Variations in tumor marker levels in metastatic breast cancer patients according to tumor subtypes.

PURPOSE: To investigate whether serum CA 15-3 and CEA levels show differences among subgroups of breast cancer patients at the time of diagnosis of early-stage disease and at disease relapse. METHODS: Patients with metastatic breast cancer diagnosed from 2000 to 2010 were retrospectively analyzed. Data were obtained from medical charts. CA 15-3 and CEA levels of patients with metastatic disease at the time of diagnosis or who relapsed during follow-up were evaluated. Four different breast cancer subtypes were defined: estrogen receptor (ER) and/or progesterone receptor (PR) positive and HER-2 negative (luminal A), ER and/or PR positive and HER-2 positive (luminal B), ER and PR negative and HER-2 positive (HER-2 overexpressing) and triple negative (ER, PR and HER-2 negative). Fifty-eight (13.7%) of the patients were metastatic at the time of diagnosis. RESULTS: 423 metastatic breast cancer patients were included. Of the patients, 232 (54.8%) had luminal A disease, 70 (16.5%) luminal B, 53 (12.5%) HER-2 overexpressing, and 68 (16.1%) triple negative disease. Preoperative CA 15-3 levels were raised in 48.1% of the luminal A group, in 42.8% of the luminal B group, in 26.0% of the HER-2 overexpressing group, and in 33.3% of the triple negative group. CA 15-3 levels after relapse were raised in 44.5% of the luminal A group, in 33.3% of the luminal B, in 28.9% of the HER-2 overexpressing, and in 38.8% of the triple negative group. Preoperative CEA levels were elevated in 44.3% of the luminal A group, in 28.5% of the luminal B, in 43.4% of the HER-2 overexpressing, and in 14.3% of the triple negative group. CEA levels after relapse were raised in 60.8%, 54.7%, 51.1%, and 36.0% of the patients in the 4 subgroups, respectively. CONCLUSION: This study showed that there are differences between the breast cancer subgroups in terms of tumor marker levels in metastatic breast cancer patients. Tumor marker elevation was lower in the triple negative group as compared to the luminal groups. Monitoring CEA levels in luminal A group may be beneficial in determining early relapses. However, this retrospective study requires further prospective confirmative cohort studies.

Effect of Intraoperative Mixed-Reality use on Nonsurgical Team Members in the Neurosurgical Operating Room: An Explorative Study.

OBJECTIVES: Mixed-reality (MxR) implementation in the neurosurgical operating room (OR) is emerging, but the impact of this technology on the nonsurgical OR staff has not been investigated yet. The purpose of this study is to evaluate the nonsurgical OR team's perception of the impact of intraoperative MxR use. METHODS: The evaluation occurred in a neurosurgical institution implementing MxR perioperatively on a daily basis for 15 months. The questionnaire measuring the impact of MxR consisted of 5 binary questions and 4 subquestions measured on a 7-point Likert scale. RESULTS: Fifteen nonsurgical staff members of a neurosurgical OR team were interviewed. Most (85%) of the cohort stated that MxR changed their perception of the surgery, improving understanding of the spatial orientation (median 6, interquartile range 5-7) and of the pathology dimensions (6, 5.5-7). One participant (7%) was of the opinion that MxR disrupted the OR workflow. The majority (60%) stated that use of the holograms improved efficiency in the OR. The participants were neutral about the potential role of MxR to improve communication among different OR team members (4, 2-5) and overall teamwork (4, 2-5). CONCLUSIONS: The use of 3-Dimensional interactive holograms of neurosurgical cases in the nonsterile intraoperative phase was not perceived as distractive, and neither was OR flow disruption by members of the nonsurgical OR staff. MxR was considered an adjunct to improve OR efficiency. A thorough understanding of the impact of MxR's implementation on the nonsurgical staff could lead to targeted improvement of the MxR use and, potentially, to increasing the quality of the teamwork.

Multiple primary malignant neoplasms: multi-center results from Turkey.

PURPOSE: Multiple primary malignant neoplasms (MPMNs) are defined as a diagnosis of two or more indepen-dent primary malignancies of different histologies/origins in an individual. The frequency of MPMN is being increasing. In this study we aimed to determine the frequency and clinical features of second primary cancers (SPCs). METHODS: From January 1990 to December 2010, patients with MPMNs were screened in 5 centers. Data were obtained retrospectively from hospital charts. RESULTS: Three hundred seventy-seven patients with MPMNs were evaluated. The median age at initial cancer diagnosis was 61 years (range 18-88). The median age at second cancer was 64 years (range 20-89). The median time between two cancer diagnoses was 15 months (range 0-504). Male to female ratio was 1.44 (M/F 223/154). The most frequent initial cancer types were head and neck (54 patients, 14.3%), breast (54 patients, 14.3%), and colorectal (43 patients, 11.4%). The most frequent second cancer types were lung (76 patients, 20.2%), colorectal (39 patients, 10.3%) and breast (33 patients, 8.8%). The most common cancer pairs in females were breast-gynecologic cancers (15 patients, 9.7%), colorectal-breast cancers (9 patients, 5.8%) and breast-colorectal cancers (7 patients, 4.5%). The most common cancer pairs in males were head and neck-lung cancers (29 patients, 13%), bladder-lung cancers (9 patients, 4%), and bladder-prostate cancers (7 patients, 3%). The median follow up was 36 months (range 17horbar;595). CONCLUSION: Physicians should be aware of SPCs probabilities. Newly developed suspicious lesions should be evaluated rigorously. Histopathologic evaluations of suspicious lesions for second tumors should be used extensively if needed. In our series, the most common pairs were breast-gynecologic cancers in females and head and neck-lung cancers in males.

Safety and efficacy of FOLFIRI-bevacizumab for metastatic colorectal carcinoma as second line treatment.

PURPOSE: To evaluate the efficacy and the safety of FOLFIRI-bevacizumab (B) in the 2nd line therapy of metastatic colorectal carcinoma (MCRC). METHODS: Between March 2006 and July 2009 35 patients with MCRC were treated with 2nd line therapy FOLFIRI- B (irinotecan 180 mg/m(2) D1, folinic acid 200 mg/m(2) D1, 5-fluorouracil/5 FU 400 mg/m(2) bolus D1, followed by 5 FU 2600 mg/m(2) 46-h continuous infusion, and bevacizumab 5 mg/kg D1, every 2 weeks) Their data were collected and analysed. RESULTS: The patient median age was 54 years (range 36-75). One patient (2.8%) had received oxaliplatin-based adjuvant chemotherapy and 33 patients (94.3%) were exposed to oxaliplatin during first line chemotherapy for MCRC. The median follow up period was 12.2 months (range 1.5-37.9). Complete remission (CR) was achieved in 5.7% of the patients and the sum of CR and partial remission (PR) was 11.4%. Disease control (CR+PR+stable disease/SD) was registered in 74.3% of the patients. During follow up, progression (PD) was seen in 32 (91.4%) patients and 23 (65.7%) patients had died. The median progression free survival (PFS) was 7.4 months (95%CI 5.5-9.3) and the median overall survival (OS) 13 months (95%CI 8.8-17.2). Grade 3-4 toxicity requiring delay of chemotherapy was observed in 12 (34.3%) patients with 10 patients (28.6%) having neutropenia and 2 (5.7%) diarrhea. CONCLUSION: FOLFIRI-B may be an efficient and safe choice in the 2nd line treatment of patients with MCRC previously treated with oxaliplatin.

Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests.

Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.

The role of NMDA receptor-dependent activity of noradrenergic neurons in attention, impulsivity and exploratory behaviors.

Activity of the brain's noradrenergic (NA) neurons plays a major role in cognitive processes, including the ability to adapt behavior to changing environmental circumstances. Here, we used the NR1DbhCre transgenic mouse strain to test how NMDA receptor-dependent activity of NA neurons influenced performance in tasks requiring sustained attention, attentional shifting and a trade-off between exploration and exploitation. We found that the loss of NMDA receptors caused irregularity in activity of NA cells in the locus coeruleus and increased the number of neurons with spontaneous burst firing. On a behavioral level, this was associated with increased impulsivity in the go/no-go task and facilitated attention shifts in the attentional set-shifting task. Mutation effects were also observed in the two-armed bandit task, in which mutant mice were generally more likely to employ an exploitative rather than exploratory decision-making strategy. At the same time, the mutation had no appreciable effects on locomotor activity or anxiety-like behavior in the open field. Taken together, these data show that NMDA receptor-dependent activity of brain's NA neurons influences behavioral flexibility.

Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice.

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT(3) receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT(3) receptor blockade. Ketamine (3-40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT(3) receptor antagonist MDL 72222 (0.3-3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50-66 and 3 mg/kg, respectively) and together (12.5-25 and 1 mg/kg). The present data suggest that 5-HT(3) receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure.

OBJECTIVES: We tested the hypothesis that, in patients with stable heart failure, measuring big endothelin-1 (ET-1) plasma level at rest predicts short-term prognosis better than peak oxygen consumption (VO2max) at exercise. BACKGROUND: Cardiopulmonary exercise testing and evaluation of neurohumoral plasma factors are established tools to estimate survival in patients with heart failure. No data, however, exist comparing the prognostic value of both marker categories simultaneously. METHODS: Two hundred twenty-six heart failure patients were studied in regard to a combined end point of death and prioritization for urgent cardiac transplantation within 1 year follow-up. RESULTS: During the study period 149 patients were without cardiac events (group A), 69 patients died or were urgently transplanted (group B) and 8 patients were alive after a nonurgent heart transplant operation. Norepinephrine (p < 0.0001), atrial natriuretic peptide (p < 0.001), big endothelin plasma levels (p < 0.0001 as well as workload, VO2max and achieved percentage of predicted peak oxygen consumption (pVO2max) (all p < 0.0001) differed significantly between groups A and B. In multivariate stepwise regression analysis, however, only big ET-1 plasma concentration (chi2=74.4, p < 0.0001), New York Heart Association function class (chi2=33.9, p < 0.0001), maximal workload (chi2=7.2, p < 0.01, and plasma atrial natriuretic peptide (ANP) concentration (chi2=4.6, p < 0.05) were independently related to outcome. Peak oxygen consumption or pVO2max did not reach statistical significance in this model. Event-free survival rates were significantly lower in patients with a big ET-1 level of 4.3 fmol/ml or more than with lower big ET-1 levels (p < 0.0001). CONCLUSION: We conclude that in patients with chronic heart failure who are stable on oral therapy measuring big ET-1 and ANP plasma levels may be a valuable noninvasive adjunct to improve the prognostic accuracy of detecting high risk patients compared with exercise testing alone.

Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor.

BACKGROUND AND PURPOSE: α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). EXPERIMENTAL APPROACH: The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg(-1) ), DMXBA and A-582941 (0.3 and 1.0 mg·kg(-1) )], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg(-1) ) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg(-1) (ASST) or A-582941: 0.1 mg·kg(-1) . KEY RESULTS: PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 µM) of DMXBA with apparent EC50 = 34 ± 3 µM and Emax = 225 ± 5 %. CONCLUSIONS AND IMPLICATIONS: Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.

In vitro binding properties of the hepatitis delta antigens to the hepatitis B virus envelope proteins: potential significance for the formation of delta particles.

To investigate the possible existence of (a) reactive binding site(s) on the hepatitis B surface antigen (HBsAg) for the hepatitis delta antigen (delta Ag) in the hepatitis delta virus (HDV), we performed binding studies using recombinant (rec)Small, recMiddle, recLarge HBsAg and recombinant small (S) and large (L) hepatitis delta antigen (recS delta Ag, recL delta Ag). Rec delta Ag was immobilized onto microtiter plates and incubated with recSmall, recMiddle and recLarge HBsAg. Of the three HBsAg proteins only the recMiddle HBsAg was found to bind to recS delta Ag. This binding was inhibited by the addition of synthetic PreS2 peptide but not by small HBsAg, indicating that the S delta Ag exhibits a PreS2 binding site. RecL delta Ag bound to all three forms of HBsAg. The binding of the HBsAg to recL delta Ag was saturable and could be blocked with an excess of HBsAg, but not with BSA. The region of the additional 19 amino acids of the L delta Ag is therefore responsible for the creation of the small HBsAg binding site on the L delta Ag. We therefore suggest that all HBsAg proteins but particularly the small HBsAg in the HDV coat seem to be involved in the interaction with the HDV core particle and that the PreS2 region of the middle HBsAg plays a crucial role in binding to small delta Ag during HDV particle formation, probably to increase the stability of the HDV particle.

Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor II, interleukin-6, and neurohumoral variables.

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.

Prostaglandin E1 infusion compared with prostacyclin infusion in patients with refractory heart failure: effects on hemodynamics and neurohumoral variables.

Prostaglandin E1 or prostacyclin were randomly infused in 18 patients with severe chronic heart failure who did not respond to oral treatment. Maximally tolerated dosages of both agents increased cardiac index; however, only prostacyclin decreased mean arterial pressure and increased plasma norepinephrine significantly. Twelve hours after 50% peak dose reduction, atrial natriuretic peptide levels, right atrial pressure, mean pulmonary artery pressure, and mean arterial pressure continued to decrease with prostaglandin E1, whereas the increase in cardiac index was sustained; in contrast, at 50% prostacyclin dose reduction, cardiac index decreased toward baseline, suggesting that, with reduced dosages for chronic infusions, desired hemodynamic changes seem to be sustained with prostaglandin E1 only.

Oral contraceptives that contain ethinyl estradiol (0.035 mg) and cyproterone acetate (2 mg) inhibit leukocyte transmigration through endothelial cell monolayers.

OBJECTIVE: To investigate the influence of ethinyl estradiol and cyproterone acetate in oral contraceptives on leukocyte migration through endothelial cell monolayers. DESIGN: Experimental in vitro prospective study. SETTING: An academic research laboratory. INTERVENTION(S): Endothelial cells were cultured on microporous membranes to produce monolayers. Polymorphonuclear leukocytes were used in a previously described migration assay (n = 7). The amount of untreated polymorphonuclear leukocytes that migrated through untreated endothelial cell monolayers was used as a control and set at 100%. In addition, a leukocyte adhesion assay was used. MAIN OUTCOME MEASURE(S): Leukocyte adhesion to and transmigration through endothelial cell monolayers. RESULT(S): Ethinyl estradiol and cyproterone acetate inhibited the migration of polymorphonuclear leukocytes through endothelial cell monolayers significantly (67% +/- 6.4%) when both cell types were treated to simulate in vivo conditions. The adhesion assay produced similar results. CONCLUSION(S): Ethinyl estradiol and cyproterone acetate were identified as potent inhibitors of leukocyte migration through endothelial cell monolayers.

Ultrasound with Levovist in the diagnosis of suspected calf vein thrombosis.

Diagnosing calf vein thrombosis (CVT) by color Doppler ultrasound (US) is often a difficult task because of swelling or obesity. The purpose of this study was to assess if IV infusion of Levovist can improve the accuracy and reduce the rate of indeterminate examinations. A total of 20 patients with suspected CVT underwent color Doppler US without and with Levovist followed by ascending venography as the "gold standard," which detected calf clots in 7 patients (35%). Compared to routine noncontrast sonography, Levovist examination reduced the rate of indeterminate scans from 55% to 20% and improved the specificity for the detection of CVT from 25% to 67% without compromising sensitivity (100% to 86%) notably. Image quality was improved in 13 (65%) of 20 scans. In conclusion, we can say that Levovist improves the quality of duplex examination of the calf veins, especially in cases with difficult conditions due to obesity or swelling.

Effects of atenolol as add-on therapy to fosinopril in heart failure.

Several trials have demonstrated functional benefit with beta-blockers in patients with chronic heart failure. The aim of this observational study was to investigate if additional beneficial effects can be obtained from beta-blockade in a heart failure population that is already receiving high-dose ACE-inhibitor therapy. Atenolol is a long-acting cardioselective beta-blocking agent and is devoid of additional vasodilatory properties. Twenty-five male patients with class II or III heart failure and background therapy of digitalis, furosemide and 20 mg fosinopril per day were treated with 40 mg fosinopril per day and additional 75 mg atenolol per day (beta-blocker group) or with 40 mg fosinopril per day alone (control group). At the end of one year, changes in left ventricular function, exercise parameters and plasma neurohumoral variables reflecting vasoconstriction (noradrenaline, big endothelin) were measured and compared in the two treatment groups. Nineteen patients completed the study. Drop-outs were due to death (4 patients) and non-compliance (2 patients) with no significant difference between the groups. There was a beta-blocker related improvement in left ventricular ejection fraction (p < 0.05 between groups) and an increase in peak oxygen consumption in the control group only (p < 0.05 between groups). Thus, in a heart failure population receiving high-dose ACE inhibitor background therapy beta-blockade with atenolol produced additional benefit by reversing left ventricular dysfunction.

Relationship between kidney function, hemodynamic variables and circulating big endothelin levels in patients with severe refractory heart failure.

UNLABELLED: Fluid retention is a major characteristic of symptomatic, progressive heart failure when a main factor implicated in the pathogenesis of renal dysfunction is renal hypoperfusion. This may be a consequence of forward cardiac failure, resulting in a low cardiac output integrating poor left ventricular function secondary to myocardial impairment and increased resistance in the regional renal vasculature secondary to locally released vasoconstrictors, e.g. endothelin. So far, the role of the pulmonary circulation in perpetuating renal dysfunction in heart failure is unclear. METHODS: We investigated the relationship of hemodynamic variables obtained during right heart catheterization and plasma big endothelin levels to renal function variables in 18 male patients aged 52 +/- 3 years, with heart failure in the NYHA function class III-IV, based on idiopathic causes in 8 and ischemic causes in 10 patients. Renal plasma flow (RPF) was established by paraaminohippurate (PAH) clearance and the glomerular filtration rate (GFR) was measured by iothalamate clearance. RESULTS: Plasma big endothelin (ET) levels were increased above the upper normal range (1.8 fmol/ml) in 16 out of 18 patients, averaging 5.0 +/- 0.8 fmol/ml (1.7-11.9 fmol/ml). Positive correlations to big ET plasma levels were detected with mean pulmonary pressure (r = 0.73, p < 0.001) pulmonary capillary wedge pressure (r = 0.56, p < 0.05) and pulmonary vascular resistance index (r = 0.69, p < 0.01). Glomerular filtration rate (70 +/- 7 ml/min) and renal plasma flow (358 +/- 36 ml/min) were considerably reduced and exhibited a tendency to correlate inversely with big ET levels (r = -0.46, p = 0.056 and r = -0.44, p = 0.069, respectively). Contrary to expectations, RPF did not correlate significantly with cardiac index, systemic vascular resistance index or arterial blood pressure. In contrast, significant correlations were detected of RPF with pulmonary capillary wedge pressure (r = -0.69, p < 0.01), mean pulmonary artery pressure (r = -0.65, p < 0.01), right atrial pressure (r = -0.47, p < 0.05) and right ventricular ejection fraction (r = 0.49, p < 0.05). CONCLUSION: The findings suggest a role for endothelin in renal vasoconstriction and accord well with the concept that in severe heart failure renal hypoperfusion--by volume retention--as well as increased endothelin synthesis--by pulmonary vasoconstriction--play a part in the increased pulmonary filling pressures.

A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice.

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.

Baculovirus-directed high level expression of the hepatitis delta antigen in Spodoptera frugiperda cells.

The hepatitis delta antigen (HDAg) is a multifunctional protein. It forms the core-like structure of the hepatitis delta virus (HDV) but also enhances replication of HDV in the nucleus of the hepatocyte. A cDNA fragment encoding HDAg was inserted adjacent to the polyhedrin promoter of Autographa californica nuclear polyhedrosis virus present in the baculovirus transfer vector pVL941. After transfection of Spodoptera frugiperda (Sf9) cells a recombinant baculovirus Ac delta 1 was isolated and purified using filter hybridization techniques. Sf9 cells infected with Ac delta 1 express the HDAg as a non-fused, non-glycosylated protein with an abundance of up to 25% of the total cellular protein mass. Immunoblot analysis using a human polyclonal anti-HD conjugate identified a 22K and a 24K protein in the nucleus of Ac delta 1-infected Sf9 cells. Electron microscopic studies using immunogold labelling showed that the recombinant HDAg (recHDAg) was associated with the hetero-chromatin of the Sf9 cells. The recHDAg produced by Sf9 cells elicited anti-HD antibodies in chimpanzees when injected intramuscularly.

The purification and characterization of rat gamma interferon by use of two monoclonal antibodies.

Two mouse monoclonal antibodies, designated DB-1 and DB-2, were isolated and used for the purification and characterization of recombinant rat interferon gamma (rRIF-gamma) derived from Chinese hamster ovary (CHO) cells. The two antibodies belong to different classes (DB-1 is an IgG1 and DB-2 an IgA) and display similar epitope specificities as shown in competition binding experiments. Both antibodies, raised against rRIF-gamma, exhibited high affinity for rat and mouse gamma interferon and efficiently neutralized the antiviral activity of both animal interferon species. Affinity chromatography analysis showed that a column with immobilized DB-1 was capable of complete binding of rat and mouse gamma interferon, both natural and recombinant DNA-derived. As visualized by SDS-polyacrylamide gel electrophoresis and Western blot analysis, the purified rRIF-gamma preparation consisted of at least seven molecular forms with Mr values ranging between 14 000 and 25 000, with a relative abundance of a 18 000 Mr protein. Gel permeation chromatography of crude rRIF-gamma gave coincident peaks of rRIF-gamma proteins (all different forms) and interferon activity corresponding to a Mr value of 45 000. The results suggest that the molecular heterogeneity was due to differential glycosylation and was not the consequence of a proteolytic degradation process.