Activation of the K-ras oncogene in colorectal neoplasms is associated with decreased apoptosis

BACKGROUND: Recent in vitro data indicate that the oncogenic effects of activated ras genes may be mediated, at least in part, through inhibition of apoptotic cell death. To examine this proposition in vivo, the relationship between mutations of the K-ras gene and the frequency of apoptosis was studied in a series of 69 sporadic colorectal neoplasms (11 adenomas and 58 carcinomas). METHODS: Mutations in codon 12 of K-ras were determined by a single tube, enriched polymerase chain reaction. Apoptotic cells in tumor sections were identified by in situ end-labeling of fragmented DNA, whereas levels of bcl-2 and p53 proteins were determined by immunohistochemistry. RESULTS: Tumors with mutant K-ras had a significantly lower apoptotic index than those with the wild-type allele (P < 0.05). They were also more likely to exhibit positive bcl-2 staining (P < 0.05). Adenomas showed significantly greater bcl-2 positivity than carcinomas (89% and 51%, respectively; P < 0.05). The frequency of apoptosis in these tumors was not related to either bcl-2 positivity or p53 status. CONCLUSIONS: These findings suggest that activation of K-ras in colorectal carcinoma may inhibit apoptosis and thus favor tumor progression. Alternatively, this association may reflect an accumulation of K-ras mutations in cells in which normal apoptotic pathways have been impaired.     

Unresectable pancreatic cancer: is a multi-modality approach a promising therapeutical alternative?

BACKGROUND/AIMS: The aim of this study was to evaluate the combination of immunochemotherapy and stop-flow upper abdominal chemotherapy in the prolongation of survival in patients with unresectable pancreatic cancer. METHODOLOGY: Thirty unresectable pancreatic cancer patients were treated with immuno-chemotherapy in combination with stop-flow upper abdominal chemotherapy, in an attempt to improve survival time. RESULTS: The results obtained in this study indicate that this kind of treatment is feasible, safe and effective for patients suffering from Stage III and IV pancreatic duct carcinoma. Twenty per cent of the patients within this group were able to undergo radical resection and remain alive and free of disease, with a mean survival rate of 16 months. CONCLUSION: The multi-modality approach used in this study achieved promising results for pancreatic cancer patients and is recommended as a promising therapeutic alternative.     

On the formulation design and rheological evaluations of pectin-based functional gels

In the current study, formulation design and development of a novel pectin-based functional gel were investigated. Amidated low methoxyl pectin (ALMP), high methoxyl pectin (HMP), sorbitol, inulin, rebaudioside-A, gardenia, phloridzin, quercetin, apple flavor, and calcium chloride (as its dihydrated salt) were selected as general ingredients. Response surface methodology was applied to design different formulations and to investigate on their experimental responses. The oscillatory tests were carried out in 2 stages with ALMP, HMP, sorbitol, and inulin as the variables of the 1st stage and ALMP and calcium chloride as the variables of the 2nd stage. Results of the 1st stage indicated relatively similar behaviors throughout the frequency range applied for all of the samples studied (true gels). However, magnitudes of the 5 rheological parameters of this study (storage modulus, loss modulus, loss tangent, complex modulus, and complex viscosity) were affected by different variables (ALMP, HMP, inulin, and sorbitol concentrations). Experimental results confirmed that sorbitol could be omitted from the formula while inulin and HMP could be used at their highest levels studied. At the 2nd stage, only 2 formulas indicated a strong gel behavior and other formulas showed typical behaviors of weaker gels or those of the concentrated solutions. At the conclusion of this study, a finished gelled product formula was suggested with the application of the best levels of the ingredients. The resultant gel was found to be set rapidly with no syneresis and showed a potential to be considered as a functional gelled dessert.     

Inhibition evoked from primary afferents in the electrosensory lateral line lobe of the weakly electric fish (Apteronotus leptorhynchus)

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering. J. Neurophysiol. 80: 3214-3232, 1998. The inhibition controlling the indirect descending feedback (parallel fibers originating from cerebellar granule cells in the eminentia posterior pars granularis) to electrosensory lateral line lobe (ELL) pyramidal cells was studied using intracellular recording techniques in vitro. Parallel fibers (PF) contact stellate cells and dendrites of ventral molecular layer (VML) GABAergic interneurons. Stellate cells provide local input to pyramidal cell distal dendrites, whereas VML cells contact their somata and proximal dendrites. Single-pulse stimulation of PF evoked graded excitatory postsynaptic potentials (EPSPs) that were blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl--aspartate (NMDA) antagonists. The EPSPs peaked at 6.4 +/- 1.8 ms (mean +/- SE; n = 11) but took >50 ms to decay completely. Tetanic stimulation (100 ms, 100 Hz) produced a depolarizing wave with individual EPSPs superimposed. The absolute amplitude of the individual EPSPs decreased during the train. Spike rates, established by injected current, mostly were increased, but in some cells were decreased, by tetanic stimulation. Global application of a gamma-aminobutyric acid-A (GABAA) antagonist to the recorded cell's soma and apical dendritic region increased the EPSP peak and decay phase amplitudes. Tetanic stimulation always increased current-evoked spike rates after GABAA blockade during, and for several hundred milliseconds after, the stimulus. Application of a GABAB antagonist did not have any significant effects on the PF-evoked response. This, and the lack of any long hyperpolarizing inhibitory postsynaptic potentials, suggests that VML and stellate cell inhibition does not involve GABAB receptors. Focal GABAA antagonist applications to the dorsal molecular layer (DML) and pyramidal cell layer (PCL) had contrasting effects on PF-evoked EPSPs. DML GABAA blockade significantly increased the EPSP peak amplitude but not the decay phase of the EPSP, whereas PCL GABAA-blockade significantly increased the decay phase, but not the EPSP peak, amplitude. The order of antagonist application did not affect the outcome. On the basis of the known circuitry of the ELL, we conclude that the distal inhibition originated from GABAergic molecular layer stellate cells and the proximal inhibition originated from GABAergic cells of the ventral molecular layer (VML cells). Computer modeling of distal and proximal inhibition suggests that intrinsic differences in IPSP dynamics between the distal and proximal sites may be amplified by voltage-dependent NMDA receptor and persistent sodium currents. We propose that the different time courses of stellate cell and VML cell inhibition allows them to act as low- and high-pass filters respectively on indirect descending feedback to ELL pyramidal cells.     

Conformal proton therapy for prostate carcinoma

The suppression of apoptosis may contribute to the carcinogenicity of the peroxisome proliferators (PPs), a class of non-genotoxic rodent hepatocarcinogens. Our previous work demonstrated that the PP nafenopin suppressed both spontaneous and transforming growth factor beta1 (TGFbeta1)-induced hepatocyte apoptosis both in vivo and in vitro. Here, we extend these observations by demonstrating the ability of nafenopin to suppress apoptosis induced by other major candidates for the signalling of cell death in the liver. Treatment of rat or mouse hepatocyte monolayers with TGFbeta1 or the DNA damaging drugs etoposide or hydroxyurea induced high levels of apoptosis. Western blot analysis did not support a role for either p53 or p21waf1 in etoposide-induced apoptosis in rat hepatocytes. Treatment of mouse hepatocytes with an agonistic anti-Fas antibody also resulted in an induction of high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all three stimuli. Overall, our studies demonstrate that the ability of nafenopin to protect hepatocytes from apoptosis is not restricted to species or apoptotic stimulus. It is possible, therefore, that the PPs may suppress apoptosis by acting on diverse signalling pathways. However, it seems more likely that nafenopin suppresses hepatocyte apoptosis elicited by each death stimulus by impinging on a core apoptotic mechanism.     

Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study

PURPOSE: To compare standard therapy with bleomycin, etoposide, and cisplatin (BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS AND METHODS: A total of 304 men with advanced disseminated germ cell tumors were randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response. Complete response rates, favorable response (complete remission, surgical free of disease, continuous partial remission for 2+ years), time to treatment failure, and overall survival were assessed. RESULTS: Overall complete remission rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two treatments. Grade 3 or worse toxicity, particularly hematologic and genitourinary toxicity, was significantly more common in patients who received VIP. CONCLUSION: BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors. The substitution of ifosfamide for bleomycin, however, was associated with significantly greater toxicity. Four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors.     

Intraarticular foot and ankle injections to identify source of pain before arthrodesis

OBJECTIVE: The purpose of our study was to evaluate the usefulness of diagnostic joint injections in patients with foot and ankle pain when the radiologist attempts to identify the source of pain. This study also correlated the results of injection with outcome after arthrodesis. MATERIAL AND METHODS: We retrospectively reviewed the records of 22 patients who had a foot or ankle joint injected to identify a source of pain and who later underwent arthrodesis of the painful joint. All patients had long-term foot and ankle symptoms of variable causes. Twenty-four joints were assessed: 13 subtalar, five talonavicular, four ankle, one calcaneocuboid, and one metatarsocuneiform. All patients had plain radiographs, 11 had CT studies, and five had bone scans. Contrast material was used to assess adequate positioning of the needle inside the joint before injection. All joints were injected under fluoroscopic control. Steroid was added in eight joints. After injection, patients were assessed for relief of symptoms. Patients subsequently underwent arthrodesis on the basis of the results of the injection. RESULTS: In 20 patients (22 joints), long-term follow-up showed that injections allowed us to correctly identify the source of pain and successfully guide arthrodesis. Of these 20 patients, 17 had significant pain relief after injection and fusion, whereas three patients had mild or no response. With one of these patients, we injected other joints and changed surgical plans. One of the two remaining patients had more pain relief after injection than after arthrodesis. The other patient had no relief after injection, but subsequent fusion because of persistent pain was successful. We found imaging studies to be less useful than diagnostic injections when we were attempting to identify the source of pain. CONCLUSION: Intraarticular injection of anesthetic in painful foot and ankle joints helped us confirm the source of pain in 20 of 22 patients, which in turn led to successful arthrodesis and good outcomes for these patients.     

Outpatient parenteral antimicrobial therapy technology

Health care costs are continuing to spiral upward despite government and public insistence on cost containment. To meet the challenge, medical professionals and organizations are seeking opportunities for cost reduction and alternatives for delivery health care. This article discusses the tools that allow the effective delivery of care using the outpatient parenteral antimicrobial therapy (OPAT) model.     

Closure versus non-closure of peritoneum at cesarean section--evaluation of pain. A randomized study

OBJECTIVE: To evaluate the effects of leaving the parietal peritoneum open at lower segment cesarean section (LSCS) measured by postoperative pain. DESIGN: A randomized, prospective and double-blind study. SETTING: Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark. POPULATION: Forty women referred for an elective cesarean section were assigned to one of two groups: peritoneum open (n=21) or peritoneum closed (n=19). METHODS: Pain was evaluated twice a day from the first to the fifth postoperative day by Visual Analog Scales. MAIN OUTCOME MEASURES: Postoperative pain. Other outcomes include usage of analgesics, bowel function, postoperative complications, and hospital stay. RESULTS: We found no overall difference in postoperative pain. A tendency to less pain was found in the non-closure group from the third postoperative day to the fifth postoperative day. No differences were found either in the incidence of postoperative complications, or the time to return of bowel function. Concerning opiate analgesics the non-closure group had a significantly higher use in the second postoperative 24-hour period, but in the remains of the registration period it was significantly lower. For oral analgesics no difference was found in the first 24-hour period, but in the remains of the period the non-closure group had a significantly lower use. CONCLUSIONS: The VAS-scales showed no difference in postoperative pain comparing closure to non-closure of the parietal peritoneum. However, the use of analgesics is lower in the non-closure group. We suggest leaving the parietal peritoneum open when performing LSCS.