illness, with a prevalence ranging from 15-60% of patient samples. It is hypothesized that some schizophrenic cocaine abusers may use cocaine as an attempt to improve anhedonic symptoms or combat neuroleptic side-effects. Flupenthixol (FLX) has the distinct advantage of being both a neuroleptic medication and a potential treatment for cocaine abuse. We evaluated the efficacy of FLX in this dually diagnosed population in an open pilot study consisting of a 4-week inpatient phase and a 6-week outpatient phase. Eight individuals were initially cross-tapered off their neuroleptic medication and were given FLX in a dose of 40 mg of the decanoate every 2 weeks. Psychiatric symptomatology was assessed weekly, using the Positive and Negative Symptom Scale (PANSS) and the Beck Depression Inventory (BDI). Medication side-effects were monitored weekly, using the Simpson Neurological Rating Scale and the Abnormal Involuntary Movement Scale (AIMS). Substantial improvement in psychiatric symptomatology was noted when preadmission scores were compared to scores obtained during the last week of study enrollment. On the PANSS, positive symptom scores and negative symptom scores decreased by 31% and 29%, respectively. Similarly, BDI scores decreased by 57%. Comparing preadmission urine results to those for the last 6 weeks of enrollment in the study showed that cocaine-positive urines decreased by 28%, although most of the patients had a reduction of >75%. Missed clinic visits decreased by 26%. Thus, FLX was well-tolerated by schizophrenic cocaine abusers, suggesting that FLX may be useful for the treatment of this dually diagnosed population.

Anatomy and histology of the A5 pulley.

Since the anatomy and actual existence of the A5 pulley have been variably reported in the literature, we sought to better define its macroscopic and microscopic structure. Thirty-one A5 pulleys were dissected from 32 fingers. The average proximal to distal length was 3.8 mm; the average width was 8.9 mm. The distal edge of the pulley was proximal to the distal interphalangeal joint, 7.7 mm from the profundus tendon insertion. On histologic study by light microscopy, 3 distinct layers were noted; fibrofatty tissue was noted in the outermost layer, hyaluronic acid-secreting cells were noted in the innermost layer, and connective tissue containing collagen bundles, fibrocytes, and interspersed elastin fibers was noted in the middle layer. The A5 pulley is a discrete structure, with measurements as noted as well as a histologic composition consistent with that reported for the other annular pulleys.

Effects of an alternative reinforcer on intravenous heroin self-administration by humans.

Five heroin-dependent research volunteers, maintained on divided daily oral morphine doses, participated in an inpatient study designed to evaluate intravenous (i.v.) heroin self-administration when money ($10, $20 or $40) was concurrently available. Each morning participants received a single injection of heroin (placebo, 6.25, 12.5, 25, or 50 mg/70 kg, i.v.) and each afternoon, they had the opportunity to self-administer all or part of the morning dose. Participants responded under a progressive-ratio schedule (50, 100, ..., 2800) during a 10-trial self-administration task. During each trial, participants could respond for 1/10th of the sampled heroin dose or 1/10th of a single money value. The progressive-ratio value increased independently for each option. The total amount of heroin and/or money chosen during the self-administration task was administered at the end of the task. Heroin dose-dependently increased ratings of 'good drug effect' and 'high', impaired task performance and decreased pupil diameter and blood oxygen saturation. Heroin also dose-dependently increased progressive-ratio break point values, which varied as a function of the alternative money amount. Consistent with previous studies, the present results demonstrate that alternative reinforcers, depending on magnitude, are effective in reducing heroin use in opioid-dependent individuals.