Effect of estrogen deficiency in the male: the ArKO mouse model.

Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is present in the mouse gonads, brain, adipose tissue and bone. Depletion of endogenous estrogens in the aromatase deficient mouse (ArKO) caused by the targeted disruption of the Cyp19 gene resulted in an impairment of sexual behaviour and an age-dependent disruption of spermatogenesis. This disruption occurred during early spermiogenesis, due possibly to increased number of apoptotic round spermatids. Development of obesity was associated with ageing, decrease in lean mass, hypercholesterolemia, hyperleptinemia, and insulin resistance and hepatic steatosis. However, it was not correlated with hyperphagia but to decreased physically-active behaviour. ArKO mice also developed osteoporosis. Thus, studies using the ArKO mice model has led to several insights into the multiple roles played by estrogens in the development and maintenance of fertility, sexual behaviour, lipid metabolism and bone remodelling.

Comprehensive approach to rejuvenation of the neck.

A comprehensive rejuvenation of the neck depends on accurate analysis of the lower face and neck with attention to the contours and deep-lying structures. Although many surgeons address the well-recognized changes in skin and soft tissue that occur with aging, we believe bone resorption is also an important component. Loss of bone volume leads to loss of support for the soft tissues of the face. The result is soft tissue ptosis and loss of angularity between the various planes of the face. Initially, there is loss of the submental shadow and loss of height of the mandibular ramus. The gonial angle loses its prominence, and the chin becomes ptotic. The line of the body of the mandible is further obscured by the appearance of jowls. As the mandible shrinks, the submandibular gland as well as the muscles that make up the floor of the mouth are pushed inferiorly. For loss of bone support, implants tailored to the areas of deficit and to the aesthetic goals are used. These implants used for the mandible are tridimensional structures made from beaded polyethylene material. This restores the bone volume and provides good support for the soft tissues. We routinely perform a deep-layer cervicoplasty. This involves removing fat from the subplatysmal layer and between the anterior bellies of the digastric muscles. The digastric muscles are plicated toward the midline. The platysma muscle is separated from the underlying submandibular gland. Ptosis of the submandibular gland is treated by suspension of the fascia with sutures or imbrication of the overlying muscle. A short corset platysmaplasty brings the platysma muscles to the midline. Above the level of the hyoid bone, the digastric muscles are included in the sutures. If the patient has an obtuse cervicomental angle, but good-quality skin, there may be no need to perform skin resection. In these patients who are candidates for nonexcisional cervicoplasty, we routinely place a neck suspension suture. Patients with poor skin quality or excessive skin on the neck and jawline will require an excisional cervicoplasty or cervicofacial rhytidectomy. We have obtained consistently good results using this comprehensive approach.

Characterization of the fertility of male aromatase knockout mice.

Previous studies employing the male aromatase knockout (ArKO) mouse have indicated that local expression of estrogens appears to be important for the progression of spermatogenesis. In the absence of estrogen biosynthesis round spermatids are observed to undergo apoptosis and thus fail to differentiate into mature, elongated spermatids. This lesion appears to arise between the ages of 18 weeks and 1 year. To ultimately determine if the disruption to spermatogenesis arises earlier than 18 weeks, we performed an intensive study to examine the fertility of younger male ArKO mice. This involved an analysis of their mating capacity together with an extensive stereological analysis, determination of the in vitro potential of mature sperm, and sexual behavior. ArKO and wild-type (w/t) males at 7 weeks of age were placed with w/t females for 7 weeks. At age 14 weeks, the males were killed and the testes removed. ArKO mice were observed to sire significantly fewer litters than the w/t mice; 5 out of the 10 sired no litters at all. Stereological analysis performed on the removed testes found a significant decrease in round spermatid numbers between w/t and ArKO mice at this age; however, there were no differences in all other germ cells and Sertoli cell numbers. When mature spermatozoa were analyzed, sperm from 15-week-old ArKO mice had a significant reduction in motility. This was further reduced by 1 year of age with a decrease in concentration. A preliminary examination of sexual behavior found that ArKO mice did not attempt to mount the females, in contrast to the w/t mice, which mounted consistently during the time period. In conclusion, we observed that ArKO mice have reduced fertility at age 14 weeks. This may be due in part to a disruption in spermatogenesis because the phenotype does appear to arise earlier than 18 weeks, possibly leading to abnormalities in the mature spermatozoa. Or, in part, this may be attributable to an impairment in the development of copulatory behavior, which is consistent with the available evidence that points to a crucial role for estrogens in the neural development and initiation of male sexual behavior.

Estrogen and spermatogenesis.

Although it has been known for many years that estrogen administration has deleterious effects on male fertility, data from transgenic mice deficient in estrogen receptors or aromatase point to an essential physiological role for estrogen in male fertility. This review summarizes the current knowledge on the localization of estrogen receptors and aromatase in the testis in an effort to understand the likely sites of estrogen action. The review also discusses the many studies that have used models employing the administration of estrogenic substances to show that male fertility is responsive to estrogen, thus providing a mechanism by which inappropriate exposure to estrogenic substances may cause adverse effects on spermatogenesis and male fertility. The reproductive phenotypes of mice deficient in estrogen receptors alpha and/or beta and aromatase are also compared to evaluate the physiological role of estrogen in male fertility. The review focuses on the effects of estrogen administration or deprivation, primarily in rodents, on the hypothalamo-pituitary-testis axis, testicular function (including Leydig cell, Sertoli cell, and germ cell development and function), and in the development and function of the efferent ductules and epididymis. The requirement for estrogen in normal male sexual behavior is also reviewed, along with the somewhat limited data on the fertility of men who lack either the capacity to produce or respond to estrogen. This review highlights the ability of exogenous estrogen exposure to perturb spermatogenesis and male fertility, as well as the emerging physiological role of estrogens in male fertility, suggesting that, in this local context, estrogenic substances should also be considered "male hormones."

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity.

The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene.

It is well established that spermatogenesis is controlled by gonadotrophins and testosterone. However, a role for estrogens in male reproduction recently was suggested in adult mice deficient in estrogen receptor alpha. These mice became infertile primarily because of an interruption of fluid reabsorption by the efferent ductules of the epididymis, thus leading to a disruption of the seminiferous epithelium [Hess, R. A., Bunick, D., Lee, K. H., Bahr, J., Taylor, J. A., Korach, K. S., and Lubahn, D. B. (1997) Nature (London) 390, 509-512]. Despite the demonstration of the aromatase enzyme, which converts androgens to estrogens, and estrogen receptors within the rodent seminiferous epithelium, the role of aromatase and estrogen in germ cell development is unknown. We have investigated spermatogenesis in mice that lack aromatase because of the targeted disruption of the cyp19 gene (ArKO). Male mice deficient in aromatase were initially fertile but developed progressive infertility, until their ability to sire pups was severely impaired. The mice deficient in aromatase developed disruptions to spermatogenesis between 4.5 months and 1 year, despite no decreases in gonadotrophins or androgens. Spermatogenesis primarily was arrested at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and there was a significant reduction in round and elongated spermatids, but no changes in Sertoli cells and earlier germ cells. In addition, Leydig cell hyperplasia/hypertrophy was evident, presumably as a consequence of increased circulating luteinizing hormone. Our findings indicate that local expression of aromatase is essential for spermatogenesis and provide evidence for a direct action of estrogen on male germ cell development and thus fertility.

Expanded polytetrafluoroethylene (Gore-Tex) augmentation of deep nasolabial creases.

OBJECTIVE: To evaluate the safety and efficacy of expanded polytetrafluoroethylene (PTFE) (Gore-Tex; W. L. Gore & Associates, Flagstaff, Ariz) for augmentation of deep nasolabial creases. DESIGN: Retrospective chart review with a minimum of 12 months of follow-up. SETTING: Private practice ambulatory surgery center. STUDY POPULATION: One hundred consecutive patients (average age, 49 years) undergoing expanded PTFE augmentation of the nasolabial crease. MAIN OUTCOME MEASURES: A standardized, reproducible rating scale assessed preoperative crease severity. Clinical effectiveness was determined by the numerical degree of improvement in crease severity rating after surgery, and by the number of procedures required to achieve the desired aesthetic results. RESULTS: Patients initially had grade 1 (14.5%), grade 2 (54.0%), grade 3 (20.0%), or grade 4 (11.5%) crease severity ratings. On average, patients with grade 1 creases required 1.17 total augmentation procedures, those with grade 2 required 1.60, those with grade 3 required 1.93, and those with grade 4 required 1.86. On average, with each augmentation, patients with grade 1 improved 0.61 relative severity points; those with grade 2, 0.85; those with grade 3, 1.29; and those with grade 4, 1.28. Nine patients developed late postoperative sequelae. Four creases (2.0%) displayed an unnatural mounded appearance because of superficial expanded PTFE placement. All 4 creases underwent elective removal of a single superficial PTFE strip, with resultant return of aesthetically correct crease augmentation. Five creases (2.5%) developed implant site infections; in all 5 cases, the involved strips were removed and the infection was resolved with a 10-day course of oral antibiotics. CONCLUSIONS: Expanded PTFE augmentation presents a safe, effective method for softening deep nasolabial creases. Patients with more severe creases are likely to show more improvement with each augmentation, but are also more likely to require multiple procedures to achieve the desired aesthetic result.

Venovenous bypass in adult orthotopic liver transplantation: routine or selective use?

BACKGROUND: The role of venovenous bypass (VVB) during orthotopic liver transplantation (OLT) remains controversial. The aims of this study were to evaluate the current role of VVB at all major centers in North America, to examine the results of OLT and complications of VVB between two periods with a strict policy for routine versus selective use of VVB, and to review the literature. STUDY DESIGN: A survey of 50 major liver transplant centers was conducted using mailed questionnaires. A retrospective chart review was performed for 547 OLT patients having transplantation during two distinct periods with a strict policy for routine versus selective use of VVB at the University of Toronto, Canada, and at Duke University Medical Center, Durham, North Carolina. The literature was reviewed with a focus on the benefits and indications for routine versus selective use of VVB. RESULTS: Thirty-eight (76%) of 50 centers responded. Sixteen (42%) of them used VVB routinely, with a reported complication rate of 10-30%. Lymphocele and hematoma were the most common complications, but patients having major vascular injury, air embolism, and death were reported. A recent change to selective use of VVB was reported in 30% of the centers (11 of 38). In the Duke-Toronto series, the complication rates were similar between the two periods, at 13.4% and 18.8%, respectively. The outcome of OLT was not influenced by the policy of routine or selective use of VVB. CONCLUSIONS: There is a trend away from the routine use of VVB during OLT. Intraoperative hemodynamic instability during the hepatectomy and a failed trial of hepatic venous occlusion were the most important criteria for using VVB. We conclude that VVB should be used selectively to avoid associated complications and to decrease operative time and costs.

Influences of monocular image degradation on the monocular components of fixation disparity.

The monocular components of the forced vergence fixation disparity curve were evaluated for equal retinal images and for two kinds of monocular retinal image degradation. Computer-generated nonius lines were used to measure the fixation disparity curve components. Monocular defocus was obtained by placing convex lenses before one eye. In the second instance monocular image degradation was achieved by placing light-scattering filters before one eye. A small percentage of subjects displayed unequal distribution of the monocular components of fixation disparity with no image degradation. For both conditions of monocular image degradation, the distribution of the monocular components was found to be biased in favor of the clear image. However, defocus, which affects the high spatial frequencies relatively more than scatter, was found to have a greater effect on the distribution of the monocular components of fixation disparity than scatter.

The multimeridional apparent frontoparallel plane: introduction of the induced effect.

The application of vertical rod stimuli to obtain apparent frontoparallel plane (AFPP) settings is well-known. A geometrical relation based on observation distance, interpupillary distance, and retinal disparity determines the deviation of the setting from the objective frontoparallel plane. Further developments of this procedure have established that a similar relation exists for oblique presentations of parallel rod stimuli, the orientation of the rods being an additional variable. This extension of the AFPP procedure is referred to as the multimeridional AFPP or MAFPP. It permits the determination of aniseikonia in oblique as well as horizontal meridians. Although oblique disparities contain a vertical component, an induced effect is absent as long as parallel rod stimuli are used alone. If an induced effect were present, the MAFPP geometrical relations would be expected to break down. To test this hypothesis, random dot arrays and a row of dots of the same frequency as a control stimulus of parallel lines were presented alone and in combination with the line stimuli. Binocular disparities were induced by a meridional afocal magnifier placed at various axes before one eye. It was found that the dot arrays caused a breakdown of the geometrical relation when presented alone or in combination with the parallel lines. The amount of deterioration varied only slightly with the number and arrangement of dot stimuli but increased as the vertical component of the oblique magnification increased. In addition to proving the main hypothesis, the data provide information pertaining to the MAFPP theory as well as offering some insight into the induced effect. The most important practical implication of the results is that the MAFPP theory can be used to measure unknown retinal disparities only if continuous parallel lines are presented in isolation.

Measurement of central and peripheral dynamic visual acuity thresholds during ocular pursuit of a moving target.

Previously, visual acuity thresholds for eccentric retinal points have been documented for targets that oscillate while the observer fixates a central point. This research describes the situation where the observer tracks a moving target in constant linear motion, thereby involving the pursuit and saccadic eye movements. The increase of visual acuity thresholds with target motion (0 to 70 degrees/s) was evaluated as a function of retinal eccentricity. Nine retinal points were evaluated, (central, 5 degrees and 10 degrees nasal, 5 degrees and 10 degrees temporal, 5 degrees and 10 degrees superior, and 5 degrees and 10 degrees inferior to the fovea). Eight normal subjects viewed computer-generated randomly oriented E's monocularly through a horizontally rotating mirror. A computer automatically calculated the minimal angle of resolution (MAR) threshold values. Result indicated that the change in visual acuity thresholds was dependent upon retinal location. The thresholds for central and peripheral eccentricities plotted as a function of angular velocity were linear but the slope of the linear function was much reduced for peripherally viewed targets compared to centrally viewed targets. Although both peripheral and central visual acuity thresholds may increase with increasing target velocity due to velocity mismatch errors and saccadic suppression and/or omission, the reduction in slope for peripherally viewed targets may be due to differential temporal summation, retinal smear, and/or separate retinogeniculate pathway processing.

Isoflurane alters the kinetics of oral cyclosporine.

Cyclosporine is an important immunosuppressive agent often given orally preoperatively to patients undergoing organ transplantation. The aim of the present study was to evaluate the effects of anesthesia on the pharmacokinetics of orally administered cyclosporine. Sixty unanesthetized fasting female Lewis rats were given 25 mg/kg cyclosporine by gastric tube and were then randomized to immediately receive an isoflurane anesthetic (n = 30) or to serve as nonanesthetized controls. At 1, 2, 3, 4, and 6 h after the administration of the cyclosporine, six animals from each group (while still anesthetized for those in the anesthesia group) were killed, and arterial blood and the entire bowel from the esophagogastric junction to the ileocecal junction were removed for measurement of cyclosporine concentrations. A subsequent study with six animals in each group was performed to examine more closely the distribution of cyclosporine in the stomach and small intestine 4 h after the oral dose. In these animals the cyclosporine concentration in the stomach and in five 10-cm-long segments of small bowel was assayed. In all studies of gastrointestinal specimens, the cyclosporine extracted is a combination of that contained in the lumen and the wall. At all times except at 6 h, the blood cyclosporine levels were significantly higher in the control group than in the isoflurane group. Conversely, the amount of cyclosporine in the distal small bowel of control rats was increased as compared with the anesthetized animals. In the animals studied at 4 h, the amount of cyclosporine in the stomach of control rats was significantly lower than that in the anesthetized animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Monocular components of the fixation disparity curve.

Experiments were conducted to characterize the distribution of the monocular components of fixation disparity, i.e., ascertain whether or not the fixation disparity measured by nonius alignments is equally divided between the two eyes or has an unequal distribution. Computer generated nonius lines were used to measure the monocular components of the forced vergence fixation disparity curve (FDC) for subjects with normal binocularity. Thirty-three percent of all subjects tested showed unequal distribution of their monocular components. The composite FDC's for subjects with unequal distribution of the monocular components tended to have steeper slopes than those with equally distributed components. It was concluded that equally divided monocular components are not a prerequisite for good binocularity.

Anaesthetic management of the brain dead for organ donation.

An increasing number of anaesthetists is being called upon to manage organ donors during organ retrieval procedures. We briefly describe the technical aspects of the surgical procedure together with a guide to the anaesthetic management. The aims of the latter may be summarized as the "Rule of 100": systolic blood pressure greater than 100 mmHg, urine output greater than 100 ml.hr-1, PaO2 greater than 100 mmHg, haemoglobin concentration greater than 100 g.L-1. Common management problems (hypotension, arrhythmias, diabetes insipidus, oliguria, and coagulopathy) are discussed in detail. The intraoperative management of the brain-dead organ donor provides the anaesthetist with the challenge of a major surgical procedure in a subject with important physiological derangements.

Ionization and hemodynamic effects of calcium chloride and calcium gluconate in the absence of hepatic function.

Serial serum ionized calcium concentrations were measured before and after administration of either calcium chloride or calcium gluconate during the anhepatic stage of liver transplantation in 15 patients to determine the release of ionized calcium in the absence of hepatic function. When hypocalcemia (Ca++ less than 0.8 mM) occurred during the anhepatic stage, patients were randomly assigned to treatment with chemically equivalent doses of either calcium chloride (10 mg/kg, n = 8) or calcium gluconate (30 mg/kg, n = 7). Serum concentrations of ionized calcium and citrate, hematocrit, arterial blood gas tensions, acid-base state, and hemodynamic profiles were determined before and up to 10 min after calcium therapy. In both groups of patients initial similar and rapid increases in Ca++ (0.98 +/- 0.14 mM in the calcium chloride group and 1.05 +/- 0.10 mM in the calcium gluconate group) were followed by gradual decreases over the next 10 min. Measured hemodynamic values were similar in the two groups, and neither group showed improvement in cardiovascular function after calcium therapy, possibly because of the decrease in preload that occurred during the anhepatic stage. Equally rapid increases in Ca++ after administration of calcium chloride and gluconate in the anhepatic state suggest that calcium gluconate does not require hepatic metabolism for the release of Ca++ and is as effective as calcium chloride in treating ionic hypocalcemia in the absence of hepatic function.

Perioperative management of the multiorgan donor.

Organ transplantation is a multidisciplinary specialty that has seen remarkable advances in the past two decades, in the tireless pursuit of providing life-saving therapy for patients suffering from end-stage organ failure. As the scientific basis and clinical practice of organ transplantation continues to evolve, it becomes increasingly apparent that "what was inconceivable yesterday, and barely achievable today, becomes routine tomorrow" (73).

Orthophorization after occlusion-induced exotropia.

A 36-year-old male had been constantly wearing a patch to avoid diplopia since an operation on the right parietal area of the brain. Postsurgical visual field evaluation indicated a complete bilateral left hemianopia with macular splitting. The patient had a constant alternating comitant exotropia with no suppression. By terminating the patching, establishing the appropriate fixing eye, and applying relieving prisms, diplopia was removed. Once binocularity was thus established, it was found (over the course of 7 months) that binocular function was possible with diminishing amounts of prism power. During this 7-month period, measurements of the patient's heterophoria, motor fusion, and sensory fusion revealed that he adapted from his occlusion-induced exotropia toward an habitual heterophoria. Such vergence adaptation has been defined as orthophorization. The occurrence of vergence adaptation after sensory fusion indicates that sensory fusion plays an important role in the etiology of prism adaptation.