Phenotype analysis of male transgenic mice overexpressing mutant IGFBP-2 lacking the Cardin-Weintraub sequence motif: Reduced expression of synaptic markers and myelin basic protein in the brain and a lower degree of anxiety-like behaviour.

Brain growth and function are regulated by insulin-like growth factors I and II (IGF-I and IGF-II) but also by IGF-binding proteins (IGFBPs), including IGFBP-2. In addition to modulating IGF activities, IGFBP-2 interacts with a number of components of the extracellular matrix and cell membrane via a Cardin-Weintraub sequence or heparin binding domain (HBD1). The nature and the signalling elicited by these interactions are not fully understood. Here, we examined transgenic mice (H1d-hBP2) overexpressing a mutant human IGFBP-2 that lacks a specific heparin binding domain (HBD1) known as the Cardin-Weintraub sequence. H1d-hBP2 transgenic mice have the genetic background of FVB mice and are characterized by severe deficits in brain growth throughout their lifetime (p<0.05). In tissue lysates from brain hemispheres of 12-21day old male mice, protein levels of the GTPase dynamin-I were significantly reduced (p<0.01). Weight reductions were also found in distinct brain regions in two different age groups (12 and 80weeks). In the younger group, impaired weights were observed in the hippocampus (-34%; p<0.001), cerebellum (-25%; p<0.0001), olfactory bulb (-31%; p<0.05) and prefrontal cortex (-29%; p<0.05). At an age of 12weeks expression of myelin basic protein was reduced (p<0.01) in H1d-BP-2 mice in the cerebellum but not in the hippocampus. At 80weeks of age, weight reductions were similarly present in the cerebellum (-28%; p<0.001) and hippocampus (-31; p<0.05). When mice were challenged in the elevated plus maze, aged but not younger H1d-hBP2 mice displayed significantly less anxiety-like behaviour, which was also observed in a second transgenic mouse model overexpressing mouse IGFBP-2 lacking HBD1 (H1d-mBP2). These in vivo studies provide, for the first time, evidence for a specific role of IGFBP-2 in brain functions associated with anxiety and risk behaviour. These activities of IGFBP-2 could be mediated by the Cardin-Weintraub/HBD1 sequence and are altered in mice expressing IGFBP-2 lacking the HBD1.

ICU personnel have inaccurate perceptions of their patients' experiences.

BACKGROUND: Intensive care unit (ICU) patient care bases - among others - upon the staff's assumptions about each patient's subjective preferences and experiences. However, these assumptions may be skewed and thus result in client-professional gaps (cp-gaps), which occur in two subtypes, hyperattention and blind spots to certain burdens. cp-gaps typically reduce quality of care. We investigated whether cp-gaps of either subtype exist in a 36-bed ICU of a university hospital. METHODS: Observational study on 82 consecutive patients of a 36-bed university ICU, who voluntarily answered a psychometric questionnaire focusing on patients' experiences during an ICU stay. The questionnaire was reliable and valid (Cronbach's alpha, factor analysis). It consisted of 31 Likert-scaled items, which represented three scales of perception (communicative, intrapersonal, somatic) supplemented by 55 binary items for more specific information. Details of the questionnaire are given in the text. Demographic, educational, and medical data were registered too. Patients reported their subjective ICU experience 2-7 days after ICU discharge. Analogously, 60 staff members (physicians and nurses) reported their assumptions about patients' experiences. After correction for a general bias, group differences indicated cp-gaps. RESULTS: Twelve cp-gaps were found. Hyperattention was found in four communicative and three intrapersonal items. Blind spots appeared in two communicative, two intrapersonal, and one somatic item. The pattern of cp-gap subtypes (hyperattention/blind spots) goes well with self-attributional bias - a model of social interaction. CONCLUSIONS: cp-gaps in ICUs can be identified using analogue questionnaires for patients and staff. Both subtypes of cp-gap occur. cp-gaps are substantially influenced by self-attributional bias.

Extreme value statistics for river quality simulations.

Various methods have been proposed to assess intermittent pollution loads and impacts on rivers in urban areas. Although the variables to describe the impact are mainly the same, the standards show significant differences in the assessment of permitted concentration level, duration and return period. The probability of an event is derived using either frequencies of occurrence or predefined extreme value distributions. Both methods have drawbacks. To bypass these, an a posteriori estimation of the statistical distribution of data based on the peak-over-threshold method is proposed. The method is exemplarily demonstrated using a semi-virtual case study.

The HSG procedure for modelling integrated urban wastewater systems.

Whilst the importance of integrated modelling of urban wastewater systems is ever increasing, there is still no concise procedure regarding how to carry out such modelling studies. After briefly discussing some earlier approaches, the guideline for integrated modelling developed by the Central European Simulation Research Group (HSG - Hochschulgruppe) is presented. This contribution suggests a six-step standardised procedure to integrated modelling. This commences with an analysis of the system and definition of objectives and criteria, covers selection of modelling approaches, analysis of data availability, calibration and validation and also includes the steps of scenario analysis and reporting. Recent research findings as well as experience gained from several application projects from Central Europe have been integrated in this guideline.

Has arteriography gotten a bad name? Current accuracy and morbidity of diagnostic contrast arteriography for aortoiliac and lower extremity arterial disease.

Recently, contrast arteriography has been challenged as the diagnostic test of choice for lower extremity arterial disease because of its associated morbidity and questionable accuracy in identifying suitable distal outflow arteries. The purpose of this report was to analyze our experience to determine if these concerns were justified. We reviewed 500 consecutive contrast arteriograms performed at our hospital for aortoiliac and lower extremity arterial disease between November 1994 and November 1998. Arteriograms performed in conjunction with therapeutic procedures such as balloon angioplasty, stent placement, and thrombolysis were excluded, leaving 244 diagnostic cases for analysis. Forty-six percent (112) of patients had diabetes mellitus, 14% (34) had an elevated baseline serum creatinine (> or =1.5 mg/dL), and an additional 7% (17) were dialysis dependent. Radiologists limited contrast volume by imaging only the symptomatic extremity when appropriate and using digital subtraction techniques as indicated. Our results showed that diagnostic contrast arteriography is associated with an acceptably low morbidity, has an accuracy that is unlikely to be surpassed by other modalities, and remains the diagnostic test of choice for lower extremity arterial disease.

Primary gastrointestinal sarcomas: analysis of prognostic factors and results of surgical management.

BACKGROUND: This study was done to review the clinical presentation, surgical management, and prognostic factors for primary gastrointestinal sarcomas. METHODS: We reviewed medical records of 55 patients who were treated for primary gastrointestinal sarcomas from 1981 through 1996. Mean follow-up time was 32 months. RESULTS: Clinical findings included gastrointestinal bleeding (51%), palpable mass (36%), and abdominal pain (33%). The stomach was the most common site of disease (53%), followed by the small intestine (33%). Tumors were high grade in 76% of patients and low-grade in 24% of patients. Complete resection of all gross disease was accomplished in 35 patients (64%), incomplete resection in 17 patients (31%), and biopsy only in 3 patients (5%). Adjacent organ resection was required in 19 patients (35%). Overall actuarial survival was 22% (median survival, 32 months). Unfavorable prognostic factors were incomplete resection, high-grade histologic features, and tumor size of 5 cm or more (P<.05). En bloc resection of contiguous organs did not adversely effect survival. In patients with complete resections, tumor grade was the most important prognostic factor (median survival, 55 months vs 19 months for low-grade vs high-grade tumors; P<.05). CONCLUSIONS: Aggressive surgical resection, including en bloc resection of locally advanced tumors, appears warranted. Despite complete resections, patients with high-grade tumors remain at risk for recurrence.

Predictors of outcome when reoperating for early infrainguinal bypass occlusion.

The purpose of this study is to identify factors that predict outcome after intervention for early (<30 days) infrainguinal graft thrombosis. We reviewed the medical records, arteriograms, and follow-up studies of patients who underwent infrainguinal bypass for limb salvage between 8/91 and 9/98 and whose graft failed <30 days from the index procedure. Five factors were analyzed: (1) conduit: single segment saphenous vein versus alternative vein or composite conduit (20 vs. 13 patients); (2) repair modality: construction of a new graft at the time of the initial take-back procedure versus local revision and/or thrombectomy alone (12 vs. 21 patients); (3) run-off: good run-off versus poor run-off (20 vs. 13 patients); (4) operative findings: the presence of a correctable problem versus noncorrectable problem (20 vs. 13 patients); and (5) surgical history: previous versus no previous ipsilateral bypass (16 vs. 17 patients). These variables are statistically significant risk factors that can be used in combination to predict outcome. Unless a focal lesion clearly responsible for graft occlusion is found, complete graft replacement should be considered even if the new bypass must be prosthetic. The costs and morbidity of repeated procedures argue for primary amputation when adverse risk factors exist.

Carotid endarterectomy in octogenarians: comparison with patient characteristics and outcomes in younger patients.

OBJECTIVES: Carotid endarterectomy has been shown to be of clear benefit to selected patients. However, recent trials of carotid endarterectomy versus best medical therapy have excluded octogenarians, and some authors have suggested that carotid endarterectomy would have an unfavorable cost-benefit relationship in octogenarians. We compared patients and results for carotid endarterectomy in octogenarians and younger patients. METHODS: We reviewed the results for 582 primary carotid endarterectomies (90 in octogenarians and 492 in younger patients) performed in 528 patients between February 1, 1985, and January 31, 1998 (all data were collected prospectively for the most recent 301 carotid endarterectomies). Conventional surgical technique was used with general anesthesia, selective shunting, and selective patching. Main outcome measures were perioperative and late ipsilateral stroke and death. RESULTS: The two groups were similar with respect to indications for carotid endarterectomy and patient characteristics, except that octogenarians were more likely to have histories of congestive heart failure or hypertension and less likely to have histories of smoking or chronic lung disease. Carotid endarterectomy was performed for asymptomatic disease in 27% of the octogenarians and 33% of the younger patients (P =.31). Stenosis was >/=80% in 90% of the octogenarians and 78% of the younger patients (P =.014). Perioperative strokes, all of which were ipsilateral, occurred in one octogenarian (1.1%) and eight younger patients (1.6%, P = 1.00). No octogenarians and two younger patients died within 30 days of surgery (P = 1.00). Length of stay and direct costs associated with carotid endarterectomy were similar for octogenarians and younger patients. Late strokes occurred in two octogenarians (one ipsilateral) and four younger patients (two ipsilateral). Life table estimates of freedom from ipsilateral stroke at 2 years were 98% and 97% for octogenarians and younger patients, respectively (log-rank P =.69), and life table estimates of patient survival at 4 years were 81% and 89% for octogenarians and younger patients, respectively (P =.11). Octogenarians represented an increasing fraction of the carotid endarterectomies performed during the study period. CONCLUSIONS: Octogenarians selected for carotid endarterectomy were similar to younger patients with respect to indications for carotid endarterectomy and comorbidities. Early mortality, early and late neurologic outcome, complications, and resource utilization were similar for the two groups, and more than 75% of octogenarians survived 4 years after undergoing carotid endarterectomy. Cost-benefit analyses for carotid endarterectomy, which are highly sensitive to expected patient survival, might not be pertinent to individual patient situations. Intellectually intact octogenarians without unusually severe comorbidities are good candidates for and should be offered the benefits of carotid endarterectomy.

Prosthetic patch remnants to treat infected arterial grafts.

PURPOSE: Our previous experience with the traditional management of infected prosthetic arterial grafts, which included graft excision and vein patch repair of the involved artery, was complicated by a high incidence of vein patch rupture. This study assessed the treatment of infected prosthetic grafts with subtotal graft excision and oversewing of small graft remnants. METHODS: During the last 20 years, we treated 53 wounds involving 45 infected prosthetic grafts in 42 patients by means of subtotal graft excision and oversewing of a residual 2- to 3-mm graft remnant (patch) at an intact arterial anastomosis. This technique was selectively used to maintain patency of small-diameter arteries (41 common femoral, five deep femoral, three axillary, two iliac, and two popliteal), which were critical for limb salvage or amputation healing. This strategy avoided difficult dissection of the underlying artery in scarred wounds and obviated the placement of a new patch in an infected field. Graft remnants were polytetrafluoroethylene in 51 cases and Dacron in two cases. Of the 45 grafts, 31 were occluded and 14 were patent. All infected tissue was widely debrided, wet-to-dry dressing changes were performed three times daily, and appropriate intravenous antibiotics were administered for at least 1 week. Secondary bypass grafting procedures were performed as needed to achieve limb salvage. The follow-up period in surviving patients averaged 32 months (range, 1 to 218 months). RESULTS: No complications were directly attributable to prosthetic patch remnants in 92% of cases (49 of 53 cases). Six of 42 patients (14%) died during hospitalization (three of cardiac complications and three of sepsis with multiple organ failure). Two infected pseudoaneurysms developed 8 and 34 months after surgery, and two wounds failed to heal. Sixteen secondary bypass grafting procedures were necessary to achieve limb salvage. Patch oversewing led to limb salvage without the need for secondary revascularization in 26 other cases and to the successful healing of 10 amputated limbs when secondary revascularization was not possible. CONCLUSION: Prosthetic patch remnants are a useful adjunct that simplify management of infected prosthetic grafts, are associated with a low incidence of wound complications, and help maintain patency of essential collaterals to achieve limb salvage or heal an amputation.

Effects of treatment with GABA(A) receptor subunit antisense oligodeoxynucleotides on GABA-stimulated 36Cl- influx in the rat cerebral cortex.

GABA(A) receptor function was studied in cerebral cortical vesicles prepared from rats after intracerebroventricular microinjections of antisense oligodeoxynucleotides (aODNs) for alpha1, gamma2, beta1, beta2 subunits. GABA(A) receptor alpha1 subunit aODNs decreased alpha1 subunit mRNA by 59+/-10%. Specific [3H]GABA binding was decreased by alpha1 or beta2 subunit aODNs (to 63+/-3% and 64+/-9%, respectively) but not changed by gamma2 subunit aODNs (94+/-5%). Specific [3H]flunitrazepam binding was increased by alpha1 or beta2 subunit aODNs (122+/-8% and 126+/-11%, respectively) and decreased by gamma2 subunit aODNs (50+/-13%). The "knockdown" of specific subunits of the GABA(A )receptor significantly influenced GABA-stimulated 36Cl- influx. Injection of alpha1 subunit aODNs decreased basal 36Cl- influx and the GABA Emax; enhanced GABA modulation by diazepam; and decreased antagonism of GABA activity by bicuculline. Injection of gamma2 subunit aODNs increased the GABA Emax; reversed the modulatory efficacy of diazepam from enhancement to inhibition of GABA-stimulation; and reduced the antagonist effect of bicuculline. Injection of beta2 subunit aODNs reduced the effect of diazepam whereas treatment with beta1 subunit aODNs had no effect on the drugs studied. Conclusions from our studies are: (1) alpha1 subunits promote, beta2 subunits maintain, and gamma2 subunits suppress GABA stimulation of 36Cl- influx; (2) alpha1 subunits suppress, whereas beta2, and gamma2 subunits promote allosteric modulation by benzodiazepines; (3) diazepam can act as an agonist or inverse agonist depending on the relative composition of the receptor subunits: and (4) the mixed competitive/non-competitive effects of bicuculline result from activity at alpha1 and gamma2 subunits and the lack of activity at beta1 and beta2 subunits.

Endovascular versus surgical treatment for thrombosed hemodialysis grafts: A prospective, randomized study.

PURPOSE: The objective of this study was to compare clinical outcome and costs for two widely used treatment strategies for hemodialysis graft thrombosis. METHODS: During a 4-year period, 80 patients with thrombosed dialysis grafts were randomly assigned to surgical thrombectomy with or without graft revision (SURG) or thrombolytic therapy with urokinase with the pulse-spray technique (ENDO), with adjunctive percutaneous transluminal angioplasty as indicated. All the procedures were performed in an endovascular operating suite with fistulography. The clinical and cost data were tabulated, and the outcome was analyzed with the life-table method. RESULTS: Fifty-six women and 24 men ranged in age from 33 to 90 years (mean, 63.7 years). The patients had undergone a mean of 2.8 prior access procedures in the ipsilateral extremity. All the grafts were upper extremity expanded polytetrafluoroethylene grafts. Lesions that were presumed to be the primary cause of graft thrombosis were identified in 73 of 80 grafts, and 60 of these were at the venous anastomosis. The procedure time averaged 99 minutes for the patients in the SURG group and 113 minutes for the patients in the ENDO group (P =.12). Eleven patients in the ENDO group crossed over to surgical revision as compared with two patients in the SURG group who required adjunctive percutaneous transluminal angioplasty (P =.005). The mean cost of treatment (including room and supply costs but not professional fees) was significantly higher for the ENDO group than for the SURG group ($2945 vs $1512; P <.001). There were no procedure-related complications in either group. At a median follow-up time of 24 months, there was no difference in primary or assisted primary patency between groups, which averaged 6 and 7 months, respectively. CONCLUSION: Although thrombolytic therapy combined with endovascular treatment can extend the life of dialysis grafts with results similar to surgical revision, there is a high rate of technical failure necessitating surgery and a substantially higher cost for thrombolysis.

The GABA(A) receptor complex as a target for fluoxetine action.

The clinically important antidepressant fluoxetine is established as a selective serotonin reuptake inhibitor. This study demonstrates that fluoxetine also interacts with the GABA(A) receptor complex. At concentrations above 10 microM fluoxetine inhibited the binding of both [3H]GABA (IC50 = 2 mM) and [3H]flunitrazepam (IC50 = 132 microM) to the GABA(A) receptor complex in brain cortical membranes. Low fluoxetine concentrations (1 nM) enhanced GABA-stimulated Cl- uptake by a rat cerebral cortical vesicular preparation. At higher concentrations (100 microM and 1 mM), however, fluoxetine inhibited GABA-stimulated Cl- uptake, an effect related to a reduction in Emax. These observations might assist in an explanation of the basis of the antidepressant action of fluoxetine.

Superior vena cava syndrome. Experience with endovascular stents and surgical therapy.

Superior vena cava (SVC) syndrome is a serious complication of benign and malignant diseases. Benign causes may be increasing because of the increased use of central venous cannulation. Modern surgical therapy is durable with a few complications. Traditional treatment for SVC obstruction from malignant causes has consisted of anticoagulation, radiation, chemotherapy, and occasionally surgery. Endovascular techniques present a new treatment option for these patients, and uses a combination of thrombolysis, angioplasty, and intravascular stents. Short-term results are excellent with relatively rapid patient recovery. Further research is needed to elucidate the long-term results of endovascular treatment and to find its role in benign and malignant disease.

Amitriptyline increases GABA-stimulated 36Cl- influx by recombinant (alpha 1 gamma 2) GABAA receptors.

WSS-1 cells expressing (alpha 1 gamma 2)GABAA receptors show an augmented 36Cl- response to GABA in the presence of amitriptyline that is increased by flumazenil, unlike augmentation by diazepam which is blocked by flumazenil. This amitriptyline effect is opposite to the inhibition of GABA-stimulated 36Cl influx manifested in membrane vesicles prepared from drug-naive rats or submissive rats (a model of depression) but is similar to that seen in tissue from amitriptyline-treated rats or dominant rats. The results suggest a novel mechanism of antidepressant drug action having a delayed onset.

Importance of the placenta and cord in the defense of neurologically impaired infant claims.

Verdicts in favor of the defense were delivered in all 12 cases tried to a conclusion in which the placenta and/or cord was available for examination and was found to be abnormal or diseased and in which testimony was provided by a placental pathologist. The St Paul (Minn) Fire and Marine Insurance Company recommends that placenta/cord specimens be retained in cases where the mother is at high risk, the fetus/newborn has certain high-risk characteristics, and/or the placenta appears to be grossly abnormal. If a claim is made against the health care providers, the specimens can subsequently be examined by a placental specialist for possible trial testimony. The placenta may well be the key to a solid defense for these cases in the courtroom.

Determination of cell line suitability for rapid isolation of herpes simplex virus.

Herpes simplex virus (HSV) is one of the most commonly identified viruses in the clinical laboratory. HSV is of clinical consequence because of its ability to produce such life-threatening infections as encephalitis and neonatal disease. A variety of cell lines are currently being used for detection of HSV in cell culture. This study compared several cell lines simultaneously in a 96-well cell culture system to determine which lines demonstrated viral CPE most quickly following infection. In considering speed at which viral CPE is demonstrated, our results showed that primary rabbit kidney cells surpassed all other cell lines at 48 h post-viral infection. Alternative cell lines demonstrated to be suitable by this study were human fetal foreskin, human embryonic lung, and Vero cells.