Patients' preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial: what makes it worthwhile?

Background: We sought to determine the survival benefits that patients judged sufficient to warrant adjuvant therapy with sorafenib for 1 year, or for 3 years after resection of renal cell carcinoma in the SORCE trial. Methods: SORCE participants from all sites in Australia and New Zealand, and selected sites in the UK, completed a validated preferences questionnaire at months 0, 3, 15, and 42 to elicit the minimum survival benefits they judged sufficient to warrant adjuvant sorafenib for 1 year (versus observation), or for 3 years (versus 1 year). The questionnaires used reference survival times of 5 and 15 years; and reference survival rates at 5 years of 65% and 85%. Results: The 233 participants had a median age of 57 years (range 29-78) and 71% were male. For 1 year of sorafenib versus no adjuvant therapy, the median benefits in survival times judged sufficient to warrant treatment were an extra 9 months beyond 5 years and an extra 1 year beyond 15 years; the median benefit in survival rates were an extra 4% beyond 65% and an extra 3% beyond 85% at 5 years. For 3 years of sorafenib versus 1 year of sorafenib, the median benefit in survival time judged sufficient to warrant extended treatment was an extra 1 year beyond both 5 and 15 years. Participants randomly allocated to treatment with sorafenib judged larger benefits necessary than those allocated to placebo. Participants' preferences were not associated with their baseline characteristics or the interval from randomisation. Conclusion: Most participants judged an extra year of survival necessary to warrant 1 year of adjuvant sorafenib worthwhile, and an additional year of survival to warrant extending the duration of sorafenib from 1 to 3 years. Patients' preferences are important in shared decision making. SORCE trial clinical trials number: NCT00492258.

Stevioside induced ROS-mediated apoptosis through mitochondrial pathway in human breast cancer cell line MCF-7.

Stevioside is a diterpene glycoside found in the leaf of Stevia rebaudiana, a traditional oriental medicinal herb, which has been shown to have various biological and ethno-medicinal activities including antitumor activity. In this study, we investigated the effects of stevioside on the cytotoxicity, induction of apoptosis, and the putative pathways of its action in human breast cancer cells (MCF-7). For the analysis of apoptotic pathway, measurement of reactive oxygen species (ROS) and assessment of mitochondrial transmembrane potential (MTP) were achieved. We showed that stevioside was a potent inducer of apoptosis and it conveyed the apoptotic signal via intracellular ROS generation; thereby inducing change in MTP and induction of mitochondrial mediated apoptotic pathway. Taken together, our data indicated that stevioside induces the ROS-mediated mitochondrial permeability transition and results in the increased expression of apoptotic proteins such as Bax, Bcl-2 and Caspase-9. Effect of stevioside on stress-related transcription factors like NF-E2-related factor-2 opens up a new vista for further studies. This is the first report on the mechanism of the antibreast cancer (in vitro) activity of stevioside.

Selective potentiation of the metabotropic glutamate receptor subtype 2 blocks phencyclidine-induced hyperlocomotion and brain activation.

Previous preclinical and clinical studies have demonstrated the efficacy of group II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA), an allosteric potentiator of mGluR2, is effective in experimental models of psychosis, blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic effects of PCP, and examined how BINA modulated the PCP-induced functional changes in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic, thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of the BOLD response to PCP in the prefrontal cortex, caudaute-putamen, nucleus accumbens, and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced behaviors in a preclinical model of schizophrenia, and, importantly, its reversal by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved in its pharmacological action. Finally, our findings bolster the growing body of evidence that mGluR2 is a viable target for the treatment of schizophrenia.

Quantification of bone mineral density to define osteoporosis in rat.

The diagnosis of osteoporosis centers on assessment of bone mass and quality. In the absence of evidence-based guidelines to assess bone status in laboratory animals and unsuitability of use of T-/Z-scores meant for clinical application in animal studies, most investigators involved in new drug research and development employ clinical biomarkers and kits to assess bone turnover rate and portray change in bone mineral density (BMD) as percentage of increase/decrease, making comparative assessment of the effect highly impractical. This study proposes threshold boundaries of BMD (rT-score) in colony-bred Sprague-Dawley rats, distinct from those used clinically. Boundaries were obtained keeping fixed Type-I error (alpha=0.025). Femur neck was considered best for defining bone status using BMD measured by dual-energy X-ray absorptiometry. Findings demonstrate that BMD-1.96 and <-0.80 rT-score as osteopenia. Performance of boundaries to ascertain bone status was examined through simulation under different physiological/ hormonal states viz. estrogen deficiency, ageing, estrus cycle, pregnancy, and lactation. The Area Under the Receiver Operating Characteristic curve of 0.98 obtained using BMD of femur neck, being close to unity, shows excellent ability of the proposed rT-score to effectively identify osteoporosis. Further studies using certain hierarchical measures of bone quality such as histomorphometry, mechanical testing etc. could supplement these findings. Since, unlike humans, most laboratory animals including rats only exhibit osteopenia and do not fracture their bones, the proposed thresholds are intended to serve as categorical tools to define bone quality and not to predict fracture risk.

Effect of ormeloxifene on ovariectomy-induced bone resorption, osteoclast differentiation and apoptosis and TGF beta-3 expression.

Effect of ormeloxifene, a multifunctional selective estrogen receptor modulator, on prevention of ovariectomy-induced bone resorption in retired breeder female rats, osteoclastogenesis using bone marrow cells from adult Balb/c mice cultured in presence of M-CSF and RANKL, osteoclast apoptosis using terminal deoxynucleotidyl transferase fragment end labeling and TGF beta-3 expression were investigated. Raloxifene, a benzothiophene reported to mimic effects of estrogen in bone, and estradiol were used for comparison. Ormeloxifene (10(-6) and 10(-8)M) significantly inhibited osteoclastogenesis (P<0.001 versus vehicle control) as evidenced by lower number of TRAP-positive osteoclasts in bone marrow cultures and caused apoptosis of osteoclasts. The effect was almost equivalent to that observed in presence of estradiol-17 beta, except that significant number of cells undergoing apoptosis was evident even at 10(-9)M concentration of estradiol-17 beta (P<0.001). Raloxifene, though inhibited osteoclastogenesis at much lower concentrations (10(-8) to 10(-12)M; P<0.001), failed to cause apoptosis of osteoclasts at any of the concentrations used. While ormeloxifene, raloxifene and ethynylestradiol significantly prevented ovariectomy-induced bone loss in vivo in retired breeder female rats, prevention of ovariectomy-induced decrease in BMD and trabecular network of proximal tibia, calcium and phosphorus levels in femur and tibia and prevention of ovariectomy-induced down-regulation of TGF beta-3 expression in lumbar vertebrae was of lower order in raloxifene- than ormeloxifene- or ethynylestradiol-supplemented females. Both the SERMs, however, produced considerable estrogenic effects at the uterine level as evidenced by increase in weight, total and endometrial area and luminal epithelial cell height; the effect being generally greater in raloxifene- than ormeloxifene-treated rats. Findings demonstrate that inhibition of estrogen-deficiency osteoporosis by ormeloxifene, as in case of estradiol, was mediated via inhibition of osteoclastogenesis, apoptosis of osteoclasts and up-regulation of TGF beta-3 expression. Raloxifene, though effective in inhibiting osteoclastogenesis in vitro at much lower concentrations, was not only less potent in preventing ovariectomy-induced bone loss in retired breeder female rats in vivo but also appeared to have a different mechanism of action than ormeloxifene and estradiol.

In vitro anti-resorptive activity and prevention of ovariectomy-induced osteoporosis in female Sprague-Dawley rats by ormeloxifene, a selective estrogen receptor modulator.

Antiosteoporotic activity of ormeloxifene, a multifunctional SERM, using inhibition in parathyroid hormone (PTH) induced resorption of 45Ca from prelabeled chick and rat fetal limb bones in chase cultures and modulation of certain biochemical markers of bone turnover and bone mineral density (BMD) in ovariectomized adult female rats, was investigated. Ormeloxifene concentration-dependently inhibited PTH-induced resorption of 45Ca from chick fetal femora with treated/control (T/C) ratio of 0.71, 0.32 and 0.20 at 50, 100 and 200 microM concentration, in comparison to 0.49, 0.53 and 0.95 in case of CDRI-85/287 (a pure antiestrogen), tamoxifen and ethynylestradiol (100 microM), respectively. Using rat fetal limb bones, ormeloxifene (100 microM) exhibited T/C ratio of 0.67, in comparison to 1.43 with PTH alone. Heat-killed bones exhibited negligible resorption (2.9%; T/C: 0.098) in response to PTH. In adult female rats, ormeloxifene (1.25 and 12.5 mg/kg per day) inhibited ovariectomy-induced increase in serum total and bone-specific alkaline phosphatase and osteocalcin and urine calcium/creatinine ratio to almost intact control level. Ovariectomy was accompanied by marked decrease in bone mineral density of isolated femur and tibia, being maximum in femur neck (28.3%; P < 0.01) and midshaft (23.7%; P < 0.01), but only marginal (6.7%; P > 0.05) in region proximal to tibio-fibular separation point. Decrease in BMD based on T-/Z-score, too, was >2.5 S.D. than mean value of normal young adult/age-matched females. This was prevented by ormeloxifene and the effect, though apparently more in females supplemented with higher dose of ormeloxifene, was not always significantly different and clear dose-response was not evident until BMD data was evaluated on T-/Z-score basis. The analysis also demonstrated much higher threshold level of tibia than femur and more so for their mid-shafts. Increase in BMD of isolated bones was also observed in ormeloxifene-treated intact females, without significantly altering biochemical markers of bone turnover or uterine weight. Findings suggest potential of ormeloxifene in management of post-menopausal osteoporosis and beneficial effect on BMD in women taking this SERM for contraception or any hormone-related clinical disorder.

Necrotising fasciitis: a life-threatening complication of acupuncture in a patient with diabetes mellitus.

Acupuncture is used for some conditions as an alternative to medication or surgical intervention. Several complications had been reported, and they are generally due to physical injury by the needle or transmission of diseases. We report a case of life-threatening necrotising fasciitis that developed after acupuncture treatment for osteoarthritis of the knee in a 55-year-old diabetic woman. She presented with multiple discharging sinuses over the right knee. As the patient did not respond to intravenous antibiotics, extensive debridement was performed. She made a good recovery. Since many old diabetic patients with degenerative joint diseases may consider this mode of treatment, guidelines on cleanliness and sterility of this procedure should be developed and practiced.

Argon plasma coagulation is an effective treatment for refractory hemorrhagic radiation proctitis.

INTRODUCTION: Chronic radiation proctitis complicating pelvic radiotherapy can be debilitating. It commonly presents with rectal bleeding, which can be difficult to control. Medical management of hemorrhagic radiation proctitis is not very successful, although surgery carries high risks. Thus, endoscopic treatments are preferred. The aim of this study is to assess the efficacy of argon plasma coagulation applied endoscopically to treat hemorrhagic radiation proctitis that has been refractory to topical formalin therapy. METHODS: Twelve patients who had ongoing bleeding from radiation proctitis, after previously failed formalin therapy, underwent endoscopic treatment using argon plasma coagulation. The efficacy of treatment was assessed by grading the frequency and severity of bleeding (0-4, 0 being no bleeding), hemoglobin level, and transfusion requirements. RESULTS: At a median follow-up of 11 months, ten patients (83 percent) had a significant reduction in the severity and frequency of bleeding, with complete cessation in six (50 percent). The presence of coexistent radiation-induced sigmoiditis in two patients was associated with reduced but persistent bleeding, because of difficulty in targeting the bleeding sites in the sigmoid colon. The median number of treatment sessions per patient was two (range, 1-3), with the number of sessions correlated with the extent of the proctitis. All patients had an improvement in their hemoglobin level, with the mean increasing from 11.2 to 12.3 g/dl. In the six months before starting therapy, all patients had been taking iron supplements, and four had required blood transfusions (median 3 units, range, 2-6). Iron supplements were ceased four weeks after the completion of therapy in all cases, and no further transfusions were required during the study period. None of the patients experienced any significant side effects or complications. CONCLUSIONS: Argon plasma coagulation is an effective and safe treatment for hemorrhagic radiation proctitis that has been refractory to topical formalin therapy.

Spectrum of antibiogram against pathogens related to respiratory tract infections with a special reference to ceftibuten: a multicentric study.

In a multicentric study at several leading hospitals of this country, microbiological assessment was carried out in 500 specimens from patients suffering from respiratory tract infections (RTIs; both upper and lower) for a period of 6 months from January, 1999 to June, 1999. The antibiotic sensitivity study was done in 201 isolates from 500 different specimens of throat swab, postpharyngeal swab, sinusitis drainage fluid, sputum, broncho-alveolar lavage (BL), etc. Ceftibuten, an orally active third generation cephalosporin showed encouraging results when compared with seven other selected antibiotics used for RTI. The majority of the patients with acute or chronic RTIs showed an excellent in vitro response to ceftibuten in the analysis of the isolates. Seventy to ninety per cent of the isolated respiratory pathogens were found to be sensitive to ceftibuten in vitro; which offers a promising alternative to other antibiotics included in this study.

Anti-inflammatory activity of topical nimesulide gel in various experimental models.

OBJECTIVE AND DESIGN: The anti-inflammatory activity of topically applied nimesulide gel was compared in different experimental models with that of diclofenac and piroxicam gels. MATERIAL: Wistar albino rats of either sex were used. TREATMENT: In acute models, 50 mg of nimesulide or diclofenac were applied to right hind paws 1 h (carrageenan) or immediately before (formalin) irritant injection (sub-plantar). In adjuvant arthritis, 50 mg of nimesulide, diclofenac or piroxicam were applied daily to injected paws for 14 days. METHODS: Paw volume was measured by plethysmograph. Statistical significance was tested with Student's t-test. RESULTS: In the carrageenan paw odema, topical nimesulide gel exhibited similar anti-inflammatory activity to diclofenac gel, and was more effective than diclofenac gel in formalin-paw odema. In both acute (18 h) and chronic (14 d) phases of adjuvant arthritis, nimesulide gel was more effective than diclofenac or piroxicam gels. CONCLUSION: Topical nimesulide gel possesses higher anti-inflammatory activity than that of diclofenac or piroxicam gels.

Variation of serum potassium and creatinine phosphokinase levels in suxamethonium-induced muscle relaxation.

Popular depolarising muscle relaxant, suxamethonium (succinylcholine chloride), produces fasciculation in group of muscles and 'after pain'. Mode of its action is neuromuscular blockage. It also may be associated with muscle fibre injury and altered membrane permeability. These may cause rise of serum K+ and creatinine phosphokinase (CPK) levels. But use of diazepam either during or as pretreatment may reduce the fasciculation, 'after pain' and rise of K+ and CPK levels. Present study was undertaken to show whether any correlation of the degree of fasciculation and postsuxamethonium myalgia is present or not and whether diazepam has any role in reducing muscle injury and in turn reducing the levels of serum K+ and CPK.

Phaseolus vulgaris L. var. HUR 15--a potential indigenous source for commercial PHA preparation.

Mitogenic potential of the partially purified lectin from P. vulgaris isolated by ammonium sulphate precipitation was assessed by lymphocyte transformation test (LTT) and was compared with three commercially available phytohemagglutinins (PHA). The blast inducing capacity and mitotic index analysis revealed that this preparation has potential to be used in the indigenous commercial production of PHA which is routinely used for human chromosomal studies from the peripheral blood culture at, at present, is imported.

Delayed management of fracture of the lateral humeral condyle in children.

Thirty-nine displaced fractures of the lateral humeral condyle in children were followed for an average of 5 (2-5) years. The results were evaluated from functional and cosmetic aspects. Patients treated within 2 weeks by open reduction and internal fixation did well. Those operated on after 6 weeks did not do better than nonoperated on cases. Complications included cubitus varus and valgus deformities, osteonecrosis, nonunion and malunion, and loss of motion. We recommend that patients presenting late be left alone and any sequelae evaluated at a late stage.

Tetracyclic chromophoric analogues of actinomycin D: synthesis, structure elucidation and interconvertibility from one form to another, antitumor activity, and structure-activity relationships.

Two different tetracyclic chromophoric analogues of actinomycin D have been synthesized by engaging two chromophoric DNA-binding functions in actinomycin D, i.e., 2-amino and 3-oxo, into either a 1,4-oxazin-2-one or an oxazole ring system. A third analogue has an extra quinone function at C-8 of the oxazole analogue. In all the analogues the chemical integrity of the peptide lactones of the parent antibiotic is kept intact, but their sterochemistry is altered. The analogues are designed as transport-modified prodrug forms of either the tricyclic active analogues of actinomycin D or actinomycin D itself. All analogues exhibit cytotoxicity that is several-fold less potent than AMD; they also have no binding affinity toward extracellular DNA. Nonetheless, the analogues of the first and the third series show improved antitumor activities (P388 leukemia, CDF1 mice). In fact, two of these analogues having a phenyl substituent at the C-3 site of the oxazinone ring or the C-2 position of the 8-oxo-8H-oxazole ring exhibit the highest antitumor effects. Most of the analogues are active over a broader dose range than actinomycin D and are 6- to 16-fold less cytotoxic to human lymphoblastic leukemia (CCFR-CEM) cells in vitro. The analogues with the most pronounced antitumor activity are those that retain most elements in the peptide stereochemistry of actinomycin D and have a quinone function or demonstrate susceptibility of their chromophores to biotransformation.

Hemagglutinating activity in extracts of mycelia from submerged mushroom cultures.

Extracts from mycelia of seven different mushrooms agglutinated erythrocytes of several species. More than one agglutinating factor was identified in the extracts of three different mycelia. Agglutination was partially inhibited nonspecifically by high concentrations of glucose, galactose, mannose, fucose, and rhamnose.

Photostimulated thermoluminescence of Al2O3 (Si, Ti) and its application to ultraviolet radiation dosimetry.

Intrinsic photostimulated thermoluminescence (PSTL) in the range 200-320 nm and radiation sensitized PSTL for 200-425 nm have been studied in Al2O3 (Si, Ti) phosphor. Causes of the effects found, partly attributed to phototransfer of electrons are described. Linearity in the intrinsic and radiation sensitized response of the 280 degree C TL peal for both pellet and powder forms has been studied with regard to ultraviolet dosimetry over the range 10(-2) to 5 x 10(4) mJ cm-2. Details of the use of powder and pellet forms for dosimetry are given.

Annealing characteristics and nature of traps in A12O3 thermoluminescent phosphor.

Thermal annealing characteristics of the glow peaks from 200 to 650 degrees c in Al2O3 thermoluminescent (TL) phosphor have been studied. All the glow peaks show exponential decay and follow first-order kinetics. The trap depths and frequency factors for the glow peaks have been determined from their isothermal decay and from their initial rise. The trap depths, E, obtained for different glow peaks (peak temperature Tm) can be approximated by the relation E(eV)=Tm (K)/325 and the corresponding frequency factor, s, varies from 10(14) to 10(16) s-1. The measured values of E, s and Tm for the glow peaks are shown to be consistent with the equation for glow peak temperature. The annealing characteristics and actual high temperature irradiations show that the 250, 475 and 635 degree c peaks can be used for elevated temperature dosimetry up to 150, 300 and 440 degrees C respectively. It is suggested that surface defects related to Si impurity in Al2O3, propagated into the lattice on high temperature treatment close to the melting point, are responsible for the TL traps. The trapped charges responsible for TL are shown to be electrons by photostimulated thermoluminescence studies under the F centre excitation in this phosphor.