Field efficacy and safety of protamine zinc recombinant human insulin in 276 dogs with diabetes mellitus.

Twice-daily (BID) insulin injections are a major deterrence to owners treating dogs with diabetes mellitus (DM). The hypothesis for this study was that Protamine Zinc Recombinant Human Insulin (PZIR) is safe and efficacious as a once-daily (SID) treatment for canine DM. This was a prospective, baseline-controlled, multi-center study over 182 ± 5 d. Two hundred seventy-six client-owned dogs with naturally occurring DM (naïve or pre-treated with insulin) were enrolled in the study. Enrollment was based upon demonstration of hyperglycemia, glycosuria, and ≥1 diabetic clinical sign (polyuria (PU), polydipsia (PD), or weight loss). Insulin treatment was initiated at 0.5-1.0 IU/kg SID. An improvement in at least one lab parameter related to DM (mean BG, min BG, Fructosamine) and one clinical parameter (PU/PD, body weight) was achieved in 72% of dogs (80% of naive, 62% of pre-treated). Dogs treated SID and BID showed improvement in 71% and 74% of cases, respectively. In naïve dogs, mean and minimum BG and fructosamine were significantly decreased (P < 0.05) by d 7 and 21, respectively, and in pre-treated dogs by d 63. By d 84, PU/PD improved in 90% and 88% of dogs, respectively, and the mean successful insulin dose was 1.4 IU/kg/d. Safety parameters were measured in 276 dogs for up to 182 d; clinical hypoglycemia occurred in 8.9% of dogs. We conclude that PZIR safely and effectively improved glycemic parameters and clinical signs in naïve and pre-treated diabetic dogs. The significant percentage of dogs on SID treatment with improvement in hyperglycemia and clinical signs confirms the prolonged action of PZIR in many dogs.

Geochemical fractionation of hazardous elements in fresh and drilled weathered South African coal fly ashes.

The chemical reactions of dry-disposed ash dump, ingressed oxygen, carbon dioxide, and infiltrating rainwater affect mineralogical transformation, redistribution, and migration of chemical species. Composite samples of weathered coal fly ash taken at various depths and fresh coal fly ash were examined using organic petrographic, X-ray diffraction, X-ray fluorescence techniques, and successive extraction procedures. Results obtained show relative enrichment of glass, Al-Fe-oxides, calcite, and tridymite in the weathered CFA, but the fresh CFA is enriched in mullite, inertinite, maghemite, and ettringite. The enrichment of the weathered CFA in amorphous glass suggests higher reactivity when compared to fresh CFA. The evident depletion of soluble oxides in the weathered CFA is attributed to flushing of the soluble salts by percolating rainwater. Comparative enrichment of examined elements in water-soluble, exchangeable, reducible, and residual fractions of the weathered CFA is partly due to the slow release of adsorbed chemical species from the alumina-silicate matrix and diffusion from the deeper sections of the particles of coal fly ash. Sodium and potassium show enrichment in the oxidisable fraction of fresh CFA. The estimated mobility factor indicates mobility for Ca, Mg, Na, Se, Mo, and Sb and K, Sr, V, Cu, Cr, Se, and B in fresh and weathered CFAs, respectively.

Comparison of 2 Doses for ACTH Stimulation Testing in Dogs Suspected of or Treated for Hyperadrenocorticism.

BACKGROUND: Lowering the cosyntropin dose needed for ACTH stimulation would make the test more economical. OBJECTIVES: To compare the cortisol response to 1 and 5 µg/kg cosyntropin IV in dogs being screened for hyperadrenocorticism (HAC) and in dogs receiving trilostane or mitotane for pituitary-dependent HAC. ANIMALS: Healthy dogs (n = 10); client-owned dogs suspected of having HAC (n = 39) or being treated for pituitary-dependent HAC with mitotane (n = 12) or trilostane (n = 15). PROCEDURES: In this prospective study, healthy dogs had consecutive ACTH stimulation tests to ensure 2 tests could be performed in sequence. For the first test, cosyntropin (1 µg/kg IV) was administered; the second test was initiated 4 hours after the start of the first (5 µg/kg cosyntropin IV). Dogs suspected of having HAC or being treated with mitotane were tested as the healthy dogs. Dogs receiving trilostane treatment were tested on consecutive days at the same time post pill using the low dose on day 1. RESULTS: In dogs being treated with mitotane or trilostane, the 2 doses were pharmacodynamically equivalent (90% confidence interval, 85.1-108.2%; P = 0.014). However, in dogs suspected of having HAC, the doses were not pharmacodynamically equivalent (90% confidence interval, 73.2-92.8%; P = 0.37); furthermore, in 23% of the dogs, clinical interpretation of test results was different between the doses. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs suspected of having HAC, 5 µg/kg cosyntropin IV is still recommended for ACTH stimulation testing. For dogs receiving mitotane or trilostane treatment, a dose of 1 µg/kg cosyntropin IV can be used.

Comparison of urine and bladder or urethral mucosal biopsy culture obtained by transurethral cystoscopy in dogs with chronic lower urinary tract disease: 41 cases (2002 to 2011).

OBJECTIVES: To compare aerobic bacterial culture of urine to cystoscopically obtained mucosal biopsies of the lower urinary tract in dogs. METHODS: Retrospective review of case records from dogs that had transurethral cystoscopy at a veterinary teaching hospital between 2002 and 2011. Dogs that had culture results from cystocentesis obtained urine and transurethral cystoscopically obtained mucosal samples were included in the study. Pathogens identified were compared between sampling methods. RESULTS: Forty dogs underwent transurethral cystoscopy for lower urinary tract disease on 41 occasions. There was significant (P = 0 · 0003) agreement between urine and mucosal biopsy cultures. Both cultures were negative in 66% and positive in 17% of dogs. There was a 17% disagreement between the sampling methods. Although not statistically significant, more mucosal samples than urine cultures were positive for Escherichia coli. CLINICAL SIGNIFICANCE: There was a good agreement between pathogen identification from urine and lower urinary tract mucosal cultures. These results do not support the utilisation of transurethral cystoscopy to obtain biopsy samples for culture in dogs with urinary tract infection and positive urine culture. Individual cases with possible chronic urinary tract infection and negative urine culture may benefit from transurethral cystoscopy to obtain biopsies for culture.

Effect of trilostane and mitotane on aldosterone secretory reserve in dogs with pituitary-dependent hyperadrenocorticism.

BACKGROUND: Maximal aldosterone secretion in healthy dogs occurs 30 minutes postadrenocorticotropin (ACTH; 5 µg/kg IV) stimulation. The effect of trilostane and mitotane on aldosterone at that time is unknown. OBJECTIVES: To assess the effect of trilostane and mitotane in dogs with pituitary-dependent hyperadrenocorticism on aldosterone secretory reserve. To determine if aldosterone concentration correlates with electrolyte concentrations. ANIMALS: Serum collected from 79 client-owned dogs and 33 stored samples. METHODS: Client-owned dogs had ACTH stimulation tests with cortisol concentrations measured at 0 and 60 minutes and aldosterone concentrations measured at 0, 30, and 60 minutes. Stored samples had aldosterone concentrations measured at 0 and 60 minutes. Ten historical clinically healthy controls were included. All had basal sodium and potassium concentrations measured. RESULTS: The aldosterone concentrations in the mitotane- and trilostane-treated dogs at 30 and 60 minutes post-ACTH were significantly lower than in clinically healthy dogs; no significant difference was detected in aldosterone concentration between 30 and 60 minutes in treated dogs. However, a significantly higher percentage of dogs had decreased aldosterone secretory reserve detected at 30 minutes than at 60 minutes. At 30 minutes, decreased secretory reserve was detected in 49% and 78% of trilostane- and mitotane-treated dogs, respectively. No correlation was detected between aldosterone and serum electrolyte concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: Decreased aldosterone secretory reserve is common in trilostane- and mitotane-treated dogs; it cannot be predicted by measurement of serum electrolyte concentrations. Aldosterone concentration at 30 minutes post-ACTH stimulation identifies more dogs with decreased aldosterone secretory reserve than conventional testing at 60 minutes.

Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003).

BACKGROUND: Serum hypercalcemia in dogs has been reported in association with a variety of diseases. Serum-ionized calcium (iCa) concentration is a more accurate measure of hypercalcemia than total serum calcium or corrected serum calcium concentrations. The severity of hypercalcemia has been utilized to suggest the most likely differential diagnosis for the hypercalcemia. HYPOTHESIS: Diseases causing ionized hypercalcemia may be different than those that cause increases in total or corrected serum calcium concentrations. The severity of ionized hypercalcemia in specific diseases cannot be used to determine the most likely differential diagnosis for ionized hypercalcemia. ANIMALS: One-hundred and nine client-owned dogs with a definitive cause for their ionized hypercalcemia evaluated between 1998 and 2003 were included in this study. METHODS: Retrospective, medical records review. RESULTS: Neoplasia, specifically lymphosarcoma, followed by renal failure, hyperparathyroidism, and hypoadrenocorticism were the most common causes of ionized hypercalcemia. Dogs with lymphoma and anal sac adenocarcinoma have higher serum iCa concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia. The magnitude of serum-ionized hypercalcemia did not predict specific disease states. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum-ionized hypercalcemia was most commonly associated with neoplasia, specifically lymphosarcoma. Although dogs with lymphosarcoma and anal sac adenocarcinoma had higher serum iCa concentrations than dogs with other diseases, the magnitude of the serum iCa concentration could not be used to predict the cause of hypercalcemia. Total serum calcium and corrected calcium concentrations did not accurately reflect the calcium status of the dogs in this study.

Evolving collective behavior in an artificial ecology.

Collective behavior refers to coordinated group motion, common to many animals. The dynamics of a group can be seen as a distributed model, each "animal" applying the same rule set. This study investigates the use of evolved sensory controllers to produce schooling behavior. A set of artificial creatures "live" in an artificial world with hazards and food. Each creature has a simple artificial neural network brain that controls movement in different situations. A chromosome encodes the network structure and weights, which may be combined using artificial evolution with another chromosome, if a creature should choose to mate. Prey and predators coevolve without an explicit fitness function for schooling to produce sophisticated, nondeterministic, behavior. The work highlights the role of species' physiology in understanding behavior and the role of the environment in encouraging the development of sensory systems.

Hyponatremia and hyperkalemia associated with peritoneal effusion in four cats.

Four cats with considerable peritoneal effusion and corresponding hyponatremia and hyperkalemia were evaluated. The Na:K ratio in all cats was < 25, which is suggestive of adrenal insufficiency. An ACTH stimulation test was performed on 3 cats for evaluation of adrenal gland function. Serum cortisol and aldosterone concentrations did not support a diagnosis of adrenal gland insufficiency. In 1 cat, histologic evaluation of the adrenal glands at necropsy also failed to support a diagnosis of hypoadrenocorticism. On the basis of these findings, and because hyponatremia and hyperkalemia could not be readily explained by another cause, the electrolyte abnormalities were presumed to be secondary to peritoneal effusion.

Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998).

OBJECTIVE: To characterize concurrent disorders in dogs with diabetes mellitus (DM). DESIGN: Retrospective study. ANIMALS: 221 dogs with DM. PROCEDURE: Medical records were reviewed, and clinical signs, physical examination findings, and results of clinicopathologic testing, urinalysis, aerobic bacterial culture of urine samples, coagulation testing, endocrine testing, histologic evaluation, diagnostic imaging, and necropsy were recorded. RESULTS: For most dogs, CBC results were normal. Common serum biochemical abnormalities included hypochloremia (127 dogs, 60%) and high alanine aminotransferase (163, 78%), aspartate aminotransferase (78, 71%), and alkaline phosphatase (188, 90%) activities. Venous pH and serum ionized calcium concentration were measured in 121 and 87 dogs, respectively, and were low in 56 (46%) and 41 (47%) dogs. Lipemia was observed in 92 (42%) dogs. Urine samples from 159 (72%) dogs were submitted for aerobic bacterial culture, and 34 (21%) yielded bacterial growth. Escherichia coli was the most commonly isolated organism. Thirty-six (16%) dogs had dermatitis or otitis. Hyperadrenocorticism was diagnosed in 51 (23%) dogs on the basis of clinical signs and results of a low-dose dexamethasone suppression test (41 dogs), an adrenocorticotropic hormone stimulation test (5), both tests (4), or histologic evaluation of necropsy specimens (1). Acute pancreatitis was diagnosed in 28 (13%) dogs. Eleven (5%) dogs had tumors for which a histologic diagnosis was obtained. Eight (4%) dogs were hypothyroid. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that dogs with diabetes mellitus may have many concurrent disorders. The most commonly identified concurrent disorders included hyperadrenocorticism, urinary tract infection, dermatitis, otitis, acute pancreatitis, neoplasia, and hypothyroidism.

Altered expression of G proteins in thyroid gland adenomas obtained from hyperthyroid cats.

OBJECTIVE: To determine whether expression of G proteins (G(i) and G(s)) is altered in thyroid gland adenomas obtained from hyperthyroid cats. SAMPLE POPULATION: Adenomatous thyroid glands obtained from 8 hyperthyroid cats and thyroid glands obtained from 4 age-matched euthyroid cats. PROCEDURE: Expression of G(i) and G(s) was quantified in enriched membrane preparations of thyroid gland tissue, using immunoblotting with G(i) and G(s) antibodies and toxin-catalyzed ADP-ribosylation. RESULTS: Expression of G(i) was significantly reduced in thyroid gland adenomas from hyperthyroid cats, compared with normal thyroid gland tissue from euthyroid cats. Expression of G(s) was similar between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: A decrease in expression of G in adenomatous thyroid glands of cats may reduce the negative inhibition of the cAMP cascade in thyroid cells, leading to autonomous growth and hypersecretion of thyroxine. Understanding the molecular mechanisms for hyperthyroidism in cats may lead to better treatment or, ultimately, prevention of the disease.

Breed distribution of dogs with diabetes mellitus admitted to a tertiary care facility.

OBJECTIVE: To determine which dog breeds are at low and high risk for developing diabetes mellitus (DM). DESIGN: Cohort study. ANIMALS: Hospital population of 221 dogs with DM and 42,882 dogs without DM during 5.5 years. PROCEDURE: 165 breeds (including a mixed-breed category) were represented in the hospital population. Breed-specific expected numbers of dogs with DM were calculated by multiplying the proportion of all dogs admitted to the hospital that were determined to have DM during the study period by the breed-specific totals during the study period. Breeds or breed groups evaluated in the analysis (n = 20) were restricted to those that had a combined observed and expected count > 5 to document breeds at low and high risk for developing DM. Proportionate changes in the risk of developing DM by breed were calculated and presented using exact odds ratios, 95% confidence intervals, and P values. Mixed-breed dogs were chosen as the reference breed. RESULTS: Samoyeds, Miniature Schnauzers, Miniature Poodles, Pugs, and Toy Poodles were at high risk for developing DM. Dog breeds found to be at low risk for developing DM were German Shepherd Dog, Golden Retriever, and American Pit Bull Terrier. CONCLUSION AND CLINICAL RELEVANCE: The finding that certain dog breeds are at low or high risk for developing DM suggests that some genetic defects may predispose dogs to development of DM, whereas other genetic factors may protect dogs from development of DM.

Effects of insoluble and soluble dietary fiber on glycemic control in dogs with naturally occurring insulin-dependent diabetes mellitus.

OBJECTIVE: To evaluate the effects of diets differing in type and quantity of fiber on glycemic control in dogs with naturally occurring insulin-dependent diabetes mellitus. DESIGN: Prospective randomized crossover controlled trial. ANIMALS: 7 dogs with well-regulated naturally occurring insulin-dependent diabetes mellitus. PROCEDURE: Dogs were fed 1 of 3 diets for 1 month each in 1 of 6 randomized diet sequences. Diets included a low-fiber diet (LF) and 2 high-fiber diets; 1 contained only insoluble fiber (HIF), and 1 contained soluble fiber in addition to insoluble fiber (HSF). Caloric intake was unchanged throughout the study. Glycemic control was assessed after each feeding trial by measuring serum fructosamine concentration and performing 5 serial measurements of blood glucose concentration every 2 hours after the morning feeding and insulin injection. RESULTS: Significant differences were not detected in body weight, required insulin dosage, or albumin concentration among dogs fed the HIF, HSF, and LF diets. Mean and maximum blood glucose concentrations and area under the blood glucose curve were significantly lower in dogs fed the HIF diet, compared with values in the same dogs fed the HSF or LF diet. Fructosamine concentration was significantly lower in dogs fed the HIF or HSF diet, compared with values in the same dogs fed the LF diet. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with naturally occurring insulin-dependent diabetes mellitus, a dry, high insoluble-fiber diet may aid in glycemic control.

Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221 cases (1993-1998).

OBJECTIVE: To evaluate glycemic response to insulin treatment in dogs with diabetes mellitus. DESIGN: Retrospective study. ANIMALS: 221 dogs with diabetes mellitus. PROCEDURE: Type and dosage of insulin used, minimum and maximum blood glucose concentrations, time of blood glucose concentration nadir, and optimal duration of action of insulin were determined on the basis of data obtained prior to initial examination at the teaching hospital (127 dogs), at the time of initial examination (212 dogs), at the time a second follow-up blood glucose curve was performed (59 dogs), and at the time of clinical control of diabetes mellitus (83 dogs). RESULTS: Prior to examination, 69 of 127 dogs (54%) received 1 s.c. insulin injection daily. Thirty-one dogs (24%) received a high dose of insulin (i.e., > 1.5 U/kg [0.7 U/lb] of body weight); 27 of these dogs (87%) received 1 injection/d. Eleven of 16 dogs (69%) that were hypoglycemic (blood glucose concentration < 80 mg/dl) also received 1 injection/d. However, optimal duration of action of insulin was > 12 hours in only 5 of 83 dogs (6%) evaluated at the time diabetes mellitus was clinically controlled. At that time, only 1 dog (1%) received a high dose of insulin, and the dog received 2 injections/d. Moreover, 8 of 10 dogs (80%) with hypoglycemia received 1 injection/d. CONCLUSIONS AND CLINICAL RELEVANCE: Most dogs with diabetes mellitus are clinically regulated with 2 daily insulin injections. Administration of a high dose of insulin or development of hypoglycemia may be more common in diabetic dogs that receive insulin once daily, compared with dogs that receive insulin twice daily.

The monomeric GTP binding protein, rab3a, is associated with the acrosome in mouse sperm.

Exocytosis of the sperm acrosome is an obligate precursor to successful egg penetration and subsequent fertilization. In most mammals, acrosomal exocytosis occurs at a precise time, after sperm binding to the zona pellucida of the egg, and is induced by a specific component of the zona pellucida. It may be considered an example of regulated secretion with the acrosome of the sperm analogous to a single secretory vesicle. Monomeric G proteins of the rab3 subfamily, specifically rab3a, have been shown to be important regulators of exocytosis in secretory cells, and we hypothesized that these proteins may regulate acrosomal exocytosis. Using alpha[32P] GTP binding to Immobilon blotted mouse sperm proteins, the presence of three or more monomeric GTP binding proteins was identified with Mr = 22, 24, and 26 x 10(3). Alpha[32P] GTP binding could be competed by GTP and GDP, but not GMP, ATP, or ADP. Anti-peptide antibodies specific for rab3a were used to identify the 24 kDa G protein as rab3a. Using immunocytochemistry, rab3a was localized to the head of acrosome-intact sperm and was lost during acrosomal exocytosis. It was identified in membrane and cytosolic fractions of sperm with the predominant form being membrane-bound, and its membrane association did not change upon capacitation. Immunogold labeling and electron microscopy demonstrated a subcellular localization in clusters to the periacrosomal membranes and cytoplasm. These data identify the presence of rab3a in acrosomal membranes of mouse sperm and suggest that rab3a plays a role in the regulation of zona pellucida -induced acrosomal exocytosis.

Carotid sinus hypersensitivity--a modifiable risk factor for fractured neck of femur.

BACKGROUND: the potential impact on morbidity, mortality and health care economics makes it important to identify patients at risk of fracture, in particular fractured neck of femur (FNOF). Older patients with carotid sinus hypersensitivity (CSH) are more likely to have unexplained falls and to experience fractures, particularly FNOF. Our objective was to determine the prevalence of CSH in patients with FNOF. DESIGN: case-controlled prospective series. METHODS: consecutive cases were admissions over 65 years with FNOF. Controls were consecutive patients admitted for elective hip surgery, frail elderly people admitted to hospital medical wards and day-hospital patients. All patients had a clinical assessment of cognitive function, physical abilities and history of previous syncope, falls and dizziness, in addition to repeated carotid sinus massage with continuous heart rate and phasic blood pressure measurement. RESULTS: heart rate slowing and fall in systolic blood pressure was greater for patients with FNOF than those admitted for elective hip surgery (P < 0.05 and P < 0.001). CSH was present in 36% of the FNOF group, none of the elective surgery group, 13% of the acutely ill controls and 17% of the outpatients. It was more likely to be present in FNOF patients with a previous history of unexplained falls or an unexplained fall causing the index fracture. The heart rate and systolic blood pressure responses to carotid sinus stimulation were reproducible. CONCLUSION: older patients with an acute neck of femur fracture who do not give a clear history of an accidental fall or who have had previously unexplained falls are likely to have CSH. CSH may be a modifiable risk factor for older patients at risk of hip fracture.

Association between hyperadrenocorticism and development of calcium-containing uroliths in dogs with urolithiasis.

OBJECTIVE: To determine, among dogs with urolithiasis, whether dogs that had hyperadrenocorticism would be more likely to have calcium-containing uroliths than would dogs that did not have clinical evidence of hyperadrenocorticism. DESIGN: Retrospective case-control study. ANIMALS: 20 dogs that had urolithiasis and hyperadrenocorticism and 42 breed-matched dogs that had urolithiasis but did not have clinical evidence of hyper-adrenocorticism. PROCEDURE: Signalment, urolith composition, results of bacterial culture of urine, and results of adrenal axis tests were recorded. A multivariate logistic regression model was created, including terms for age, sex, and hyperadrenocorticism. The outcome variable was presence or absence of calcium-containing uroliths. RESULTS: Among dogs with urolithiasis, those that had hyperadrenocorticism were 10 times as likely to have calcium-containing uroliths as were dogs that did not have clinical evidence of hyperadrenocorticism (odds ratio, 10.5; 95% confidence interval, 1.5 to 23.4). Neutered and sexually intact females were less likely to have calcium-containing uroliths than were neutered males (odds ratios, 0.041 [95% confidence interval, 0.0057 to 0.29] and 0.024 [95% confidence interval, 0.0012 to 0.51, respectively). CLINICAL IMPLICATIONS: Prompt diagnosis and treatment of hyperadrenocorticism may decrease prevalence of calcium-containing uroliths in dogs.

Diabetes mellitus, hyperadrenocorticism, and hypothyroidism in a dog.

An unusual combination of three endocrinopathies found in one dog is described. A six-year-old, spayed female, mixed-breed dog presented with polyuria, polydipsia, polyphagia, and weight loss. She was diagnosed with diabetes mellitus but was suspected of having insulin resistance and was diagnosed subsequently with hyperadrenocorticism. Persistent hypercholesterolemia led to the suspicion and eventual diagnosis of hypothyroidism. The dog has responded well to medical therapy, and her clinical signs and biochemical changes have resolved. A literature search did not identify a similar-reported polyendocrinopathy.

Midodrine: a role in the management of neurocardiogenic syncope.

OBJECTIVE: To determine the benefit of midodrine, an alpha agonist, on symptom frequency and haemodynamic responses during head up tilt in patients with neurocardiogenic syncope. SETTING: Cardiovascular investigation unit (a secondary and tertiary referral centre for the investigation and management of syncope). PATIENTS: 16 outpatients (mean (SD) age 56 (18) years; five men) with frequent hypotensive symptoms (more than two syncopal episodes and fewer than 20 symptom free days per month), and reproducible syncope with glyceryl trinitrate (GTN) during head up tilt. DESIGN AND INTERVENTION: Randomised double blind placebo controlled study. Patients were randomised to receive either placebo or midodrine for one month. Symptom events were recorded during each study month. At the end of each study month patients completed a quality of life scoring scale (Short Form 36) and a global assessment of therapeutic response. They received GTN with head up tilt for measurement of heart rate (electrocardiography), phasic blood pressure (digital photoplethysmography), and thoracic fluid index (transthoracic impedance plethysmography) during symptom provocation. RESULTS: Patients administered midodrine had an average of 7.3 more symptom free days than those who received placebo (95% confidence interval (CI) 4.6 to 9; p < 0.0001). Eleven patients reported a positive therapeutic response with midodrine (p = 0.002). All domains of quality of life showed improvement with midodrine, in particular physical function (8.1; 95% CI 3.7 to 12.2), energy and vitality (14.6; 95% CI 7.3 to 22.1), and change in health status (22.2; 95% CI 11 to 33.4). Fourteen patients who were given placebo had tilt induced syncope compared with six given midodrine (p = 0.01). Baseline supine systolic blood pressure was higher and heart rate lower in patients who received midodrine than in those who were given placebo (p < 0.05). A lower thoracic fluid index in patients administered midodrine indicates increased venous return when supine and during head up tilt. There were no serious adverse effects. CONCLUSIONS: Midodrine had a conspicuous beneficial effect on symptom frequency, symptoms during head up tilt, and quality of life. Midodrine is recommended for the treatment of neurocardiogenic syncope in patients with frequent symptoms.

A hook-traction technique for Norplant removal.

We describe a simple technique to facilitate the removal of difficult-to-remove Norplant implants. Through a standard skin incision for Norplant removal, the fibrous capsule surrounding the implant is secured using either a dermatologic skin hook or a 25-gauge hypodermic needle fashioned into a hook with a hemostat. Traction is applied to bring the fibrous sheath into the incision site, where the implant tip is dissected free using a scalpel. The precisely localized countertraction afforded by this technique provides increased accuracy and speed for the removal of difficult-to-extract implants. Tissue trauma is minimized and the need to extend the skin incision is reduced.

Activation of a Gi protein in digitonin/cholate-solubilized membrane preparations of mouse sperm by the zona pellucida, an egg-specific extracellular matrix.

Mammalian sperm possess guanine nucleotide-binding regulatory proteins (G proteins) that are involved in signal transduction pathways leading to zona pellucida (ZP)-mediated acrosomal exocytosis. We have previously examined ZP-G protein dynamics in mouse sperm homogenates, as well as cell-free membrane preparations, and our data support the existence of ZP receptor-G protein complexes in sperm membranes. However, the composition of this complex has not been identified due to experimental limitations of the membrane preparations. In the present study, a detergent-solubilized preparation from mouse sperm membranes that retained the signaling properties of cell homogenates and cell-free membrane preparations was developed using buffers containing digitonin and cholate. GTP gamma S, a poorly hydrolyzable analogue of GTP, bound to these solubilized preparations in a specific and concentration-dependent fashion that reached saturation at 100 nM. Incubation of this solubilized membrane preparation with heat-solubilized ZP resulted in an increase in specific GTP gamma S binding in a concentration-dependent manner, with a maximal response at 4-6 ZP/microliters. Mastoparan (50 microM) increased GTP gamma S binding to levels similar to that seen with solubilized ZP. Mastoparan plus ZP stimulated GTP gamma S binding to the same extent as mastoparan or ZP alone. Pertussis toxin completely inhibited ZP-stimulated GTP gamma S binding and decreased mastoparan-stimulated GTP gamma S binding by 50-60%. Purified ZP3, the ZP component that possesses quantitatively all of the sperm binding and acrosomal exocytosis-inducing activities of the intact ZP, stimulated GTP gamma S binding to an extent similar to that of solubilized ZP.(ABSTRACT TRUNCATED AT 250 WORDS)