Adverse drug reactions (ADRs) associated with hospital admissions - elderly female patients are at highest risk.

BACKGROUND: ADRs represent a significant problem in drug utilisation. The prevalence of admissions caused by ADRs varies depending on the observational site, studied population, data collection method and the used definitions. Women seem to be more frequently affected than men. OBJECTIVE: To assess the incidence and quality of ADRs related to hospital admissions, to identify the drugs most commonly involved and to define risk factors and preventive strategies for those ADRs. MATERIAL AND METHODS: 3,190 medical records of all newly admitted internal ward patients were assessed in a prospective observational study in an internal hospital over 6 months. Potential ADRs at hospital admission were identified following a list of suspicious symptoms and laboratory results. Cases were evaluated by means of a computer tool and data-base specialized on detecting causality and severity of ADRs. RESULTS: 304 ADRs were identified in 242 patients (7.6%), with 60% directly leading to admission. More women than men encountered an ADR (10 vs. 6%, p < 0.005). Analyzed separately by age groups, this gender difference became significant at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances and over-anticoagulation. Diuretics and vitamin K antagonists were significantly correlated with ADRs. 62% of all ADRs were severe or life-threatening. CONCLUSION: ADRs leading or related to hospital admission are highly prevalent. Older age and female gender are significantly associated with ADR related hospital admissions. Causative drugs are the ones prescribed most frequently. Multidisciplinary preventive strategies and surveillance methods are necessary to ensure better care and patient safety especially for elderly women.

Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms.

The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-ß (TGFß) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFß/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFß to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFß was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.

Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression.

The canonical WNT signaling pathway is crucial for intestinal stem cell renewal and aberrant WNT signaling is an early event in colorectal cancer (CRC) development. Here, we show for the first time that WNT2 is one of the most significantly induced genes in CRC stroma as compared to normal stroma. The impact of stromal WNT2 on carcinoma formation or progression was not addressed so far. Canonical WNT/ß-catenin signaling was assessed using a 7TGP-reporter construct. Furthermore, effects of WNT2 on fibroblast migration and invasion were determined using siRNA-mediated gene silencing. Tumor cell invasion was studied using organotypic raft cultures and in vivo significance was assessed via a xenograft mouse model. We identified cancer-associated fibroblasts (CAFs) as the main source of WNT2. CAF-derived WNT2 activated canonical signaling in adenomatous polyposis coli/ß-catenin wild-type colon cancer cells in a paracrine fashion, whereas no hyperactivation was detectable in cell lines harboring mutations in the adenomatous polyposis coli/ß-catenin pathway. Furthermore, WNT2 activated autocrine canonical WNT signaling in primary fibroblasts, which was associated with a pro-migratory and pro-invasive phenotype. We identified FZD8 as the putative WNT2 receptor in CAFs. Three-dimensional organotypic co-culture assays revealed that WNT2-mediated fibroblast motility and extracellular matrix remodeling enhanced cancer cell invasion of cell lines even harboring mutations in the adenomatous polyposis coli/ß-catenin pathway. Thus, suggesting a tumor-promoting influence on a broad range of CRC. In line, WNT2 also promotes tumor growth, invasion and metastasis in vivo. Moreover, high WNT2 expression is associated with poor prognosis in human CRC. The identification of the pro-malignant function of stromal derived WNT2 in CRC classifies WNT2 and its receptor as promising stromal targets to confine cancer progression in combination with conventional or targeted therapies.

Colloidal properties of human transferrin receptor in detergent free solution.

The colloidal properties of transferrin receptor, isolated from human placenta, in detergent free solution has been investigated by light scattering techniques and analytical ultracentrifugation. In detergent free solution at 293.2 K, hTfR forms stable aggregates with an apparent hydrodynamic radius of 17 nm. The molecular mass was determined by ultracentrifugation to lie between (1722+/-87) kDa (sedimentation equilibrium) and (1675+/-46) kDa (sedimentation velocity). This implies that the aggregates are build up from nine hTfR dimers. Based on model calculations, which are in good agreement with the experimental data, we propose a torus-like structure for the aggregates. Upon pH shift from pH 7.5 to 5.0 or removal of the N-linked carbohydrate chains, formation of larger aggregates is induced. These aggregates can be described in terms of porous fractal structures. We propose a simple model, which accounts for that behaviour assuming that the aggregation is mainly due to the reduction of negative surface charge.

Adult rhabdomyoma of the extremity: a case report and review of the literature.

The adult rhabdomyoma is a rare, benign skeletal muscle neoplasm that usually occurs in the head and neck. A case report of an adult rhabdomyoma arising in the thigh is presented with a review of the literature. This is the first case of an extremity adult rhabdomyoma to be reported. It is also the largest at 13 centimeters. Distinction from a highly differentiated rhabdomyosarcoma is important. Recent chromosomal studies suggest that the adult rhabdomyoma is a true neoplasm. Total resection is curative but the lesion may recur if incompletely excised.

Ultrasonography of blood during stasis and coagulation.

A series of in vitro and animal experiments were performed to determine ultrasonic features of blood during stasis and coagulation. Liquid whole blood became echogenic within a few seconds to 3 minutes following the onset of stasis. This occurred in citrated human blood allowed to stand and in occluded segments of vena cava and aorta of dogs. Mechanical agitation of the blood in stasis caused a disappearance of echoes. This echogenicity occurred with gray-scale and real-time ultrasonography using 7.5-mHz transducers, but was not observed with 3.5-mHz transducer used in real-time scanning. Whole blood clot was echogenic both with 7.5- and 3.5-mHz scanning. Fibrin clot was sonolucent. Echogenicity with stasis did not occur with plasma, serum, or packed erythrocytes. The development of echogenicity required the presence of fibrinogen or its products plus erythrocytes. The echogenicity of blood during stasis detectable by high-frequency ultrasonography probably was related to physical layering of blood products. The disappearance of reflective echoes following agitation suggested that the layering could be readily disrupted.

Detection of experimental arterial defects by portable and serial biplanar operative arteriography.

The accuracy of arteriography in detecting vascular defects similar to those encountered during vascular surgery was evaluated experimentally. Intimal flaps, thrombi, and strictures were created in dog aortas and studied under circumstances resembling operating room conditions by single-view portable and serial biplanar contrast arteriography. The specificity of both types of arteriography was comparable and high for detecting vascular defects. The sensitivity for diagnosing strictures was also comparable and high. However, both radiographic techniques were relatively insensitive in the detection of small intimal flaps and thrombi. In the detection of these two types of defects, serial biplanar arteriography was significantly more sensitive than portable arteriography. The degree of the superiority of serial bi-plane and the possible clinical insignificance of small defects indicates that portable arteriography in the operating room may still be an adequate methodology.

Bile peritonitis from a cholecystohepatic bile ductule: an unusual complication of cholecystectomy.

A case is presented of postoperative bile peritonitis from an accessory cholecystohepatic bile ductule after cholecystectomy for acute cholecystitis. Accessory bile ductules (ducts of Luschka) are occasionally encountered in the gallbladder fossa but do not drain directly into the gallbladder fundus. Nevertheless, they may be injured during surgery and may go unrecognized. When recognized intraoperatively, ligation is acceptable; however, when they are actively leaking bile and are greater than 2 mm in diameter, repair of injured cholecystohepatic ducts may be indicated. This case serves to reemphasize one argument for the routine placement of drains after cholecystectomy for acute cholecystitis.

Liver infarct after sigmoid resection: an unusual case of mesenteric ischemia.

Hepatic infarction is an unusual event. A patient is described who had a hepatic infarct after a sigmoid resection. She was found to have occluded superior mesenteric and celiac arteries, with visceral circulation dependent on the inferior mesenteric artery. Disruption of the collateral circulation was presumed to have caused the subsequent liver infarct. A review of the pathophysiology of liver infarction is presented with particular reference to the relation of arterial occlusion to infarction.

Intraoperative ultrasonic imaging of the carotid artery during carotid endarterectomy.

Intraoperative real-time B-mode ultrasonography was used to evaluate the technical results of 155 carotid endarterectomies in 143 patients. Technical defects created as a result of the endarterectomy were detected in 43 of the 155 endarterectomies (27.7%) and included intimal flaps (73% of defects); strictures (18%); and arterial kinks, residual plaque, and intraluminal thrombi (9% collectively). Eleven of the 43 endarterectomy sites (7% of all endarterectomies) were reentered to correct a defect; none of these patients had neurologic deficits, which suggests that reentering an endarterectomy and correcting a defect does not, in and of itself, lead to a higher incidence of stroke. The incidence of stroke in patients with normal results of intraoperative ultrasonography was 3.8%, whereas the incidence of perioperative stroke in those patients with insignificant and thus uncorrected defects was 3.3%; this suggests that intraoperative ultrasonography is sufficiently sensitive to detect defects that, when left uncorrected, do not lead to a higher than usual incidence of stroke. Because intraoperative ultrasonography is safe and highly sensitive, we believe it is the method of choice for assessing the technical results of carotid endarterectomy.

Hemodynamic evaluation of the aortoiliac system based on pharmacologic vasodilatation.

Selection of the appropriate vascular reconstructive procedure in patients with multisegment disease requires the differentiation of aortoiliac from femoropopliteal occlusive disease and the detection of subcritical stenoses in the aortoiliac segment. Triplane arteriography and common femoral intra-arterial papaverine injection (30 mg) were done in 43 lower extremities in patients who subsequently had arterial bypass. The percent diameter stenosis was measured on the arteriograms and common femoral intra-arterial pressure was continuously monitored before and after papaverine injection. A resting femoral/brachial pressure index (FBI) was obtained and the percent decrease in this index (% delta FBI) was calculated using the maximum decrease in FBI following injection. Regression analysis revealed a significant correlation between % delta FBI and percent aortoiliac stenosis (r = 0.5446, P less than 0.005). In relation to clinical course, receiver-operator characteristic curve analysis revealed a % delta FBI of greater than or equal to 0.15 to be optimal in the detection of hemodynamically significant aortoiliac stenoses. When compared to clinical course, this % delta FBI was 88% sensitive, 100% specific, and 95% accurate. However, when analyzed with arteriography as the standard (50% stenosis), the same % delta FBI was only 70% sensitive, 100% specific, and 86% accurate. All limbs with a % delta FBI of 0.15 or greater improved following aortoiliac revascularization; 21% of these limbs had a normal preoperative resting FBI. No patient with a % delta FBI lower than 0.15 had improvement following aortoiliac revascularization. All limbs that had infrainguinal bypass had normal FBIs and % delta FBIs before bypass. After operation 90% of these limbs improved. Overall, this technique correctly predicted the clinical course in 95% of the limbs tested.

Prebypass operative arteriography.

Complete arteriographic delineation of lower extremity arterial anatomy is not always possible preoperatively. Nonvisualization of patent arterial segments may lead to amputation in lieu of arterial bypass grafting. During a 3-year period (1978 to 1981), 31 patients evaluated for lower extremity arterial bypass had incomplete preoperative arteriographic studies. Eighty-seven percent of these patients were in limb salvage categories. In order to obtain better arterial visualization, 33 operative arteriograms, preceding 32 operative procedures, were performed through the femoral (n = 14), popliteal (n = 17), posterior tibial (n = 1), and dorsal pedial (n = 1) arteries. All arteriograms were performed following arterial dissection and clamp occlusion of arterial inflow. The operative arteriogram was found to be beneficial in 91% of cases (29 of 32). In 66%, bypass was performed to vessels that were not visualized preoperatively. In 25%, bypasses were performed to vessels that were visualized preoperatively but intraoperative arteriograms showed better visualization of the vessels and distal runoff, thus allowing bypass to the optimal recipient artery. In three cases (9%), the intraoperative technique was not beneficial, as no additional arterial visualization was provided. Only one patient could not undergo bypass because of nonvisualization of recipient vessels. Overall, major amputation was avoided in 86% of patients (24 of 28) suffering from severe rest pain or gangrene during the period of study. Prebypass operative arteriography is a technique that clearly provides for increased limb salvage. Ninety-three percent of patients (14 of 15) otherwise facing immediate major amputation had their limbs salvaged through the use of this technique.

Cardiovascular lymphoscintigraphy.

The technique of lymphoscintigraphy when applied to the heart and blood vessels correlates well with results of anatomic investigations of arterial and cardiac lymphatic vessels reported in the literature. Five dogs and eight rabbits underwent lymphoscintigraphy of the heart and aorta, as well as the iliac, femoral, and tibial arteries. After surgical exposure, approximately 500 microCi of 99mTc-labelled antimony sulfide was injected into the myocardium or the adventitial-medial plane of an artery. The colloid particle size of 4 to 12 m mu causes resorption and transport only via the lymphatic vessels. Twenty-one preparations were imaged from 2 to 48 hours after administration. This method provides a functional demonstration that the tibial and femoral arteries of both species are invested with lymphatics. The first echelon of lymph nodes which drain muscular arteries are imaged within 2 hours. Regional lymph nodes could not be seen to drain the aorta or iliac arteries. Anterior left ventricular myocardial injection in the dog showed a single cardiac lymph node. This drainage pattern has been described previously by other investigators. In the rabbit a similarly placed injection visualized a group of regional cardiac nodes. Ligation of the collecting ducts afferent to the cardiac node in the dog prevented removal of the isotope from the heart at 3, 6, and 9 hours. At 24 hours the liver and spleen were imaged, the radiocolloid gaining entrance to the blood vascular system presumably via myocardial lymphaticovenous anastomoses. Lymphoscintigraphy reflects physiologic processes such as lymph transport, filtration, and reticuloendothelial function. It defines regional patterns of cardiac and arterial lymph drainage. It can confirm experimentally produced impairment of lymph drainage from a defined area of tissue. Lymphoscintigraphy should be useful in the investigation of the significance of lymph drainage to diseases of the heart and blood vessels.

Utility of wide and narrow blood pressure cuffs in the hemodynamic assessment of aortoiliac occlusive disease.

One hundred lower extremities were evaluated by measurement of common femoral intra-arterial pressure and high-thigh Doppler-derived segmental pressures using wide and narrow blood pressure cuffs to assess the accuracy of high-thigh pressures in the evaluation of aortoiliac disease. Sixty-four extremities were also studied by arteriography. The results were analyzed using the common femoral intra-arterial pressure as the standard. The accuracy was poor for both the wide (52%) and narrow (73%) cuff techniques. No significant differences between the two techniques were evident in regard to the incidence of false positive (wide cuff, 75%; narrow cuff, 65%) and false negative (wide cuff, 3%; narrow cuff, 8%) tests. Superficial femoral artery disease was found to be responsible for all false positive tests using the narrow cuff technique (20 of 20) and all but one of the false positive tests using the wide cuff technique (34 of 35). These data indicate that segmental high-thigh pressures are useful primarily as a screening technique (low false negative rate) to exclude hemodynamically significant aortoiliac occlusive disease at rest.

The effect of carotid siphon stenosis on stroke rate, death, and relief of symptoms following elective carotid endarterectomy.

It has been suggested that carotid endarterectomy for carotid bifurcation disease may be contraindicated in the presence of carotid siphon lesions. This study was undertaken to assess any difference in stroke rate, mortality, or relief of symptoms in patients with and without such "tandem" lesions following elective carotid endarterectomy. Ninety-one bifurcation endarterectomies were performed in 79 patients. The patients were divided into two groups. Group I (44 patients, 47 endarterectomies) had carotid bifurcation stenosis only; group I (35 patients, 44 endarterectomies) had siphon stenosis plus bifurcation stenosis. All patients in both groups who were symptomatic before operation were relieved of their symptoms. In group I there were no intraoperative or perioperative strokes, four late strokes (8.7%), one operate death (2.1%), and no late deaths. Group II patients had two intraoperative strokes (4.5%), three perioperative strokes (6.8%), two late strokes (5.1%), four operative deaths (9.1%), and three late deaths (7.5%). Eighteen of the 35 patients in group II had a greater degree of carotid siphon stenosis than bifurcation stenosis. In this subgroup, there was one operative stroke (5.6%), only perioperative stroke (5.6%), one late stroke (5.9%), one postoperative death (5.6%), and one late death (5.6%). None of these differences were statistically significant. Relief of symptoms was the same in patients with and without tandem carotid lesions, and there was no significantly increased risk of stroke or death following bifurcation endarterectomy in patients with tandem carotid lesions.

The necessity of mandatory exploration of penetrating zone II neck injuries.

To reevaluate the validity of our policy of mandatory surgical exploration of penetrating zone II neck injuries, the charts of 110 patients who underwent surgical exploration for such injuries were reviewed. Fifty-three percent of the patients had normal findings at exploration, whereas 33% had injuries involving vascular structures of the neck and 14% had nonvascular injuries. Injuries were not suspected on clinical grounds preoperatively in 23% of the patients in whom surgical exploration revealed injury. The injuries most likely to escape preoperative diagnosis were isolated venous injuries and isolated pharyngoesophageal injuries. Arteriography yielded false-negative results in two arterial injuries. No deaths and only a 5% incidence of minor complications occurred in the group with no injuries detected at exploration. We conclude that surgical exploration of penetrating zone II neck injuries is safe and appropriate.

Spontaneous splenic rupture. The role of nonoperative management.

Spontaneous splenic rupture associated with infectious mononucleosis is an infrequent occurrence. Splenectomy has been advocated as the appropriate treatment for these patients. Recently, three patients with spontaneous splenic rupture were successfully treated at our institution without surgery. Management of spontaneous splenic rupture in 37 other patients in the literature was reviewed. Nine of these patients also were treated nonoperatively. Although it has been suggested that splenectomy is the treatment of choice for patients with spontaneous splenic rupture, we believe selective nonoperative treatment of these patients is a realistic and safe option if it is employed appropriately.

Endotoxin-challenged monkeys and rats.

Studies in our laboratory with both the monkey and the rat showed that, after three hours of endotoxemia, there was a significant decrease in the number of circulating platelets, total hemolytic complement (CH 50 units), and blood serotonin (5-HT) levels. Administration of dexamethasone sodium phosphate in the clinical dose range at the time of endotoxin challenge significantly attenuated the decrease in blood 5-HT levels when compared to the untreated groups in both the monkey and the rat experiments. In the monkey, CH 50 units remained at a higher level when dexamethasone was administered; however, the difference between the treated and untreated groups was not statistically significant. The number of circulating white blood cells and platelets did not appear to be significantly altered by corticosteroid treatment. It is suggested that glucocorticoids may interfere with lipopolysaccharide-induced alterations in complement components or factors regulating hemostasis that influence platelet 5-HT release.

Glucocorticoid and antibiotic effect on experimental gram-negative bacteremic shock.

This study was designed to answer the three following questions: (1) Are glucocorticoids as protective in Gram-negative bacteremic shock as they are in endotoxic shock? (2) Is there any difference in efficacy between a bacteriostatic and a bactericidal antibiotic in bacteremic shock? (3) Does the combination of glucocorticoid with antibiotic potentiate the individual protective effects of both? Bacteremia was induced in male Sprague-Dawley rats by a single intravenous injection of viable Escherichia coli. The results showed that dexamethasone sodium phosphate alone afforded significant protection against Gram-negative bacteremic shock up to eight hours after challenge. The choice of a bactericidal vs a bacteriostatic antibiotic did not influence the survival rates in this study. The survival rate was maximal when dexamethasone was used with both ampicillin sodium and gentamicin sulfate.

The new era in breast cancer. Invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening.

OBJECTIVE: To describe the magnitude of changes and opportunities that may arise for simplified surgical procedures for women with breast cancer because of the decreasing size and lymph node involvement in invasive breast cancer and earlier presentation of noninvasive and invasive breast cancer. DESIGN AND MAIN OUTCOME ASSESSMENT: Cases (N=1001) of breast cancer from a tertiary and a community hospital between 1989 and 1993 were analyzed for invasion, size, nodal status, and change over time. RESULTS: Ductal carcinoma in situ constituted 14% and 18% of the cancers at the two hospitals. At the tertiary and community hospitals, the mean maximum diameters were 2.1 and 2.0 cm, respectively, and the median maximum diameters were 1.5 and 1.7 cm, respectively, for invasive breast cancer. Twenty-nine percent and 28%, respectively, were 1 cm or less in diameter. Axillary nodal metastases occurred in only 31% of the invasive cancers (tertiary hospital); only 10% had more than three nodal metastases. In the T1a and T1b cases, nodal metastases occurred in only 10% and 43% of the positive nodes were solitary; only 16% had more than three nodal metastases. The proportion of ductal carcinoma in situ, T1a and T1b, and node-negative cases increased significantly over time. CONCLUSIONS: Within the next decade, the proportion of all breast cancers that are ductal carcinoma in situ will approach 33%, and invasive cancers will approach 1 cm in median maximum diameter. Therapy simplification will be logical because of very small size, low risk of recurrence after breast conservation, and excellent prognosis, and might include increased breast conservation, avoidance of axillary nodal dissection, and omission of radiation therapy to conserve breasts. Adjuvant therapy will be based on the prognostic features of the primary cancer and findings from careful histologic examination of the sentinel lymph nodes.