Effect of Zn2+ on the proteolytic inhibitory action of insulin and biguanide antihyperglycemic drugs.

The involvement of Zn2+ in the inhibitory action of insulin and phenformin on bulk proteolysis was studied in the Langendorff rat heart with a Zn(2+)-buffering perfusate (0.1 mM citrate, physiological complete amino acids and 0.2% albumin). Proteins were biosynthetically labeled in vitro for 10 min with [3H]leucine. Rapidly degraded proteins were eliminated during a 3-h preliminary degradation without insulin or added Zn2+ (2 mM nonradioactive leucine). Insulin (5 nM), the lysosomal inhibitor chloroquine (30 microM), and the biguanide antihyperglycemic agent phenformin (2 microns) each caused a sustained 35-40% inhibition of [3H]leucine release beginning within 1-2 min and reaching a maximum at 1-1.5 h. When these agents were combined, their simultaneous proteolytic inhibitory effects were not appreciably greater than the effect of chloroquine alone. Infusion of supraphysiological perfusate Zn2+ (greater than 15 microM) mimicked the inhibitory effect of insulin and chloroquine on lysosomal proteolysis. Infusion of supraphysiological Co2+, Mn2+, Fe2+, and Cr3+ (30 microM, 0.5 h) caused no change in proteolysis; however, 30 microM Cu2+ caused a slight inhibition. Presumptive chelation of the background (approximately 20 nM) Zn2+ by infusion of 3 microM CaNa2 EDTA caused no change in protein degradation over 1-2 h. The infusion of a physiological concentration of 1 or 5 microM Zn2+ (as ZnCl2) caused no change in protein degradation over 1-2 h. Biguanides are known to reversibly form a Zn2+ complex with affinity less than that of Zn2+ for EDTA. Prior infusion of 3 microM CaNa2 EDTA inactivated the proteolytic inhibitory effect of maximal (2 microM) phenformin over at least 1.25 h of concurrent infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

The renal elimination of procainamide.

The question of pH or flow dependence for the renal elimination of procainamide (PCA) was studied under 4 conditions in each of 4 subjects. Each subject received 500 mg of PCA intravenously at weekly intervals while in a state of (1) acid load (NH4Cl) and water deprivation, (2) acid load and water excess, (3) alkali load (NaHCO3) and water deprivation, and (4) alkali load and water excess. Plasma and urine were collected at frequent intervals for PCA and N-acetyl PCA (NAPA) analysis. Urine flow rates varied markedly between the water deprivation and water excess states (approximately 1.2 vs 5 ml/min, respectively), and urine pH varied markedly between the acid and alkali load states (pH = ca 5 vs 8, respectively). Despite this marked variation, there were no significant changes in PCA renal clearance or 24-hr PCA or NAPA excretion. If passive diffusion of PCA were taking place, such flow and pH changes would have caused marked changes in PCA clearance were the pH partition hypothesis true. We therefore conclude that passive diffusion is not an important mechanism in the renal elimination of PCA in man and that there must be tubular secretion. The implication for the clinical use of the drug is that dose adjustments need not be made in response to variations in urine flow and pH.

Renal excretion of pseudoephedrine.

A patient with renal acidosis developed unanticipated toxicity after ordinary doses of pseudoephedrine, prompting us to study renal determinants of its elimination. We presumed that our patient accumulated the drug because of her persistently alkaline urine, which would favor tubular resorption of this weak base (pKa = 9.4). We studied normal adults and children and one adult and one child with renal tubular acidosis. Increasing urine pH increased the serum elimination half-life from 1.9 to 21 hr. While urinary pH remained alkaline, renal excretion of pseudoephedrine and its metabolite, norpseudoephedrine, was directly correlated with the flow rate of urine in each subject. Both urine pH and flow are important determinants of the elimination of pseudoephedrine in man and could be critical determinants of unanticipated toxicity.

Redox control of protein degradation.

This review summarizes evidence that most of cell protein degradation is maintained by pathways transferring energy from glucose to reduction of enzymic and nonenzymic proteins (redox-responsive). In contrast, a major subcomponent of proteolysis is simultaneously independent of the cell redox network (redox-unresponsive). Thus far, direct and indirect redox-responsive proteolytic effector mechanisms characterized by various investigators include: several classes of proteases, some peptide protease inhibitors, substrate conjugation systems, substrate redox and folding status, cytoskeletal-membrane kinesis, metal homeostasis, and others. The present focus involves redox control of sulfhydryl proteases and proteolytic pathways of mammalian muscle; however, other mechanisms, cell types, and species are also surveyed. The diversity of redox-responsive catabolic mechanisms reveals that the machinery of protein turnover evolved with fundamental dependencies upon the cell redox network, as observed in many species. The net redox status of a reversible proteolytic effector mechanism represents the balance between combined oxidative inactivating influences versus reductive activating influences. Similar to other proteins, redox-responsive proteolytic effectors appear to be oxidized by mixed disulfide formation, nitrosation, reactive oxygen species, and associations or reactions with metal ions and various pro-oxidative metabolites. Systems reducing the proteolytic machinery include major redox enzyme chains, such as thioredoxins or glutaredoxins, and perhaps various reductive metabolites, including glutathione and dihydrolipoic acid. Much of mammalian intracellular protein degradation is reversibly responsive to noninjurious experimental intervention in the reductive energy supply-demand balance. Proteolysis is reversibly inhibited by diamide or dehydroascorbic acid; and such antiproteolytic actions are strongly dependent on the cell glucose supply. However, gross redox-responsive proteolysis is not accompanied by ATP depletion or vice versa. Redox-responsive proteolysis includes Golgi-endoplasmic reticulum degradation, lysosomal degradation, and some amount of extravesicular degradation, all comprising more than half of total cell proteolysis. Speculatively, redox-dependent proteolysis exhibits features expected of a controlling influence coordinating distinct proteolytic processes under some intracellular conditions.

Pseudocholelithiasis in an elderly man with calcified hydatid cysts.

A 69 year old man with intrabiliary rupture of a calcified echinococcal cyst mimicking acute cholelithiasis is discussed. This case is of interest because the correct diagnosis was not recognized preoperatively despite the fact that certain aspects of the illness were classic features of this complication of hydatid disease. Although this is a common complication of hydatid disease, which is well recognized in other countries, only seven cases have been reported in the American literature. Treatment of our patient included successful use of a Roux-en-Y drainage procedure which, to the best of our knowledge, has not previously been employed in treating this disease.

Inactivation of intracellular proteolysis and cathepsin B enzyme activity by dehydroascorbic acid and reactivation by dithiothreitol in perfused rat heart.

The selective inhibition of some subcomponents of intracellular protein degradation was characterized under exposure to the cyclic multiketone thiol oxidizing agents dehydroascorbic acid (DHA) and alloxan. Proteins of the isolated perfused rat heart were labeled in vitro with a 10-min infusion of [3H] leucine, and subsequent release of radiolabeled amino acid from cell proteins was measured. As determined previously, four subcomponents of total proteolysis can be distinguished; the first three subcomponents are reversibly inhibited by the thiol-reactive agent diamide: (a) The rapid turnover proteins comprise most of the [3H] leucine release from 20 min to 3 hr after labeling. (b) Following 3 hr of degradation, the lysosomal (insulin-responsive) subcomponent comprises 35-40% of [3H] leucine release. (c) A third nonlysosomal (adrenergic-responsive) subcomponent comprises 35%. (d) A fourth nonlysosomal subcomponent consisting of 25% of [3H] leucine release is uninhibited by diamide. Infusion of supraphysiologic DHA (1 mM) or alloxan (1.5 mM) promptly mimicked the proteolytic inhibitory action of diamide on the first three subcomponents, but did not inhibit the diamide-resistant subcomponent. Infusion of a physiologic extracellular DHA concentration of 5 microM caused little or no change in proteolysis. The proteolytic inhibitory action of DHA (1 mM) could be reversed by concurrent infusion of dithiothreitol (DTT, 1.5 mM) simultaneously with continued DHA. DHA (1 mM) caused direct inhibition of the purified sulfhydryl proteinase cathepsin B (EC 3.4.22.1), which was reversible by subsequent excess DTT (5 mM). Results indicate that a nontoxic endogenous multiketone thiol oxidant can reversibly inhibit some proteolytic processes in viable tissue; however, approximately 25% of the observed proteolysis is uninhibited. Reversible inactivation of sulfhydryl proteinases, including cathepsin B, is among the possible multiple mechanisms of this DHA action.

Opposing actions of cholinergic agonist and trinitroglycerin on net vascular resistance in perfused rat heart.

The effects of cholinergic agonist and nitrovasodilator on transorgan pressure-flow relationships were characterized under antegrade aortic perfusion of the rat heart. Under basal conditions, the preparation exhibited a stable linear dependence of perfusion pressure upon regulated transorgan flow rate from 0 to 9 ml/min with a transorgan vascular resistance of 5 +/- 0.6 mmHg/ml per min. Maximal acetyl-beta-methacholine (10 microM) caused a 3-fold increase in net transorgan vascular resistance to flow of non-cellular perfusate as observed over the range of constant flow rates from 1 to 8 ml/min. Trinitroglycerin (20 microM) reversed cholinergic-induced vasoconstriction. The effects of acetylcholine on transorgan flow were characterized at constant perfusion pressures approximating mean aortic pressures under lethal hypotension (40 mmHg), sublethal hypotension (70 mmHg) and normotension (100 mmHg). Under maximal acetylcholine (5 microM), flow remained adequate at 4.6 ml/min under 100 mmHg aortic pressure, marginally adequate at 1.2 ml/min under 70 mmHg, and sublethally inadequate at 0.4 ml/min under 40 mmHg. It is concluded that acetylcholine is among the factors increasing vascular resistance that can be opposed by nitrovasodilator. It is estimated that inadequate flow might result from maximal cholinergic agonist under hypotensive but apparently not normotensive aortic perfusion pressure as observed in hearts from normal animals.

Ascorbate stimulation of salicylate absorption in isolated rat intestine.

Salicylate transport across the rat intestine was measured using both in vitro and in vivo procedures. After the steady state for labeled salicylate was reached, the addition of ascorbate stimulated tracer flux with the establishment of a new steady state. The tissue permeability had a saturable dependence on ascorbate concentration. Also, ascorbate stimulated the tissue short-circuit current.

Urinary cadmium elimination as a biomarker of exposure for evaluating a cadmium dietary exposure--biokinetics model.

The Cadmium Dietary Exposure Model (CDEM) utilizes national survey data on food cadmium concentrations and food consumption patterns to estimate dietary intakes in the U.S. population. The CDEM has been linked to a modification of the cadmium biokinetic model of Kjellström and Nordlberg (KNM) to derive predictions of kidney and urinary cadmium that reflect U.S. dietary cadmium intake and related variability. Variability in dietary cadmium intake was propagated through the KNM using a Monte Carlo approach. The model predicts a mean peak kidney cadmium burden of approximately 3.5 mg and a 5th-95th percentile range of 2.2-5.1 mg in males. The corresponding peak renal cortex cadmium concentration in males is 15 microg/g wet cortex (10-22, 5th-95th percentile). Predicted kidney cadmium levels in females were higher than males: 5.1 (3.3-7.6) mg total kidney, 29 (19-43) microg/g wet cortex. Predicted urinary cadmium in males and females agreed with empirical estimates based on the NHANES III, with females predicted and observed to excrete approximately twice the amount of cadmium in urine than males. An explanation for the higher urinary cadmium excretion in females is proposed that is consistent with the NHANES III data as well as experimental studies in humans and animals. Females may absorb a larger fraction of ingested dietary cadmium than males, and this difference may be the result of lower iron body stores in females compared to males. This would suggest that females may be at greater risk of developing cadmium toxicity than males. The predicted 5th-95th percentile values for peak kidney cadmium burden are approximately 60% of the peak kidney burden (8-11 mg) predicted for a chronic intake at the U.S. Environmental Protection Agency (EPA) chronic reference dose of 1 microg/kg-d.

The role of excisional lifting in body contour surgery.

While excess fat deposits are the major component of body contour problems, skin laxity and skin contour irregularities-cellulite- are significant problems in many women. Often the aesthetic contour deformity in a given patient consists of both fat and skin excess problems, requiring liposuction and lifting techniques for optimal results. In the past decade, significant progress has occurred in the understanding of aged aesthetic body deformities, allowing new body life designs based on modern surgical principles. Body lifts are a useful adjunct to liposuction and should be considered when developing an overall surgical plan for an individual patient.

Lower body lift with superficial fascial system suspension.

Multiple body contour deformities of the trunk and thighs are commonly treated in separate stages to limit postoperative complications and disability. Recent advances in the surgical design of the medial thigh lift and the lateral thigh/buttock lift along with an understanding of the functional anatomy of the superficial fascial system have significantly improved results and decreased complications of trunk/thigh lifts. The enhanced safety of current trunk/thigh lifts has allowed new combinations to treat multiple body contour deformities in a single stage. Laxity of the entire lower trunk and thigh regions can be treated in one stage in selected patients. The lower body lift combines the transverse flank/thigh/buttock lift and the fascial anchoring medial thigh lift in one operation. In addition to the expected tightening of the flank, buttocks, and total thighs, this procedure results in a surprising degree of epigastric and hypogastric tightening of mild to moderate abdominal laxity without direct surgical undermining or umbilical transposition. Ten patients having the lower body lift alone or in combination with liposuction and other body contouring procedures were followed for 6 to 24 months. The primary indication for surgery is moderate to severe soft-tissue laxity of the lower trunk and thighs with minimal or mild residual fat deposits. Skin contour irregularities due to skin laxity (cellulite of laxity) or to postliposuction adhesions are frequently present and may be severe. Patients with significant fat deposits may be treated initially with liposuction 3 to 4 months earlier to become candidates for this procedure. Key technical elements of this procedure include (1) both supine and lateral decubitus positioning with the hip flexed and abducted to allow overcorrection, (2) appropriate direct surgical undermining through superficial fascial system zones of adherence in the superior thigh while avoiding the lymphatics of the femoral triangle, (3) more distal undermining of the thighs with an atraumatic undermining cannula, (4) resection of redundant lower trunk and thigh tissues with incisional closure within high-cut bikini lines, and (5) complete superficial fascial system and dermal suspension throughout the repair. The lower body lift requires 5 to 6 hours of operating time, 2 units of autologous blood, 2 nights of nursing care, and 3 weeks off work. Although no major complications occurred, minor complications were significantly higher than with the component procedures alone and occurred in 50 percent of patients. Technical changes and improved patient selection have significantly improved the rate of complications in subsequent patients. Results have been consistent, and patient satisfaction has remained high.

Rectus muscle diastasis in males: primary indication for endoscopically assisted abdominoplasty.

Endoscopic techniques through umbilical and mons pubis ports have provided a method to plicate rectus muscle diastasis without skin resection. Limited or no skin excision is performed. Major series have included only women. The criteria for patient selection for endoscopic abdominoplasty include a protuberant abdomen caused by rectus muscle diastasis with minimal actual or potential skin laxity. There should not be significant intra-abdominal obesity. Extra-abdominal familial fat deposits may be part of the abdominal aesthetic deformity. In most women, rectus muscle diastasis because of pregnancy, obesity, or aging is associated with actual or potential skin laxity of the abdomen and lateral trunk. Endoscopic abdominoplasty in these women would produce mediocre early results and poor aging potential for the future. There are a limited number of women who are reasonable candidates for the endoscopic approach. In contrast, rectus muscle diastasis without skin laxity is a common finding in men older than 30 to 40 years of age. There may be a history of weight fluctuations, weightlifting, or full-excursion sit-up exercises, which may lead to progressive separation of the rectus muscles over time. Other etiologic factors include chronic or intermittent abdominal distension, advancing age, or familial weakness of the abdominal musculofascial tissues. Endoscopically assisted abdominoplasty was performed in four male patients with good to excellent results at 4 to 18 months. Minor complications occurred in half the patients but were successfully treated without re-operation. Men with prominent abdominal contours who are diet- and exercise-resistant should be examined both for familial fat deposits and for significant rectus muscle diastasis. Contouring of the male abdomen may be the primary indication for endoscopically assisted abdominoplasty.

Brachioplasty with superficial fascial system suspension.

Although significant innovations in brachioplasty occurred in the 1970s, it remains an unpopular procedure. Current brachioplasty techniques are somewhat unpredictable and are commonly associated with significant untoward results. Recent anatomic studies demonstrate that in youth the posteromedial arm soft tissues are firmly suspended to a tough yet dynamic fascial system sling that ultimately gains its strength from the clavicular periosteum by means of the clavipectoral and axillary fasciae. Loosening of the connections of the arm superficial fascial system to the axillary fascia, as well as relaxation of the axillary fascia itself, with age, weight fluctuations, and gravitational pull yields a "loose hammock" effect, resulting in significant ptosis of the posteromedial arm. On the basis of this anatomic concept, the brachioplasty procedure was modified to provide secure anchoring of the arm flap to the axillary fascia along with strong superficial fascial system repair of incisions, reducing the risk of widening or migration of scars and unnatural contours. Five patients having brachioplasty with or without liposuction were followed for 6 to 12 months. The primary indication for surgery is moderate to severe skin laxity of the arms with or without associated arm fat deposits. Results were consistent, and complications were limited.

High-lateral-tension abdominoplasty with superficial fascial system suspension.

Modern abdominoplasty techniques were developed in the 1960s. The advent of liposuction has reduced the need for classic abdominoplasty and allowed more aesthetic sculpting of the entire trunk. However, the combination of significant truncal liposuction and classic abdominoplasty is not recommended due to the increased risk of complications. Although the surgical principles of classic abdominoplasty certainly have stood the test of time, they are based on two theoretical assumptions that may be proved to be inaccurate. The first assumption is that wide direct undermining to costal margins is essential for abdominal flap advancement. In fact, discontinuous undermining allows effective loosening of the abdominal flap while preserving vascular perforators. The second inaccurate assumption is that with aging and weight fluctuations (including pregnancy), abdominal skin relaxation occurs primarily in the vertical direction from the xiphoid to the pubis. This is true in the lower abdomen, but in most patients a strong superficial fascial system adherence to the linea alba in the epigastrium limits vertical descent. Epigastric laxity frequently results from a progressive horizontal loosening due to relaxation of the tissue along the lateral trunk. Experience with the lower-body lift procedure has shown that significant lateral truncal skin resection results in epigastric tightening. In these patients, the ideal abdominoplasty pattern would resect as much or more laterally than centrally, leading to more natural abdominal contours. Fifty patients who underwent high-lateral-tension abdominoplasty with and without significant truncal liposuction and other aesthetic procedures were followed for 4 to 16 months. The primary indication for surgery was moderate to severe laxity of abdominal skin and muscle with or without truncal fat deposits. Complication rates were equal to or less than those of historical controls and did not increase with significant adjunctive liposuction. The key technical elements of this procedure include direct undermining limited to the paramedian area, discontinuous undermining to costal margins and flanks as needed, skin resection pattern with significant lateral resection and highest-tension wound closure placed laterally, superficial fascial system repair with permanent sutures along the entire incision, and liberal use of adjunctive liposuction in the upper abdomen and the lateral and posterior trunk.

Reduction mammaplasty and mastopexy with superficial fascial system suspension.

Classic descriptions of breast reduction and mastopexy techniques have relied on dermal suspension with or without glandular shaping to contour the breast. Dermal suspension is often an unreliable and inconsistent anchor for high-tension wound repairs, resulting in unpredictable or poor scarring along with inadequate long-term lifting of the soft tissues. Hypertrophic scarring commonly occurs after dermal suspension reduction mammaplasty, being noted in 50 to 55 percent of patients at 6 months. Current studies regarding the anatomy and function of the superficial fascial system (SFS) have led to multiple applications of suspension with permanent (nonabsorbable) sutures in high-tension wound repairs of the body. As in other areas of the body, this system can be used effectively for suspension of breast-contouring procedures. Suturing the anterior SFS layer with nonabsorbable sutures (separately from the breast tissue or dermis) provides minimal tension skin repair. This should result in more predictable scarring with reduced risk of scar widening and hypertrophy. In addition, using SFS suspension in mammaplasties may result in longer-lasting contour results. The keyhole pattern used for dermal suspension techniques must be modified for SFS suspension. Reduction mammaplasty or mastopexy using these suspension wound repair techniques was performed in 109 patients (218 breasts) with a 6- to 36-month follow-up. The incidence of hypertrophic scarring was 3 percent at 6 months in this series. Suspension in mammaplasty procedures improved scar quality and provided more predictable and stable breast contours over long-term follow-up.

Fascial anchoring technique in medial thigh lifts.

The medical thigh lift has not gained widespread acceptance since its introduction 20 years ago because of problems such as inferior scar migration, labial separation, and early recurrence of ptosis. Anchoring of the inferior skin flap to the tough, inelastic deep layer of the superficial perineal fascia has reduced such complications. Originally described by Colles in 1811, this fascial layer helps define the perineal-thigh crease. Eighteen patients having medial thigh lifts in combination with liposuction were followed for 6 to 24 months. The technique involves initial liposuction followed by resection of a crescent of redundant skin and fat at the superior medial thigh. The inferior skin flap is suspended from Colles' fascia of the perineum with subdermal PDS sutures. No undermining or deepithelialization of flaps is performed. Complications are few, and patient satisfaction is high.

How valuable is feedback of information on hospital referral patterns?

OBJECTIVES: To determine general practitioners' responses to and explanations for variation in rates of referral to hospital and how feedback of data on rates of referral could be used to facilitate practices in auditing their own referral behaviour. DESIGN: Visits by audit facilitators to general practices after feedback of details of rates of referral to hospital derived from annual reports in general practice. SETTING: 92 general practices in East Anglia. RESULTS: General practitioners judged that access to specialist care, the individual skill of general practitioners, patient demand, and fear of litigation were major determinants of referral behaviour. Because there was widespread scepticism about the accuracy of the data on which the feedback was based and because there is no clear relation between rates of referral and quality of care, it was extremely difficult to encourage doctors to use the feedback as a basis for auditing their own hospital referrals. CONCLUSION: If general practitioners are to contribute meaningfully to monitoring future changes in referral patterns it will be essential to develop reliable information systems in which doctors have confidence. Furthermore, audits need to be based on analysis of clinical cases rather than on rates of referral.

Lower-body lift.

The lower-body lift, designed for patients with multiple lower-body contour deformities, uses a circumferential bikini-line incision to simultaneously lift relaxed trunk and thigh tissues. The author describes 2 lower-body lift procedures, focusing primarily on the high-lateral-tension abdominoplasty with transverse-thigh/buttock lift, which he developed in 1996. (Aesthetic Surg J 2001;21:355-370.).