[Transobturator correction of cystocele]. / Corrección transobturatoria de los cistoceles.

OBJECTIVE: We present our initial experience with the Perigee system for anterior vaginal wall prolapses repair. MATERIAL AND METHOD: 15 patients with anterior vaginal wall prolapse (mean age: 62 years old) underwent implanted with Perigee system which is composed by a mesh for correcting central defect and four self-attached horns for correcting lateral defect. The implanted procedure consist of four steps: 1) lateral vaginal wall dissection as far as isquiopubic branch; 2) performance of two upper marks at genitofemoral fold and two lower marks at 2 cm laterally and 3 cm lower; 3) insertion of the upper needles parallel to the isquiopubic branch and connection with the mesh's "arms" plus insertion of the lower needles vertically and connection with mesh's "legs"; 4) to adjust the mesh free tension. The system POP-Q was used as an objective measure of correction rate. RESULTS: Preoperatively, the point Aa was 0.09. After 6 weeks and three months postoperatively was -3.00 and -2.73 respectively. Preoperatively, the point Ba was 1.73. After 6 weeks and three months postoperatively was -2.82 and -2.82 respectively. No major complications were presented. No vascular damage or significant bleeding was observed. CONCLUSION: The transobturator correction of cystocele is an attractive alternative. The initial good outcome may be expected to be long lasting.

Cloning and characterization of a vacuolar ATPase A subunit homologue from Plasmodium falciparum.

The distribution of the antimalarial drug chloroquine is determined to a significant extent by a transvacuolar pH gradient in Plasmodium falciparum. A proton pump similar to the vacuolar ATPase found in many cell types has been suggested to maintain a pH gradient across the membranes of acidic compartments in the parasite. In order to understand and define the components involved in the mechanism of acidification of parasite vesicles, we have cloned and characterized a gene, designated VAP-A, encoding a P. falciparum homologue of the catalytic A subunit of the vacuolar ATPase. The VAP-A gene encodes a polypeptide of 611 amino acids which shows between 56 to 61% amino acid identity over its entire length with the sequences of vacuolar ATPase A subunits from several species. The VAP-A gene exists as a single copy gene on P. falciparum chromosome 13 and gives rise to a transcript of 3.7 kb. Antibodies raised against a VAP-A gene segment expressed in Escherichia coli react specifically with a 67-kDa polypeptide, consistent with the size predicted from the sequence and with the size of the corresponding polypeptide in other organisms. The 67-kDa protein is present throughout the asexual erythrocytic cycle and is expressed at similar levels in 5 P. falciparum isolates of differing chloroquine sensitivity. Sequence analysis of the coding region of the VAP-A gene from 2 chloroquine-sensitive and 3 chloroquine-resistant isolates has shown no changes that are linked to chloroquine resistance. Therefore, a proposed chloroquine resistance-linked vacuolar acidification defect does not involve mutations in the VAP-A gene in the isolates we have studied.

Cloning and characterization of the vacuolar ATPase B subunit from Plasmodium falciparum.

The transvacuolar pH gradient determines, to a significant extent, the distribution of the antimalarial drug chloroquine in Plasmodium falciparum. A proton pump, similar to the vacuolar ATPase found in many cell types, appears to regulate a pH gradient across the membranes of acidic compartments of the parasite. In order to understand and define the components involved in the maintenance of the vacuolar pH gradient, we have cloned and characterized a gene, designated VAP B, encoding a P. falciparum homologue of the B subunit of the vacuolar ATPase. The VAP B gene encodes a protein of 494 amino acids which has between 69% and 74% amino acid identity with the sequences of vacuolar ATPase B subunits of other organisms. The VAP B gene exists as a single copy gene on chromosome 4 that gives rise to a RNA transcript of 2.4 kb. Antibodies raised to the VAP B protein react specifically with a protein of 56-kDa, consistent with the size predicted from the gene sequence and with the homologous protein from other organisms. The 56-kDa protein is expressed throughout the asexual life cycle and subcellular localization by indirect immunofluorescence shows that the protein has a heterogeneous distribution over most of the parasite. This suggests that the function of the vacuolar proton ATPase is not confined to the regulation of the pH of the digestive vacuole.

Further characterisation of the Schistosoma japonicum protein Sj23, a target antigen of an immunodiagnostic monoclonal antibody.

Sj23, the 23-kDa target antigen in Schistosoma japonicum adult worms of the hybridoma monoclonal antibody (mAb) I-134, has been identified and cloned from cDNA libraries, mAb I-134 has been successfully used in immunodiagnostic assays to detect S. japonicum infection in Philippine patients. Sequence analysis has shown that Sj23 is the homologue, with 84% amino acid identity, of Sm23, a 23-kDa molecule from S. mansoni worms previously described from our laboratory. The domain structures of Sj23 and Sm23 are strikingly similar to the human membrane proteins ME491, CD37, CD53 and TAPA-1, which may suggest a functional role for the schistosome molecules in cellular proliferation.

Adenocarcinoma of the vermiform appendix.

Primary carcinoma of the appendix, though rare, occurs often enough to warrant its inclusion in diagnostic possibilities when the symptoms of acute appendicitis, without leukocytosis, are present in geriatric patients. A case of mucinous adenocarcinoma of the appendix in an 88-year-old white woman is presented. The substantial relief following right hemicolectomy has persisted for several months of follow-up.

Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans.

Beta2-adrenergic receptors (beta2-AR) contribute to cardiovascular regulation by influencing several functions and previous studies suggest that a decreased function of the beta2-AR may be involved in essential hypertension. Beta2-AR are polymorphic and certain polymorphisms of these receptors are of functional importance. We focus here on the Arg16-->Gly16 beta2-AR polymorphism, which shows enhanced agonist-promoted downregulation of the receptor and which, in two recent studies, yielded opposite results in terms of association with essential hypertension: an increased frequency of the Gly16 variant in African-Caribbean hypertensives and of the Arg16 variant in offspring of Norwegian white hypertensive parents. In the current study, we genotyped 243 subjects, including both African-American and white individuals, for codon 16 polymorphism and assessed blood pressure and cardiovascular function using impedance cardiography and pressor sensitivity to phenylephrine. We found similar patterns of cardiovascular function and expression of hypertension with the two genotypes of codon 16. There was no statistically significant difference in the overall allelic distribution of the two genotypes: among African-Americans, 51% of the hypertensives and 50% of the normotensives carried the Arg16 allele, whereas among the white subjects 40% of the hypertensives and 47% of the normotensives were carriers of the Arg16 allele. Although we observed a statistically significant increase in the Arg16/Gly16 heterozygotes in the African-American population, the Gly16 allele was not significantly increased in the African-Americans compared to whites. These findings indicate that the codon 16 polymorphisms are not associated with hypertension in a mixed American study population nor do they appear to substantially impact on a variety of hemodynamic variables.

Evaluation of intragastric pH in acutely ill patients.

The effect of various modalities on maintaining a high intragastric pH in acutely ill patients was evaluated. Twelve patients with one or more organ system failures had the effect of nasogastric suction, intragastric antacid instillation, and intravenous cimetidine administration on intragastric pH determined by an indwelling, intragastric pH probe. Each therapeutic modality was administered for 12 hours and the order of performance randomized. Nasogastric suction was associated with a constant intragastric pH of less than 2.0. Mean intragastric pH with cimetidine administration was significantly higher than with antacid administration and consistently greater than 5.0. If low intragastric pH represents susceptibility to acute mucosal lesions, cimetidine therapy was more effective than antacids in the doses and frequency of administration used in this study in maintaining a high intragastric pH, and it may be effective in preventing stress ulcer formation.

Pancreatitis after biliary tract surgery.

Pancreatitis associated with biliary tract operations continues to be an important clinical problem. The results of biliary tract operations performed on 1256 patients were carefully scrutinized for the presence of postoperative hyperamylasemia and pancreatitis persisting after 48 hours. Patients were evaluated in the context of the presence or absence of preoperative pancreatic dysfunction. Similarly, various operative risk factors were evaluated, including cholangiography, choledocholithiasis, common duct exploration, choledochoscopy, choledochoduodenostomy, and sphincteroplasty. Operative cholangiography did not induce postoperative pancreatitis. The incidence of postoperative pancreatitis following cholecystectomy was 0.6%, which was significantly greater than the incidence following common duct exploration (8.4%). Pancreatitis following biliary tract surgery seemed to be not directly related to the performance of choledochoscopy, sphincteroplasty, or choledochoduodenostomy, as it developed with similar frequency in patients undergoing common duct exploration alone. The timing of operative therapy in patients with biliary tract pancreatitis did not significantly alter the frequency with which pancreatitis persisted in the postoperative period. In 970 patients undergoing cholecystectomy, one patient who had preoperative pancreatitis died of postoperative pancreatitis. Of 286 patients undergoing common duct exploration, seven patients died with pancreatitis. In three of these patients there was no active preoperative pancreatitis, and in one of these patients pancreatitis was the cause of death. Four patients with preoperative pancreatitis eventually died of pancreatitis in the postoperative period. Pancreatitis is an important complication of biliary tract disease and operations, and all efforts should be extended to suppress its occurrence and development.

The Blalock-Hanlon procedure. Simple transposition of the great arteries.

Between 1959 and 1975 at St. Louis University Medical Center, 71 patients underwent surgery with the Blalock-Hanlon technique. Thirty-nine had simple transposition of the great vessels. The mean age at the time of operation was 3.4 weeks. Sixty-four percent were less than 1 month of age. Eighty-five percent survived the operation. In 11 the Blalock-Hanlon procedure was performed after failure of ballon septostomy. Arterial saturation was increased from a mean of 47% to 73%. There were three late deaths prior to Mustard repair (intra-atrial baffle procedure). Sixteeen patients underwent Mustard repair at a mean age of 4 years and a mean follow-up of 2 1/2 years. There were three deaths after surgery and three late deaths after the Mustard procedure. The Blalock-Hanlon procedure achieves prolonged palliation, avoiding an emergency Mustard procedure in infancy with its risk of late vena caval obstruction.

Hyperbilirubinemia without common bile duct abnormalities and hyperamylasemia without pancreatitis in patients with gallbladder disease.

OBJECTIVE: To determine the incidence of jaundice and hyperamylasemia in the absence of common bile duct abnormalities or clinical pancreatitis in patients undergoing cholecystectomy. DESIGN: A continuous, prospective analysis of a consecutive case series was performed on all patients undergoing cholecystectomy. SETTING: An urban, tertiary care university hospital. PATIENTS: Adult patients with gallbladder disease. INTERVENTION: All patients underwent cholecystectomy. MAIN OUTCOME MEASURES: The presence or absence of common bile duct abnormalities was evaluated by cholangiography, and pancreatitis was identified by clinical signs, imaging studies, and direct visual inspection during cholecystectomy. RESULTS: All patients (N = 1746) undergoing cholecystectomy were prospectively categorized as having chronic calculous (n = 1410), acute calculous (n = 217), chronic acalculous (n = 70), or acute acalculous (n = 49) gallbladder disease. It was uncommon for patients with chronic calculous cholecystitis to have an elevated bilirubin level with no choledocholithiasis and a normal common bile duct or to have hyperamylasemia without pancreatitis. Twenty-five percent of the patients with acute calculous cholecystitis had a serum bilirubin level between 34 and 86 mumol/L (2.0 and 5.0 mg/dL) with no common bile duct abnormality and 4% had hyperamylasemia without pancreatitis. Over one third of the patients with acute acalculous cholecystitis had an elevated bilirubin level with a normal common bile duct or an elevated amylase level without pancreatitis. CONCLUSION: Jaundice and hyperamylasemia can be produced by gallbladder disease alone.

Repair of aortic coarctation in the first year of life.

Twenty-five infants under 1 year of age (mean, 10.3 weeks and 4.0 kg) underwent coarctation repair. Eight had ventricular septal defect (VSD), 3 had transposition of the great arteries with VSD, and 5 had severe tubular hypoplasia. One infant required mitral valve replacement, and 1 required repair of total anomalous pulmonary venous return. Fifteen had repair by primary anastomosis. Seven underwent Dacron or subclavian aortoplasty; the advantages and technique of angioplasty are reviewed. Three patients required bypass grafts. Seventeen patients survived operation. All 5 patients who had severe tubular hypoplasia died postoperatively. The mortality for repair of coarctation with VSD by simultaneous pulmonary artery banding was high; for coarctation with VSD we currently recommend repair without banding, followed by VSD closure if indicated. Three infants have been treated successfully in this manner, with early VSD closure in 1 and regression of the VSD during follow-up in 2. The 17 survivors have been followed for a mean of 41 months with 3 late deaths. Of the 17 survivors, all of whom had a primary anastomosis, 3 have residual gradients. Of the 11 survivors who had preoperative hypertension, 6 are still hypertensive; 3 of these have a gradient between the upper and lower extremities. It is striking that 3 have persistent hypertension despite repair under the age of 1 year.

Planned reoperation for generalized intraabdominal infection.

Intraabdominal infection remains a common cause of death in surgical patients. Progress in this area with improved survival rates is difficult to demonstrate despite the use of antibiotics, nutritional support, and aggressive maintenance of function of failed organs. This report documents our experience with planned reoperation to cleanse the abdominal cavity in 77 patients with generalized intraabdominal infection. In 34 of the patients, reoperation to cleanse the abdominal cavity was performed every 24 to 48 hours after the first operation until the abdominal cavity was judged to be clean. Forty-three patients underwent a single operation for intraabdominal contamination and were treated expectantly, only undergoing reoperation for signs of recurrent infection. In all patients, the hole in the intestinal tract was controlled primarily by stoma formation at the initial operation to treat intraabdominal infection. Patients with appendiceal disease were excluded. The severity of illness in the two patient groups was compared by a modified acute physiologic score. Planned reoperation was not associated with improvement in survival when compared with patients managed expectantly. Patients managed by planned reoperation had significantly more laparotomies than patients managed expectantly without improving survival. The results of this study disclosed that empiric reoperation to clean the abdominal cavity in patients with generalized intraabdominal infection produced no improvement in survival when compared with observation and reoperation when indicated.

Colonization and sepsis from triple-lumen catheters in critically ill patients.

Sepsis from central triple-lumen catheters remains a serious and life-threatening problem. Patients requiring triple-lumen catheter placement frequently have multiorgan failure or very serious illness. Every effort should be made to reduce the incidence of catheter-related sepsis. Earlier recognition of catheter sepsis may allow removal of the offending line before sepsis becomes clinically apparent. These data indicate that line colonization occurs early and frequently after triple-lumen catheter placement, and suggests that early, frequent line changes may reduce the incidence of clinical sepsis.

Ethical issues in instituting and discontinuing enteral feeding.

The shift from inpatient care has not lessened the importance of ethical issues in caring for patients. Dilemmas involving withholding and withdrawing enteral nutrition require input from the patient, family, and caregivers. Decisions to forego or discontinue treatment such as home enteral support should never be distinguished from the responsibility of providing support and compassionate care throughout life, even during dying.

A fast 3D-imaging technique for performing dynamic Gd-enhanced MRI of breast lesions.

The characterization of breast lesions by their Gd-enhancement profiles has been proposed as a method for differentiating benign from malignant breast lesions. The limitations of dynamic contrast enhanced 2D imaging of the breast are the low number of slices that can be acquired, and the need to know the location of the lesion a priori to correctly select the noncontiguous 2D slice locations. These problems are exacerbated when multi-focal disease is present but not anticipated. Standard fast 3D gradient-echo imaging has a variable delay between successive acquisitions. We have developed a fast 3D gradient-echo imaging technique for dynamic Gd-DTPA enhanced breast imaging which obtains multiple 3D image sets of 32 contiguous images at 44 s intervals without an interscan delay time. This rapid 3D imaging technique achieves good temporal resolution and reduces patient motion between pre- and postcontrast images while covering a much larger portion of the breast and eliminating the need for a priori knowledge concerning the location of the lesion(s) when performing Gd-enhanced dynamic MR imaging.

Dynamic sequential 3D gadolinium-enhanced MRI of the whole breast.

Dynamic contrast-enhanced 2D MR imaging of the breast has shown high sensitivity and specificity for the detection and characterization of breast lesions. We investigated the ability of a dynamic fast 3D MR imaging technique that repeatedly scans the whole breast in 44-s intervals without an interscan delay time to obtain similar sensitivity and specificity as 2D imaging. Fifty-six patients scheduled for breast biopsy were entered into the study, and 83 lesions detected by 3D dynamic scanning were biopsied. Dynamic 3D contrast-enhanced breast imaging with subtraction detected and correctly classified all 23 cancers, and 44 of the 60 benign lesions yielding a sensitivity of 100%, a specificity of 73%, and a 100% predictive negative value. The enhancement profiles of metastatic lymph nodes were similar to those of primary cancer. This technique allowed detection of multifocal and multicentric lesions and did not require a prior knowledge of lesion location. These results indicate that dynamic contrast-enhanced 3D MRI of the whole breast is a useful and economically feasible method for staging breast cancer, providing a comprehensive noninvasive method for total evaluation of the breast and axilla in patients considering breast conservation surgery or lumpectomy.

Pancytopenia after removal of copper from total parenteral nutrition.

Patients who develop cholestatic jaundice during chronic total parenteral nutrition (TPN) can develop significant hematologic complications due to hypocupremia if copper supplementation is withheld. A 36-year-old female with short bowel syndrome developed progressive liver dysfunction 6 months after initiation of TPN. Trace elements were omitted from her TPN because of cholestasis and persistent hyperbilirubinemia. Despite chronic diarrhea, absorption of some dietary copper was anticipated from her oral diet. Fifteen months later, the patient became red cell transfusion dependent, and her neutrophil and platelet counts steadily declined. After 19 months of receiving TPN without trace elements, her serum copper level was 25 microLg/dL (normal: 70 to 155 microg/dL). Provision of trace elements for 2 months was associated with increased serum copper, neutrophil and platelet counts and independence from red cell transfusions. When the serum copper level reached 186 microg/dL, copper supplementation was discontinued. Over the next 3 months, serum copper level fell to 10 microg/dL, neutrophil and platelet counts fell precipitously, and red cell transfusions were resumed. Once again, copper, neutrophil and platelet levels promptly rebounded with parenteral copper supplementation. Although anemia and neutropenia are well-recognized hematologic consequences of copper deficiency, thrombocytopenia rarely has been reported. This is the first report of pancytopenia secondary to TPN-related copper deficiency in which the association was confirmed when hypocupremia recurred.

Repeated lipoinjections for stress urinary incontinence.

A total of 30 women with stress incontinence underwent periurethral injection of autologous fat under spinal anesthesia. The fat was harvested from the abdominal wall by liposuction. Preoperative evaluation consisted of history, physical examination, and urodynamic evaluation. For study purposes, some patients also underwent bladder and urethral ultrasonography and magnetic resonance imaging studies. The first 13 patients received a single periurethral lipoinjection, and the following 17 patients received sequential injections when needed at 3-month intervals. Results were assessed by subjective questionnaire performed at 3 and 12 months. All patients had intrinsic sphincteric deficiency. Of the first group, there were only four patients (31%) cured after 1 year of follow-up. On the other hand, in the group that received repeated injections, there were 11 patients (64%) cured with a mean of two injections at 1-year follow-up. Our results show that this procedure warrants continued clinical investigation because it may be useful in selected cases of urinary stress incontinence.

Pharmacodynamic and pharmacokinetic properties of an angiotensin II receptor antagonist--characterization by use of Schild regression technique in man.

OBJECTIVE: The pharmacodynamic properties of a new angiotensin II receptor antagonist (BAY 10-6734) in humans were to be quantitatively characterized from the rightward shifts of the agonist dose-response curves after administration of different doses of the antagonist. METHODS: 24 healthy male volunteers received single oral doses of 20-300 mg BAY 10-6734. Before and up to 23 h post dosing (p.d.) plasma was obtained for HPLC measurement of parent compound and active metabolite BAY 10-6735. Exogenous angiotensin II was infused in increasing dose steps until blood pressure had increased by +25 mmHg. Angiotensin II dose-response curves were fitted individually using the sigmoidal Emax model. From the antagonist-induced rightward shifts, as compared to a premedication curve, dose ratios (DR) were determined and DR-1 plotted versus applied dosages and measured plasma concentrations. From these Schild regression plots the fictive doses and concentration (Ki) inducing a DR-1 = 1, i.e. a 2-fold shift in agonist dose-response curves, were derived. The "doubling (t2.0) time" of the apparent Ki doses was calculated. RESULTS: BAY 10-6734 dose-dependently induced rightward shifts of the angiotensin II blood pressure response curves, mean maximum DR at 2 h p.d. ranged from 42 (80 mg) to 216 (300 mg), and at 23 h p.d. decreased to about 2 (80 mg) to 4 (300 mg). Pharmacodynamic (3.4-4.6 h) and pharmacokinetic half-lives (3.4-4.3 h) were nearly identical. Apparent Ki doses increased from about 1-2 mg at 2 h p.d. to about 80-100 mg at 23 h p.d., their time course revealed a doubling (t2.0) time of 3.5-3.8 h. A Ki concentration of about 10 micrograms/l was obtained for the active metabolite BAY 10-6735. CONCLUSIONS: Oral administration of BAY 10-6734 in man antagonized angiotensin II dose blood pressure response curves in a dose-dependent manner. The time kinetics of the pharmacodynamic effect, derived from the decay of DR-1 values, as well as the doubling time of the apparent Ki values well agreed with the pharmacokinetic half-life. Schild regression revealed competitive angiotensin II antagonistic properties within the dose/concentration range tested. This technique was shown to be an adequate means to evaluate pharmacodynamic potency and kinetic behavior of an angiotensin II receptor antagonist in vivo.

Comparative pharmacodynamics and pharmacokinetics of candesartan and losartan in man.

The angiotensin II antagonistic effects of candesartan and losartan were compared in-vivo after single and repeated doses. Effects were related to antagonistic activity in plasma. In this double-blind, crossover study, 12 healthy male volunteers received, in random order, daily oral doses of 8 mg candesartan cilexetil or 50 mg losartan for seven days. On day 1 and day 8, dynamics and kinetics were assessed up to 48 h after dosing. Antagonistic effect was determined from the antagonist-induced rightward shifts of the diastolic blood pressure response curves to exogenously administered angiotensin II measured as the dose ratio (DR). The antagonistic activity in plasma was measured using an ex-vivo/in-vitro radioreceptor assay. Specific high-performance liquid chromatography assays determined plasma concentrations of candesartan, losartan and its active metabolite EXP-3174. The pharmacokinetic properties of candesartan and losartan were comparable and antagonistic activity in plasma almost identical (ratio candesartan: losartan = 0.97 and 1-2 after single and multiple doses, respectively). However, the antagonistic effects of candesartan and losartan in-vivo were quite different. Twenty-four hours after single dosing with candesartan a clinically relevant rightward shift in the angiotensin II dose-response curve (DR= 3.2) occurred that was more pronounced than that following losartan administration (DR=2.1, ratio candesartan: losartan= 1.65). Twenty-four hours after multiple doses of candesartan or losartan, the values of the DR were 4.8 and 2.3, respectively (ratio candesartan: losartan = 1.94). The values of DR for candesartan were significantly higher compared with losartan between 6 and 36h after a single dose and between 3 and 24 h post-dose following multiple dose administration. A counter-clockwise hysteresis was apparent between antagonistic activity in plasma and antagonistic effect. Despite equivalent angiotensin II antagonistic activity in plasma, the pharmacodynamic effect of candesartan cilexetil was greater than that of losartan. Candesartan appeared to have a slower off-rate from the angiotensin AT1-receptor compared with losartan, nevertheless differences in distributional phenomena or the extent of insurmountable antagonistic activity cannot be ruled out.