Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Induction of hyperandrogenism in lean reproductive-age women stimulates proatherogenic inflammation.

We determined the effect of hyperandrogenemia as observed in polycystic ovary syndrome (PCOS) on fasting and glucose-stimulated proatherogenic inflammation markers in lean healthy reproductive-age women. Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n=8 each) for 5 days. Interleukin-6 (IL-6) mRNA and IL-6 release from mononuclear cells (MNC), plasma IL-6 and C-reactive protein (CRP), and MNC-derived (matrix metalloproteinase-2) MMP-2 protein were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment. Before treatment, subjects receiving dehydroepinadrosterone (DHEA) or placebo exhibited no differences in androgens, or any proatherogenic inflammation markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate (DHEA-S), and increased the percent change from baseline in fasting IL-6 mRNA, IL-6 release, plasma IL-6, and CRP and MMP-2 protein. However, there were no differences in any of the proatherogenic inflammation markers following glucose ingestion after DHEA administration. We conclude that in lean reproductive-age women, proatherogenic inflammation in the fasting state increases after raising circulating androgens to levels observed in PCOS. However, this hyperandrogenemia-induced MNC activation does not provoke a similar response to subsequent glucose ingestion.

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG).

Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.

Palliative treatment of advanced pancreatic carcinoma in community-based oncology group practices.

This study was aimed at evaluating the feasibility, effectiveness, and toxicity of palliative chemotherapy/supportive care in patients with advanced pancreatic cancer being treated on an outpatient basis. A retrospective analysis was performed on 127 consecutive, unselected patients with advanced pancreatic cancer in four community-based oncology group practices. Median age was 63 years and WHO performance status ranged from 0 to 3. Forty-three patients (34%) had locally advanced disease, and 84 patients (66%) had distant metastases; 94 patients (74%) received cytotoxic treatment during the course of their disease, and 33 (26%) received best supportive care only. First-line treatment consisted of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) in 81 patients (86%), 5-fluorouracil (5-FU) in 8 patients (9%), radiochemotherapy in 4 patients (4%), and radiation therapy only in 1 patient (1%). A total of 1,501 gemcitabine treatments were given during the study period. Toxicity was moderate. Four patients (3%) required hospitalization for treatment-related side effects, and 111 patients (88%) died during the observation period. Symptom control, as measured by reduction of pain medication, was seen in 25% of patients receiving gemcitabine, whereas no reduction in pain medication was seen in the best supportive care group. The median survival of patients receiving cytotoxic treatment (mainly gemcitabine) was 42 weeks, and the median survival of patients receiving best supportive care was 21 weeks. The overall survival rate at 6, 12, 24, and 36 months was 65%, 32%, 14%, and 7%, respectively. Based on these outcomes, it appears that patients with locally advanced and metastatic pancreatic cancer benefit from adequate palliative treatment, including cytotoxic chemotherapy with gemcitabine, and this can be accomplished on an outpatient basis.

Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome-c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle.

High-fat diets are reported to increase oxidative stress in a variety of tissues, whereas antioxidant supplementation prevents many diseases attributed to high-fat diet. Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage. We hypothesized that the effects of a high-fat diet on skeletal muscle DNA functions would be attenuated or partially reversed by antioxidant supplementation. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle from male rats after feeding one of three diets (control, high-fat diet with or without antioxidants) for 36 wk. The high-fat diet altered transcript levels of 18 genes of 800 surveyed compared with the control-fed rats. Alterations included reduced expression of genes involved in free-radical scavenging and tissue development and increased expression of stress response and signal transduction genes. The magnitude of these alterations due to high-fat diet was reduced by antioxidant supplementation. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome c oxidase subunit III and superoxide dismutase-1 and -2 noted by microarray approach. Mitochondrial ATP production was unaltered by dietary changes or antioxidant supplementation. It is concluded that the high-fat diet increases the transcription of genes involved in stress response but reduces those of free-radical scavenger enzymes, resulting in reduced DNA repair/metabolism (increased DNA damage). Antioxidants partially prevent these changes. Mitochondrial functions in skeletal muscle remain unaltered by the dietary intervention due to many adaptive changes in gene transcription.

Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise.

Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20-27 yr), 12 middle-aged (47-60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46-79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% (P < 0.05) from young to middle age and further decreased 50% (P < 0.05) from middle to old age. MHCIIx decreased 84% (P < 0.05) from young to middle age and 48% from middle to old age (P < 0.05). Exercise increased FSR of MHC by 47% (P < 0.01) and mixed muscle protein by 56% (P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.

A quantitative PCR measurement of messenger RNA expression of IGF-I, IGF-II and IGFBP-5 in human skeletal muscle.

Insulin-like growth factor-I and -II (IGF-I and IGF-II) and their binding proteins are important components in growth promotion and tissue maintenance. We determined the presence of IGF-I, -II, and binding protein 5 (IGFBP-5) gene expression in human skeletal muscle and that mRNA abundance is not altered by nutrients and insulin. In the first protocol, (control) subjects were given water. In the second protocol, half of these subjects drank Polycose (carbohydrate) and the remaining subjects drank equal calories as a mixed meal. Quadriceps muscle biopsies were taken at 10 h. A semi-quantitative polymerase chain reaction was designed to measure gene expression. IGF-I, IGF-II and IGFBP-5 mRNA are present in adult human skeletal muscle, but no significant changes between meal groups were observed for IGF-I, IGF-II or IGFBP-5 mRNA levels, indicating that the expression of these genes are not altered acutely by nutrients and insulin.

Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotoxin.

The presence of endotoxin from Gram-negative bacteria signals the innate immune system to up-regulate bacterial clearance and/or killing mechanisms. Paradoxically, such responses also contribute to septic shock, a clinical problem occurring with high frequency in Gram-negative septicemia. CD14 is a receptor for endotoxin (lipopolysaccharide, LPS) and is thought to have an essential role in innate immune responses to infection and thereby in the development of septic shock. Using a novel rabbit model of endotoxic shock produced by multiple exposures to endotoxin, we show that anti-rabbit CD14 mAb, which blocks LPS-CD14 binding, protects against organ injury and death even when the antibody is administered after initial exposures to LPS. In contrast, anti-rabbit tumor necrosis factor mAb treatment fails to protect when administered after LPS injections. These results support the concept that anti-CD14 treatment provides a new therapeutic window for the prevention of pathophysiologic changes that result from cumulative exposures to LPS during septic shock in man.

Centrifugal projections upon the retina: an anterograde tracing study in the pigeon (Columba livia).

Previous work has shown that the avian retina receives two types of centrifugal fibers from the brain. These types can be distinguished based on the size and the morphology of their terminal endings and have been termed convergent and divergent. The centrifugal fibers arise from the isthmooptic nucleus (ION) and the surrounding ectopic cell region (ECR). We used injections of anterograde tracers either to the ION/ECR or to the ECR only to determine the morphology, depth of termination, and regional distribution of the centrifugal fibers arising from each. We found that the ECR gives rise only to the divergent type of the centrifugal fiber, whereas the ION gives rise mainly to the convergent type but may also send some fibers of the divergent type. Most of the fibers project contralaterally, although a few from the ECR project ipsilaterally. The terminals of either type are not uniformly distributed throughout the retina; instead, they are found mainly in the inferior, midtemporal, to nasal portion of the retina and appear to avoid the fovea and most of the red field. By comparison, the ION receives a major projection from portions of the tectum that receive input from the fovea and the red field in a type of neural loop. The neural loop does not project to the same point (homotopic), but projects from the red field to the inferior retina (heterotopic), as was recently proposed by Holden (1990; Vis. Neurosci. 4:493-497). The distribution of centrifugal axons corresponds to displaced ganglion cells that selectively innervate the nuclei of the accessory optic system (AOS), including the nucleus of the basal optic root (dorsal, ventral, and lateral) and the nucleus lentiformis mesencephali, pars magnocellularis. We suggest that the centrifugal axons act by increasing the gain on the AOS, thereby enhancing retinal stabilization of gaze with improved accuracy of pecking of small objects.

Continuous 5-fluorouracil and leucovorin as a second-line therapy for advanced gastric carcinoma.

Eleven patients with chemotherapeutically pretreated advanced gastric cancer were treated in a phase II study with a combination of 5-fluorouracil (5-FU) and Leucovorin (LV, folinic acid). 5-FU (1,200 mg/m2) and LV (100 mg/m2) were given as a parallel continuous intravenous infusion over 48 h every 2 weeks for at least 8 weeks. Toxicity and response rates were evaluated. Results show that this chemotherapeutic regimen is well tolerable, without any side effects exceeding WHO grade 1 toxicity, but that it has no considerable effects on tumor growth. None of the patients achieved disease remission. In 8 out of the 11 study patients therapy had to be discontinued prematurely because of disease progression. Therefore we conclude that the studied protocol of 5-FU/LV as second-line treatment of advanced gastric cancer although well tolerable is not effective.

Oral tramadol, a mu-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain.

BACKGROUND: Opioid and spinal monoaminergic agonists have distinct analgesic properties, which may potentiate each other. Tramadol has both opioid and monoaminergic agonist actions. This initial study compared the analgesic and toxic effects of tramadol and morphine in patients with strong cancer pain. PATIENTS AND METHODS: Pain control and side-effects with tramadol and morphine were compared in 20 cancer patients hospitalised for the treatment of strong pain. Doses of oral solutions of tramadol or morphine were individually titrated in the double-blind, randomized, cross-over study. Cross-over was after day 4, the day of statistical evaluation. RESULTS: The mean pain intensity (+/- SD) on a verbal rating scale (0 = none, 4 = unbearable) was similar with morphine (1.6 +/- 1.2, n = 17) and with tramadol (1.5 +/- 1.3, n = 16) on the fourth day of dosing. The mean daily doses on day 4 were 101 +/- 58 mg of morphine and 375 +/- 135 mg of tramadol, indicating a relative potency of 4:1 with oral dosing. The total number of side-effects per person was lower on the fourth day with tramadol (p < 0.05), as was the severity of nausea (p < 0.05) and constipation decreased with tramadol (p < 0.05). Three patients dropped out of the morphine group due to side-effects and 4 out of the tramadol group due to inadequate analgesia. Overall, 8 patients (40%) preferred morphine, 3 (15%) favoured tramadol and 9 (45%) expressed no distinct choice. Nurses rated pain control better with morphine (p < 0.03), but the tolerability of tramadol was judged superior (p < 0.002). CONCLUSIONS: In certain cancer patients with strong pain, tramadol achieved good pain control with fewer side-effects than morphine. The non-opioid mode of action may result in a different spectrum of analgesia and side-effects. Longterm studies are required to confirm this study of brief duration.

Cinnarizine for prevention of nausea and vomiting during platin chemotherapy.

The antiemetic efficacy of cinnarizine was assessed in 17 cancer patients receiving platin-based chemotherapy (cisplatin dose-range 30-160 mg, or carboplatin 270-600 mg) in a randomised, cross-over study. The patients were prophylactically given oral metoclopramide 3 x 1 mg/kg and lorazepam 2 x 1 mg with or without cinnarizine 3 x 75 mg. The antiemetic combination with cinnarizine prevented emesis completely on 51% of 35 days with chemotherapy and less than 3 emetic episodes occurred on 86% of the days, compared with 43% and 57% (p less than 0.01) without cinnarizine respectively. Severe nausea was significantly less frequent with cinnarizine and 59% of the chemotherapy days were without nausea, compared to 46% of the days without cinnarizine (p less than 0.05). Side-effects were uncommon and minor with both antiemetic regimens. The study suggests that addition of cinnarizine to metoclopramide and lorazepam improves antiemetic prophylaxis in low to medium dose platin-based chemotherapy.

Long term effects of monthly low dose whole body irradiation on the glutathione status and thiobarbituric acid-reactive substances in different organs of male Wistar rats.

Male Wistar-H-rats were exposed monthly to a 60cobalt-source low dose whole body irradiation (0.25 Gy, total dose: 4.5 Gy). The glutathione disulphide:total glutathione ratio, the concentration of thiobarbituric acid-reactive substances and the activities of glutathione peroxidase and glutathione transferase in eight different organs and blood were analysed. The low dose irradiation is accompanied by distinct peroxidative changes in organs. These oxidative loadings occur in the small intestine, the spleen and the kidneys. The measurements of glutathione status and of thiobarbituric acid-reactive substances are proposed as sensitive parameters for low dose radiation induced changes.

Suitability of long-acting metoclopramide for prophylaxis of chemotherapy-induced delayed nausea and vomiting.

Delayed nausea and emesis are common after cancer chemotherapy, especially cisplatin-containing regimens. Often no, or inadequate, prophylactic antiemetic cover is prescribed in these usually ambulant patients. Metoclopramide is a very effective drug in preventing the acute emetic and nauseating effects of cisplatin. The long-acting metoclopramide formulations (in the present study: Gastrosil retard) may be effective in preventing the delayed toxicity. 12-hourly dosing of 60 mg long-acting metoclopramide in a typical oncology ward situation led to stable metoclopramide levels of approximately 100ng/ml in the observed 74 h in 18 patients, with the well-known wide plasma concentration variability. The clinical efficacy of long-acting metoclopramide in this indication remains to be evaluated.

Improved protection in myocardial ischemia by combined prostacyclin administration and intraaortic balloon pumping.

The influence of prostacyclin (PGI2) alone or in combination with intraaortic balloon pumping (IABP) on the levels of energy-rich phosphate compounds was investigated before and after coronary artery ligation in canine myocardium. There was a higher level in creatine phosphate in the ischemic as well as non-ischemic areas of the myocardium after treatment with PGI2, however the most protective effect was registered after a combination of PGI2 and IABP. PGI2 also reduces the release of cathepsin D activity into the blood independently whether or not a mechanical support of the heart after coronary artery ligation was performed.