Surgical Management of Stuttering Ischemic Priapism: A Case Report and Concise Clinical Review.

Stuttering priapism is an extremely rare and poorly understood entity. We present a rare case of a 47-year-old Afro-Caribbean gentleman who required proximal shunt procedure to treat his ischemic stuttering priapism after he had failed medical management. We provided a concise review of the literature on the surgical management of ischemic priapism. This case highlighted the importance of prompt surgical intervention in prolonged stuttering priapism to avoid serious psychological and functional complications.

Profiles of gonadal gene expression in the developing bovine embryo.

Our current understanding of the molecular basis of sex determination and gonadal development in humans is mostly an extrapolation of knowledge gained from studies in the mouse. However, the timing of gene expression in the mouse is unusual among mammals, and it is therefore important that data from other models are also available to help elucidate this pivotal process in human development. Here we describe the sequence of molecular and morphological events marking testis differentiation in bovine embryos. The genital ridges first appeared at CRL 12 (day 32). SRY expression began at CRL 18 (day 37) and peaked at CRL 20 (day 39), leading to a cascade of regulatory, signaling, and steroidogenic gene expression at later stages, detected by quantitative real-time RT-PCR and immunohistochemistry. Testis cords were distinguishable at CRL 27 (day 42). We conclude that the timing of gene expression observed in developing human embryos is much more similar to bovine development than it is to the mouse. Therefore, Bos taurus may represent a useful model in which to study gene expression during sex determination, relevant to human development.

Predicting surgically remedial primary aldosteronism: role of adrenal scanning, posture testing, and adrenal vein sampling.

Distinguishing surgically remedial forms from other causes of primary aldosteronism (PA) may be difficult, and it is made more challenging by the earlier detection of milder disease. The technical demands of bilateral adrenal vein sampling (AVS)-increasingly advocated for localizing a unilateral autonomous lesion (UAL)- and lack of agreed criteria for establishing unilateral autonomy, add further to the diagnostic challenge. This retrospective review of 49 hypokalemic patients with unequivocal PA (41 with surgically proven and remedial UAL, eight patients with bilateral adrenal hyperplasia) analyzes the value of computerized tomography adrenal scanning (n = 32), 4 h erect posture testing (n = 42), and AVS (n = 27) in predicting and lateralizing a surgically remedial lesion. A fall in plasma aldosterone during 4 h erect posture (positive test) occurred in 63% of patients with UAL and in none with bilateral adrenal hyperplasia. A positive posture test or computerized tomography adrenal scan (single focal macroadenoma) both had high positive predictive value (100% and 89% respectively), but low sensitivity for diagnosis of UAL. AVS, undertaken during low dose ACTH stimulation, localized the UAL in all cases (positive predictive value 100%) where the aldosterone/cortisol ratio of blood drawn from the uninvolved gland was less than that of peripheral blood (contralateral ratio <1). Biochemical severity, reflected by overnight supine plasma aldosterone, was strongly correlated with the degree of contralateral gland suppression (n = 16, r = 0.79, P < 0.001). Importantly, the AVS findings show that when bilateral access is not possible, UAL can be successfully lateralized when only one adrenal vein (the contralateral) is accessed, or the ipsilateral vein is sampled in subjects whose posture test was positive. In this series of patients with overt (hypokalemic) PA, preoperative testing successfully identified a surgically remedial lesion in 39 of 41 cases. Confirmation of the recommended diagnostic approach must now await larger prospective studies.

Subchronic Exposure of [3H]- 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female B6C3F1 mice: relationship of steady-state levels to disposition and metabolism.

The present study of subchronic low exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at or near steady-state levels tries to emulate the most probable mode for human exposure, dietary consumption. This study is the first and most intensive pharmacokinetic study to be reported with repeated dosing, multiple times, and multiple doses examining disposition of TCDD-derived radioactivity and CYP1A activities in mice. For time-course relationships, animals were dosed (daily, Monday-Friday) with 0, 1.5, or 150 ng [3H]TCDD/kg for 4, 8, 13, or 17 weeks and also for 13 weeks followed by 4 weeks with no dosing. For dose-response relationships, animals were dosed for 13 weeks (daily, Monday-Friday) with 0, 0.15, 0.45, 1.5, 4.5, 15, 45, 150, or 450 ng [3H]TCDD/kg. Additional animals dosed for 13 weeks (daily, Monday-Friday) with 1.5 or 150 ng [(3)H]TCDD/kg were housed in metabolism cages. Time- and dose-dependencies of TCDD were confirmed in all measured tissues. Liver/fat (L/F) concentration ratios ranged from 0.2-3.4 (low to high dose). Hepatic CYP1A1 enzymatic activity increased (p < 0.05) starting at 0.15 ng/kg/day with L/F of 0.2 and body burden of 2.8 ng TCDD/kg body weight. By examining TCDD exposures at or near steady state, this study reports for the first time and provides direct evidence of low-dose effects on a measured reversible response at body burdens that are within background levels of the general human population. In addition, this study emphasizes cumulative effects of daily dosing and suggests the importance of tissue dosimetry or body burden for a persistent chemical such as TCDD.

Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants, are ubiquitous environmental contaminants. PBDEs act as endocrine disruptors via alterations in thyroid hormone homeostasis. We examined thyroid hormone concentrations and hepatic enzyme activity in weanling rats exposed to three commercial PBDE mixtures: DE-71, DE-79, and DE-83R. Female Long-Evans rats, 28 days old, were orally administered various doses of DE-71, DE-79, or DE-83R for 4 days. Serum and liver samples were collected 24 h after the last dose and analyzed for serum total thyroxine (T(4)), triiodothyronine (T(3)), thyroid-stimulating hormone (TSH), hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD), and uridinediphosphate-glucuronosyltransferase (UDPGT) activities. The PBDE-treated groups did not exhibit significant changes in body weight; however, increased liver weights, as well as 10- to 20-fold induction in EROD and 30- to 40-fold induction in PROD were found in the DE-71-- and DE-79--treated animals. DE-71 and DE-79 caused dose-dependent depletion of T(4), accompanied by up to 3- to 4-fold induction in UDPGT activities. Serum total T(4) was decreased a maximum of 80% for DE-71 and 70% for DE-79 in the highest dose, with benchmark doses (BMDs) of approximately 12.74 mg/kg/day for DE-71 and 9.25 mg/kg/day for DE-79. Dose-related effects in serum T(3) levels were less apparent, with maximal reductions of 25-30% at the highest dose for both DE-71 and DE-79. The two mixtures showed no effect on serum TSH levels. Benchmark dose analysis revealed that the two mixtures were comparable in altering thyroid hormone levels and hepatic enzyme activity. DE-83R was not effective in altering any of the measured parameters. The present study suggests that short-term exposure to some commercial PBDE mixtures interferes with the thyroid hormone system via upregulation of UDPGTS:

Dose-response relationships for induction of CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin in female mice following subchronic exposure to polychlorinated biphenyls.

The Toxic Equivalency Factor (TEF) method is used to estimate potential health risks associated with exposure to dioxin-like chemicals. The TEF method is a relative potency (REP) scheme that assumes dose additivity, that the chemicals produce the same response through the same mechanism, and that the REP of a chemical is equivalent for all responses. The present study estimates the REP for five PCBs with dioxin-like activity. Mice were exposed to either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,3',4, 4'-pentachlorobiphenyl (105), 2,3',4,4',5-pentachlorobiphenyl (118), 3,3',4,4',5-pentachlorobiphenyl (126), or 2,3,3',4,4'-, 5-hexachlorobiphenyl (156), five days/week for 13 weeks by oral gavage in a corn oil vehicle. Three days after the last dose, animals were euthanized and the ethoxyresorufin-O-deethylase activity was determined in liver, lung, and skin. Acetanilide-4-hydroxylase activity was determined in liver. In addition, liver and skin disposition of the chemicals were determined. REPs were estimated using a statistical method previously described (DeVito et al., Toxicol. Appl. Pharmacol.147, 267-280, 1997). For any given compound, the REP generally varied by less than a factor of four across endpoints when calculated based on an administered dose. However, typically there was one response for every chemical in which the REP was different by an order of magnitude or more from the other responses. There was some evidence that the REPs may be dose-dependent. While, in general, these data support the use of a single point estimate of the REP, the issue of dose-dependency requires targeted investigation.

A pharmacodynamic analysis of TCDD-induced cytochrome P450 gene expression in multiple tissues: dose- and time-dependent effects.

The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) to alter gene expression and the demonstration that the induction of CYP1A2 is responsible for hepatic TCDD sequestration suggest that both pharmacokinetic and pharmacodynamic events must be incorporated for a quantitative description of TCDD disposition. In this paper, a biologically based pharmacodynamic (BBPD) model for TCDD-induced biochemical responses in multiple tissues was developed. The parameters responsible for tissue response were estimated simultaneously with a refined physiologically based pharmacokinetic (PBPK) model developed by Wang et al. (1997a), by using the time-dependent effects of TCDD on induced CYP1A1/CYP1A2 gene expression in multiple target tissues (liver, lungs, kidneys, and skin) of female Sprague-Dawley rats treated with 10 microgram TCDD/kg for 30 min, 1, 3, 8, or 24 h, or 7, 14, or 35 days. This refined BBPD model developed based on the time-course of TCDD-induced CYP1A1/CYP1A2 protein expression, and associated enzymatic activities well described the dose-dependent effects of TCDD on cytochrome P450 protein expression and associated enzyme activities in the multiple tissues of female Sprague-Dawley rats at 3 days following a single exposure to TCDD (0.01-30.0 micromgram TCDD/kg). This is the first BBPD model to quantitatively describe the time- and dose-dependent effects of TCDD on induced CYP1A1/CYP1A2 protein expression and associated enzyme activities in multiple target tissues for TCDD-induced biochemical responses.

Dose-response relationships for disposition and hepatic sequestration of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice.

Humans are exposed to mixtures of polyhalogenated dibenzo-p-dioxins, dibenzofurans, and biphenyls mainly through the diet. Many of these chemicals are dioxin-like and their relative toxicity is related to their ability to bind and activate the Ah receptor. The present study examines the structure-activity relationship for disposition of these chemicals in female B6C3F1 mice following subchronic exposures. Mice were treated 5 days/week for 13 weeks by oral gavage with different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD),2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), octachlorodibenzofuran (OCDF), 3,3',4,4',5-pentachlorobiphenyl (126), 3,3',4,4',5,5'-hexachlorobiphenyl (169), 2,3,3',4,4'-pentachlorobiphenyl (105), 2,3',4,4',5-pentachlorobiphenyl (118), and 2,3,3',4,4',5-hexachlorobiphenyl (156). All of the chemicals examined exhibited dose-dependent increases in the liver/fat concentrations except PCBs 105, 118, and 156. While TCDD is the most potent toxicant in this class of chemicals, 4-PeCDF, PeCDD, OCDF, TCDF, and PCB126 were sequestered in hepatic tissue to a greater extent than was TCDD. The high affinity for hepatic tissue supports the presence of an inducible hepatic binding protein for some dixin-like chemicals. The differences in disposition between these chemicals suggests that pharmacokinetic differences between congeners is important in the relative potency of these chemicals.

Methoxyresorufin: an inappropriate substrate for CYP1A2 in the mouse.

Hepatic microsomes derived from Cypla2(-/-) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin-O-demethylase (MROD, 25.5+/-6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64+/-0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin-O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse.

Differential time-course and dose-response relationships of TCDD-induced CYP1B1, CYP1A1, and CYP1A2 proteins in rats.

This study examined the relationship between dose- and time-dependent hepatic localization of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and expression of CYP1B1, CYP1A1 and CYP1A2 proteins. A dose-dependent increase in hepatic TCDD in female Sprague-Dawley rats treated with 0.01-30.0 microg TCDD/kg was observed. TCDD induced CYP1A1 protein in rats treated with 0.3 microg TCDD/kg or higher. TCDD induced CYP1A2 and CYP1B1 proteins in rats treated with 1.0 microg TCDD/kg or higher. The in vivo ED50 (microg TCDD/kg) for TCDD-induced CYP1A1, CYP1A2 and CYP1B1 proteins were 0.22, 0.40 and 5.19, respectively. Hepatic accumulation of TCDD reached a maximum at 8 hours post dosing with a t1/2 of approximately 10 days. TCDD-induced CYP1A1/CYP1A2 protein expression was increased time-dependently, reaching a maximum at 3 days after dosing and remaining elevated for 35 days. In contrast, TCDD-induced CYP1B1 protein showed significant expression at 3 days after dosing and decreased to basal concentrations by 35 days. This study demonstrates that TCDD exhibits differential dose-response and time-course relationships on hepatic localization and cytochrome P-450 protein expression.

Restorative certainty and varying perceptions of dental caries depth among dentists.

OBJECTIVE: The question of whether dentists who most frequently identify tooth surfaces for definite restoration perceive dental caries as significantly deeper than other dentists is assessed. METHODS: One group of 20 dentists independently examined 145 unrestored approximal tooth surfaces on 16 bitewing radiographs and recorded their restorative and depth decisions. Another group of 15 dentists similarly scored 304 unrestored surfaces on 30 bitewing radiographs. Each group of dentists was later divided into four subgroups according to the number of surfaces designated for definite restoration by each dentist. RESULTS: As the number of tooth surfaces designated for definite restoration increased, mean caries depth (P < .05 for the high vs low subgroups) and the percent of dentinally carious surfaces increased, while the percent of surfaces assessed as sound decreased. Dentists with the lower numbers of surfaces designated for definite restoration came closest to the true histologic mean caries depth of the examined tooth surfaces. CONCLUSIONS: Dentists who designated high numbers of approximal tooth surfaces for definite restoration assessed caries as deeper than other dentists, and deeper than was proven histologically.

Dose-response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I. CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin.

The dose-response relationships for induction of liver, lung, and skin ethoxyresorufin-O-deethylase (EROD) activity and liver acetanilide-4-hydroxylase (ACOH) activity following subchronic exposure to either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,7,8-tetrabromodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), or octachlorodibenzofuran (OCDF) were determined in female B6C3F1 mice in order to estimate the relative enzyme inducing potency of these chemicals in three different tissues. The relative potencies were calculated based on tissue concentrations as well as administered dose. A dose-dependent induction of EROD activity in liver, lung, and skin and of ACOH activity in liver was found for all seven chemicals. When based on administered dose, the relative potencies for specific congeners did not vary substantially among tissues. The relative potencies for TCDF and 1-PeCDF, congeners which have much shorter half-lives than TCDD, increased for all enzymes when estimated from tissue concentrations. The relative potency of OCDF, which is poorly absorbed, was greater when estimated from tissue concentrations than when estimated from administered dose. 4-PeCDF is highly sequestered in hepatic tissue and when the relative potency was estimated based on tissue concentration, its potency for skin enzyme induction increased. These data indicate that the relative potency of these chemicals is influenced not only by the relative binding affinity to the Ah receptor, but also by differences in pharmacokinetic properties of these chemicals. In addition, it may be useful to derive two sets of toxic equivalency factor values, one used for estimating intake equivalents and the other for estimating tissue equivalents.

Interactive effects between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl in female B6C3F1 mice: tissue distribution and tissue-specific enzyme induction.

The distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was studied in female B6C3F1 mice. Single doses of TCDD alone (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg), PCB 153 alone (0, 3.58, 35.8, or 358 mg [14C]PCB 153/kg), and all possible combinations of these doses were administered in corn oil, po. At 7 days after dosing, 11 different tissues were analyzed for radioactivity. When TCDD was administered alone, TCDD-derived radioactivity distributed to all tissues in a dose-dependent manner, increasing with dose in the liver, while decreasing (as a percentage of the administered dose) in all other tissues. When PCB 153 was administered alone, the PCB 153 concentration was dose-dependently (percentage of dose) decreased in liver, skin, lung, adrenals, kidney, and blood; no dosimetric effects were observed in the other organs. Coadministration of low doses of both TCDD and PCB 153 resulted in little or no effect on the distribution of either compound. Interactive effects occurred in the pharmacokinetic behavior of both compounds only at higher doses. For example, the amount of TCDD in the liver was increased by 358 mg PCB 153/kg. In most other organs administration of PCB 153 resulted in a dose-dependent decrease in the TCDD content. Coadministration of PCB 153 with 10 micrograms TCDD/kg increased PCB 153 in the liver, but not in other tissues. These results clearly demonstrate that interactive effects on pharmacokinetic behavior occur only at high doses.

Chronic compartment syndrome.

Chronic compartment syndrome (CCS) is a possible explanation of leg pain in the exercising patient. This review article provides background information on CCS, focusing on its most frequent site of occurrence, i.e., the lower leg. Clinical history, diagnosis, compartmental tissue pressure measurement, conservative therapy, surgical intervention, postoperative nursing care and rehabilitation are discussed.

Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls derived from hepatic porphyrin accumulation in mice.

Hepatic porphyrin accumulation was studied after subchronic dosing of female B6C3F1 mice by gavage with single congeners of polychlorinated or polybrominated dibenzo-p-dioxins (PCDDs, PBDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Quantitative hepatic porphyrin profile analyses in selected samples showed uroporphyrin and heptacarboxylporphyrin as the main porphyrins detected. Dose-dependent increases in total hepatic porphyrins were found for all congeners tested. At lower dose levels, relative potencies, based on administered dose as well as target tissue dose, of PCDDs, PCDFs, and coplanar PCBs, using 2,3,7,8-tetrachlorodibenzo-p-dioxin as a reference compound, were in the same range as those previously derived from the induction of hepatic CYP1A1 and CYP1A2 enzyme activities. CYP1A2 has been reported to be involved in the oxidation of uroporphyringen III to uroporphyrin III. All these facts suggest the involvement of an aryl hydrocarbon receptor-medicated mechanism in hepatic porphyrin accumulation, possibly via CYP1A2. However, the relative potencies of the mono-ortho-substituted PCBs were higher for hepatic porphyrin accumulation than for hepatic CYP1A1 and CYP1A2 induction. In addition, hepatic porphyrin accumulation was the highest after exposure to mono-ortho-PCBs. Since mono-ortho- substituted PCBs induce the phenobarbital-inducible CYP2B isoforms of cytochrome P450, an additional induction of delta-aminolevulinic acid synthetase may also contribute to hepatic porphyrin accumulation following subchronic exposure to these particular congeners. Relative potencies derived from hepatic porphyrin accumulation after PCDD, PCDF, or coplanar PCB administration are a useful tool in risk assessment. However, the higher potencies of the mono-ortho-substituted PCBs have important implications for risk assessment of these compounds.

Aberdeen polygons: computer displays of physiological profiles for intensive care.

The clinician in an intensive therapy unit is presented regularly with a range of information about the current physiological state of the patients under care. This information typically comes from a variety of sources and in a variety of formats. A more integrated form of display incorporating several physiological parameters may be helpful therefore. Three experiments are reported that explored the potential use of analogue, polygon diagrams to display physiological data from patients undergoing intensive therapy. Experiment 1 demonstrated that information can be extracted readily from such diagrams comprising 8- or 10-sided polygons, but with an advantage for simpler polygons and for information displayed at the top of the diagram. Experiment 2 showed that colour coding removed these biases for simpler polygons and the top of the diagram, together with speeding the processing time. Experiment 3 used polygons displaying patterns of physiological data that were consistent with typical conditions observed in the intensive care unit. It was found that physicians can readily learn to recognize these patterns and to diagnose both the nature and severity of the patient's physiological state. These polygon diagrams appear to have some considerable potential for use in providing on-line summary information of a patient's physiological state.