Beneficial Systemic Effects Research Articles

Weekly Cisplatin Therapy Compared With Triweekly Combination Chemotherapy as Concurrent Adjuvant Chemoradiation Therapy After Radical Hysterectomy for Cervical Cancer

To evaluate whether the use of triweekly combination chemotherapy together with radiation exerts a more beneficial systemic effect than weekly cisplatin chemoradiation in patients with cervical cancer after radical surgery. We retrospectively analyzed patients with stage IB1 to stage IIB cervical cancer who had undergone radical hysterectomy with pelvic lymph node dissection, followed by concurrent adjuvant chemoradiation therapy. The patients were divided into 2 groups: the triweekly combination chemotherapy group and the weekly cisplatin chemotherapy group. We evaluated the survival and adverse effects of the 2 groups. In total, 201 patients were included. The mean duration of follow-up was 52.2 months. Of the 201 patients, 130 received triweekly combination chemotherapy, and 71 patients received weekly cisplatin chemotherapy as an adjuvant treatment. The 5-year disease-free survival was 82.2% for patients treated with weekly cisplatin chemotherapy and 74.3% for those treated with triweekly combination chemotherapy (P = 0.3929). The 5-year overall survival was 81.4% and 79.3% for the same treatment groups, respectively (P = 0.9833). The overall survival of the patients with stage IIB cervical cancer was marginally higher in the triweekly combination chemotherapy group than in the weekly cisplatin group (P = 0.0582). Leukopenia, neutropenia, thrombocytopenia, anemia, and hepatopathy were significantly more common in the triweekly combination chemotherapy group. The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly combination chemotherapy group but with less toxicity. Therefore, weekly cisplatin chemotherapy is considered the more useful concurrent adjuvant chemoradiation regimen after radical surgery.

Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. To date, no unifying mechanism explains how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, adipoR1 and adipoR2, and enhances ceramide catabolism and formation of its anti-apoptotic metabolite – sphingosine-1-phosphate (S1P), independently of AMPK. Using models of inducible apoptosis in pancreatic β-cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8 mediated death, while genetic adiponectin ablation enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a novel unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream component.

Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression

Surgery is the primary therapeutic strategy for most solid tumours; however, modern oncology has established that neoplasms are frequently systemic diseases. Being however a local treatment, the mechanisms through which surgery plays its systemic role remain unknown. We have investigated the influence of cytoreduction on the immune system of primary and recurrent ovarian cancer. All ovarian cancer patients show an increase in CD4+CD25+FOXP3+ circulating cells (CD4 Treg). CD4/CD8 ratio is increased in primary tumours, but not in recurrent neoplasms. Primary cytoreduction is able to increase circulating CD4 and CD8 effector cells and decrease CD4 naïve T cells. CD4+ Treg cells rapidly decreased after primary tumour debulking, while CD8+CD25+FOXP3+ (CD8 Treg) cells are not detectable in peripheral blood. Similar results on CD4 Treg were observed with chemical debulking in women subjected to neoadjuvant chemotherapy. CD4 and CD8 Treg cells are both present in neoplastic tissue. Interleukin (IL)-10 serum levels decrease after surgery, while no changes are observed in transforming growth factor-β1 and IL-6 levels. Surgically induced reduction of the immunosuppressive environment results in an increased capacity of CD8+ T cells to respond to the recall antigens. None of these changes was observed in patients previously subjected to chemotherapy or affected by recurrent disease. In conclusion, we demonstrate in ovarian cancer that primary debulking is associated with a reduction of circulating Treg and an increase in CD8 T-cell function. Debulking plays a beneficial systemic effect by reverting immunosuppression and restoring immunological fitness.

A20 suppresses inflammatory responses and bone destruction in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis

Nuclear factor-kappaB (NF-kappaB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF-kappaB, might have antiarthritic effects. An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast-like synoviocytes (FLS) in vitro as well as to mice with collagen-induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally. In vitro experiments demonstrated that AdA20 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus-injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF-kappaB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF-kappaB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study. These results suggest that using A20 to block the NF-kappaB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.

FC12 Long term follow-up of 72 melanoma patients after intratumoral treatment with interleukin-2: favorable survival and high rate of objective responses upon subsequent chemotherapy

Systemic high dose Interleukin-2 (IL-2) achieves long-term survival in a subset of advanced melanoma patients. As we reported previously, intratumorally applied IL-2 induced complete local responses of all metastases in more than 60% of patients and may be regarded as a promising local treatment option for patients with surgically not curable dermal metastases (Weide et al. Cancer in press). Unexpectedly, we observed frequent objective responses to the first chemotherapy after intratumoral IL-2 and favorable survival rates. This prompted us to ask whether there might be also a beneficial systemic effect after the local IL-2 treatment. Therefore we now reanalyzed the long term outcome of a combined cohort including patients with up to 11 years of follow-up after start of intratumoral IL-2 treatment of a previous study conducted at our institution. For the analysis of long term outcome 72 patients were evaluable. Among them 30 received chemotherapy subsequent to intratumoral IL-2. In more than 10 patients an objective response was observed. Overall survival was favorable particularly for stage IIIb and stage IV M1a patients. Updated survival data will be presented. These data are indicative for a systemic mode of action of locally applied IL-2. Further studies are required to investigate the mode of action and the impact on survival.

Probiotics in Allergy Management

The gut contains a diverse bacterial flora that is acquired at birth and has a number of physiological functions. Administration of prebiotics or probiotics may favourably alter this gut microflora. Prebiotics are poorly digested oligosaccharides that promote the growth of desirable bacteria and may have other beneficial gastrointestinal and systemic effects. Probiotics are "helpful" human bacteria that provide a variety of health benefits when administered exogenously. Probiotics produce beneficial effects in the prevention and treatment of traveller's diarrhoea, viral diarrhoea, and diarrhoea in day care centres. Moreover, probiotics have been shown to reduce relapses associated with Clostridium difficile, and Lactobacilli are effective in the prevention of antibiotic-associated diarrhoea. Probiotics may also be efficacious in the treatment of gastroenteritis. Clinical studies of probiotics in inflammatory bowel disease have proved disappointing, but beneficial effects in adults with irritable bowel syndrome have been reported with Bifidobacterium infantis 35624. Lactobacilli GG reduces the incidence of gastrointestinal symptoms and gut permeability in patients with atopic dermatitis, and administration of probiotics reduces the frequency and severity of atopic eczema when administered to pregnant women and then to newborn infants. In conclusion, probiotics are effective in the treatment and/or prevention of a number of conditions, including diarrhoea, irritable bowel syndrome and atopic dermatitis, and the product used should be selected based on the particular indication.

Aromatase inhibitors and mammographic breast density in postmenopausal women receiving hormone therapy

One of the main concerns regarding long-term use of hormone therapy (HT) in symptomatic menopausal women is the perceived increased risk of breast cancer. A method to reduce breast cancer risk in this population of women is urgently needed. We hypothesized that adding aromatase inhibitors (AIs) to HT would reduce local breast estrogen exposure and breast cancer risk without altering the beneficial systemic effects of HT on menopausal symptoms or bone density. The aim of this study was to investigate the effect of AIs and HT on mammographic breast density (MBD) as a surrogate marker of breast cancer risk in postmenopausal women receiving low-dose HT. This was a retrospective cohort study conducted at private clinics affiliated with a university hospital. One group of postmenopausal women (n = 28) received low-dose HT daily plus letrozole 2.5 mg three times weekly. Postmenopausal women receiving HT alone (n = 28) served as controls. MBD, the primary outcome, was measured using quantitative image analysis software as well as by visual analysis by a radiologist. Hypoestrogenic effects, adverse reactions, and bone mineral densities were secondary outcome measures. The mammograms of 18 women in the study group and 22 women in the control group were suitable for comparison. A statistically significant reduction in MBD occurred in the women who received HT plus an AI, whereas no significant change was observed in the women receiving HT alone. There was no significant increase in hypoestrogenic symptoms during the use of AIs, and bone mineral densities were not significantly reduced. Adding an AI to HT may lower MBD in postmenopausal women. AIs could be good candidates for primary chemoprevention of breast cancer in postmenopausal women using HT.

Dietary restriction and induced tumorigenesis in mice with altered hypothalamic appetite regulation

Dietary restriction (DR), the reduction of calorie intake or meal frequency, profoundly effects the health of laboratory animals including cancer incidence. One recurring theme among DR manipulations is the induction of hunger, which may play a critical role in mediating the neuroendocrine response and driving beneficial systemic effects like reduced tumorigenesis. We examined the effects of DR on tumorigenesis under appetite suppression in two mouse models: Neuropeptide‐Y knockout mice (NPY, a major orexigenic peptide) and monosodium glutamate‐injected mice (MSG damages the arcuate nucleus, the ‘satiety center’ of the hypothalamus that coordinates feeding behavior). Calorie restriction (CR) at 30% was compared with every‐other‐day (EOD) feeding, a high‐fiber, low‐calorie chow (LC), and ad libitum (AL) feeding. A two‐stage skin tumor induction model was employed to assess tumorigenesis in the groups. While CR lowered blood leptin levels in both the NPY‐knockout and MSG‐injected mice, tumor latency was not increased by CR in the MSG mice. The LC diet lowered blood leptin in both models and reduced tumor incidence in the MSG mice but not the NPY mice. The EOD diet alone was protective in both models. These data suggest DR's anticancer effects involve both hypothalamus‐dependent and hypothalamus‐independent mechanisms. Funded by the NIH/NIA Intramural Research Program.

Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis

Background:Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor α (TNFα). Therefore, we tested...

Hypothalamic involvement in the beneficial effects of restricted diets on glucose tolerance in mice

Dietary restriction (DR) is the only consistent nutritional intervention that increases longevity while decreasing the incidence and onset of age-related diseases and functional decline in various species. However, the mechanism of the DR effect remains unknown. Furthermore, while DR studies involve the manipulation of caloric intake they have not sought to control or eliminate the induction of hunger. The inability to account for the contribution of hunger to the effects of DR becomes more critical as evidence accumulates supporting the hypothesis that the neuroendocrine response to DR is the primary mechanism driving its beneficial systemic effects. If hunger is indeed a critical component of DRs immediate effects that triggers protective adaptations seen in DR, then examining the effects of DR under appetite suppression would provide a means for observing the role of hunger in the DR mechanism, the aim of this study. Two animal models were employed: Neuropeptide-Y knockout mice (NPY, a major orexigenic peptide) and monosodium glutamate-injected mice (MSG damages the arcuate nucleus, the ‘satiety center’ of the hypothalamus that coordinates feeding behavior). While the NPY-knockout mice displayed equivalent feeding behavior and body composition compared with controls, the MSG-injected mice were obese yet hypophagic. Furthermore, while the NPY-knockout mice exhibited lower fasting glucose and glucose tolerance by oral glucose tolerance test following DR, the response was attenuated in the MSG-injected animals. These data suggest at least some of the beneficial effects of DR rely on unimpaired arcuate nucleus activity but are not contingent on NPY expression. Funding: NIH Intramural Research Program.

Ventilatory muscle activation and inflammation: cytokines, reactive oxygen species, and nitric oxide

Strenuous diaphragmatic contractions that are induced by inspiratory resistive breathing initiate an inflammatory response that involves the elevation of pro- and anti-inflammatory cytokines within the diaphragm, which may then spill into the circulation. The production of reactive oxygen species within working respiratory muscles increases in response to these strenuous diaphragmatic contractions. At the same time, diaphragmatic nitric oxide (NO) production declines significantly, despite a time-dependent increase in NO synthase isoform protein expression. The increase in adhesion molecule expression and infiltration of granulocytes and macrophages that follows may contribute to the contraction-induced diaphragm injury. Enhanced generation of reactive oxygen species, oxidative stress augmentation, reduced NO production, and glycogen depletion are potential stimuli for the cytokine induction that is secondary to strenuous diaphragmatic contractions. This production of cytokines within the diaphragm may contribute to the diaphragmatic muscle fiber injury that occurs with strenuous contractions or to the expected repair process. TNF-alpha is a cytokine that compromises diaphragmatic contractility and may contribute to muscle wasting. IL-6 is a cytokine that may have beneficial systemic effects by mobilizing glucose from the liver and free fatty acids from the adipose tissue and providing them to the strenuously working respiratory muscles. Thus cytokine upregulation within the working diaphragm may be adaptive and maladaptive.

Effects of Lactobacillus acidophilus DSM13241 as a probiotic in healthy adult cats

To evaluate the effect of dietary supplementation with the probiotic strain Lactobacillus acidophilus DSM13241 in healthy adult cats. 15 adult cats. Cats were fed a nutritionally complete dry food for 5 weeks. Fecal character was assessed daily, and a single fecal sample and 3-mL blood sample were collected for bacterial enumeration and hematologic analysis, respectively. Cats were then fed the same diet supplemented with L acidophilus DSM13241 (2 x 10(8) CFU/d) for 4.5 weeks. Repeat fecal and hematologic measurements were taken prior to the return to control diet for a 4-week period. The probiotic species was recovered from feces, demonstrating survival through the feline gastrointestinal tract. Probiotic supplementation was associated with increased numbers of beneficial Lactobacillus and L acidophilus groups in feces and decreased numbers of Clostridium spp and Enterococcus faecalis, indicating an altered bacterial balance in the gastrointestinal tract microflora. Fecal pH was also decreased suggesting a colonic environment selective for the beneficial lactic acid bacterial population. Systemic and immunomodulatory effects were associated with administration of L acidophilus DSM13241 including altered cell numbers within WBC subsets and enhanced phagocytic capacity in the peripheral granulocyte population. In addition, plasma endotoxin concentrations were decreased during probiotic feeding, and RBCs had a decreased susceptibility to osmotic pressure. Probiotic strain L acidophilus DSM13241 fed at 2 x 10(8) CFU/d can alter the balance of gastrointestinal microflora in healthy cats. Furthermore, administration of this probiotic results in beneficial systemic and immunomodulatory effects in cats.

Individual cognitive‐behavioural anger treatment for people with mild‐borderline intellectual disabilities and histories of aggression: A controlled trial

Anger is a significant predictor and activator of violent behaviour in patients living in institutional settings. There is some evidence for the value of cognitive-behavioural treatments for anger problems with people with intellectual disabilities. In this study, a newly designed treatment targeted at anger disposition, reactivity, and control was provided to intellectually disabled offenders with aggression histories living in secure settings. About forty detained patients with mild-borderline intellectual disabilities and histories of serious aggression were allocated to specially modified cognitive-behavioural anger treatment (AT group) or to routine care waiting-list control (RC group) conditions. AT group participants received 18 sessions of individual treatment. The AT and RC groups were assessed simultaneously at 4 time points: screen, pre- and post-treatment, and at 4-month follow-up using a range of self- and staff-rated anger measures. The effectiveness of the treatment was evaluated using ANCOVA linear trend analyses of group differences on the main outcome measures. The AT group's self-reported anger scores on a number of measures were significantly lower following treatment, compared with the RC wait-list condition, and these improvements were maintained at follow-up. Limited evidence for the effectiveness of treatment was provided by staffs' ratings of patient behaviour post-treatment. Detained men with mild-moderate intellectual disabilities and histories of severe aggression can successfully engage in, and benefit from, an intensive individual cognitive-behavioural anger treatment that also appears to have beneficial systemic effects.

Systemic remission of non-Hodgkin's lymphoma after intralesional interferon alpha-2B to bilateral conjunctival lymphomas

To report the beneficial systemic effect of a 5-week course of intralesional interferon alpha-2b (IFN-A) injections to bilateral conjunctival lymphomas in a patient with relapsing non-Hodgkin's lymphoma. Interventional case report. A patient in relapse with non-Hodgkin's lymphoma who declined further systemic therapy received 1.5-million IU IFN-A injected intralesionally to each of two conjunctival lymphomas to reduce ocular discomfort. This dose was repeated 10 times over 5 weeks. Conjunctival, postauricular, and facial lesions clinically resolved within 3 months of the start of treatment. Inguinal lymph nodes reduced in size, and the patient reported increased well-being and less fatigue. Side effects included injection discomfort and mild flulike symptoms, which were well tolerated. The improvement lasted 6 months from the first IFN-A injection. Intralesional treatment of conjunctival lymphomas with IFN-A induced disappearance of the tumors and also had a beneficial systemic effect.

Lower Limb Ischemia: Phase 1 Results of Salvage Perfusion

Revascularization of an ischemic lower extremity is associated with high morbidity (20–30%) and perioperative mortality (10–20%) regardless of the mode of intervention, surgical or thrombolytic, considered to be due to polymorphonuclear (PMN) activation and mediator release. In this study, the safety and feasibility of cell-free extracorporeal perfusion of the limb with a solution designed to minimize both local and systemic injury was tested.Methods. Patients with severe limb ischemia (sensory/motor loss, rest pain/gangrene) were studied prospectively by random assignment into the treatment arm (n = 14) or control arm (n = 21). Surgical management consisted of restorative procedure, thrombectomy or embolectomy (n = 21), or reconstruction (n = 14). Reperfusion of the ischemic limb was achieved with hypertonic, hyperoncotic perfusate containing anti-oxidants delivered via the arterial tree (mean volume 1835 ± 824 ml) with initial venous drainage (mean volume 775 ± 263 ml) in the restorative group. Means were compared by paired t test.Results. No adverse systemic effects were detected after limb perfusion (electrolytes, coagulation, platelet function, CBC). Rapid lactate wash-out was observed within 30 min of perfusion (preperfusion 3.2 ± 4.1 mM, 30 min postperfusion 0.7 ± 0.71 mM, P < 0.01). Blunting of PMN activation was shown by chemiluminescence (CL) analysis (preischemic CL: 0.68 ± 0.2; 30 min CL: 0.47 ± 0.2; P < 0.013). F2-isoprostanes, a marker of free radical-mediated systemic lipid peroxidation, were significantly reduced in patients treated with study perfusion method (70.55 ± 39.54 versus control 194.38 ± 25.24, P < 0.005). Mortality with treatment was 0/14 versus 5/21 in the control. Complication frequency: MI 0/14 vs 3/21; renal 0/14 vs 1/21; leg edema 1/14 vs 5/21; amputations 2/14 vs 1/21.Conclusion. Modification of limb perfusion in patients with severe limb ischemia, using our simple and rapid (15–20 min) method provides beneficial systemic effects.

NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint.

The transcription factor NF-kappaB is a pivotal regulator of inflammatory responses. While the activation of NF-kappaB in the arthritic joint has been associated with rheumatoid arthritis (RA), its significance is poorly understood. Here, we examine the role of NF-kappaB in animal models of RA. We demonstrate that in vitro, NF-kappaB controlled expression of numerous inflammatory molecules in synoviocytes and protected cells against tumor necrosis factor alpha (TNFalpha) and Fas ligand (FasL) cytotoxicity. Similar to that observed in human RA, NF-kappaB was found to be activated in the synovium of rats with streptococcal cell wall (SCW)-induced arthritis. In vivo suppression of NF-kappaB by either proteasomal inhibitors or intraarticular adenoviral gene transfer of super-repressor IkappaBalpha profoundly enhanced apoptosis in the synovium of rats with SCW- and pristane-induced arthritis. This indicated that the activation of NF-kappaB protected the cells in the synovium against apoptosis and thus provided the potential link between inflammation and hyperplasia. Intraarticular administration of NF-kB decoys prevented the recurrence of SCW arthritis in treated joints. Unexpectedly, the severity of arthritis also was inhibited significantly in the contralateral, untreated joints, indicating beneficial systemic effects of local suppression of NF-kappaB. These results establish a mechanism regulating apoptosis in the arthritic joint and indicate the feasibility of therapeutic approaches to RA based on the specific suppression of NF-kappaB.

Glucagon Effect on Postischemic Recovery of Intestinal Energy Metabolism

Glucagon is a potent mesenteric vasodilator, inotrope, and stimulant of intestinal metabolism that enhances survival when given during reperfusion after intestinal ischemia. However, the mechanism of improved survival is unclear and may be due to systemic hemodynamic effects rather than intestinal metabolic changes. We examined the effects of glucagon on intestinal energy metabolism during reperfusion after intestinal ischemia. Sprague-Dawley rats were subjected to 50 min intestinal ischemia by clamping the superior mesenteric artery. All received 10 ml/kg · hr 5% glucose in normal saline for 3 hr. One group ( n = 17) received 1.6 μg/kg · min glucagon for 2 hr beginning at reperfusion. Control rats ( n = 10) received only vehicle. Jejunal biopsies preischemia, end ischemia, 10, 20, 45, 80 min, and 24 hr after reperfusion were analyzed for ATP, ADP, and AMP. ATP decreased more than 60% with ischemia and recovered substantially in all animals by 10 min postischemia. ATP recovered steadily in control rats and by 24 hr was not distinguishable from baseline. In contrast, in glucagon-treated rats, ATP decreased at 20 and 45 min during reperfusion, but recovered incompletely by 24 hr after ischemia. Energy charge (EC = ([ATP] + 1/2[ADP]) ÷ ([ATP] + [ADP] + [AMP])) decreased during ischemia but recovered immediately after reperfusion in both groups, implying that energy was available, energy metabolic enzyme systems were at least partially intact, and immediate recovery was not limited by available substrate and blood flow. However, energy charge decreased slightly during glucagon infusion, suggesting increased utilization of energy or some derangement of energy metabolism. Despite the previously demonstrated survival benefit of glucagon in this model, recovery of intestinal energy metabolism was no better with glucagon treatment. Thus, recovery of intestinal energy metabolism does not appear to be linked to animal survival after ischemia. Other investigators have shown that glucagon may worsen ischemic damage when administered before or during intestinal ischemia. This study provides evidence for intestinal metabolic stimulation by glucagon after intestinal ischemia which might be detrimental if not compensated for by beneficial systemic hemodynamic effects of glucagon.

Effects of dynamic exercise training on the metabolic and cardiocirculatory responses to exercise in the rat model of myocardial infarction and heart failure

In an effort to produce significant systemic circulatory training effects, including adaptations of the heart, myocardial infarcted (MI) rats were subjected to 2 training regimens: low-intensity endurance training (LIET) and high-intensity endurance training (HIET). When compared with sedentary controls, the MI rats subjected to LIET had small but significant beneficial systemic circulatory training effects exclusive of any training effects on the heart. MI rats subjected to HIET had similar but more extensive and quantitatively greater circulatory adaptations than those found in MI rats subjected to LIET. Unlike LIET MI rats, the HIET MI rats had an increase in maximal heart rate when compared with sedentary MI rats. However, despite the reversal of this chronotropic incompetence, the HIET MI rats did not have significant increases in parameters indicative of increased left ventricular pump function (maximal cardiac output) and maximal stroke volume. To further study the effect of incrementally increasing exercise intensity, a high-intensity sprint training (HIST) regimen was developed and studied in normal rats. In response to HIST, normal rats had central myocardial adaptations (increases in maximal cardiac output and stroke volume) in response to training that were not found in the MI rats subjected to LIET and HIET. Although the effects of HIST in normal rats is now known, the question of whether a training paradigm consisting of HIET and HIST will produce increases in maximal cardiac output and stroke volume in the MI rat has yet to be determined.

Effects of dichloroacetate in the treatment of hypoxic lactic acidosis in dogs.

The metabolic and systemic effects of dichloroacetate (DCA) in the treatment of hypoxic lactic acidosis were evaluated in the dog and compared with the infusion of equal quantities of volume and sodium. Hypoxic lactic acidosis was induced by ventilating dogs with an hypoxic gas mixture of 8% oxygen and 92% nitrogen, resulting in arterial PO2 of less than 30 mmHg, pH below 7.20, bicarbonate less than 15 mM, and lactate greater than 7 mM. After, the development of hypoxic lactic acidosis dogs were treated for 60 min with either DCA as sodium salt or NaCl at equal infusions of volume and sodium. Dogs treated with DCA showed a significant increase of arterial blood pH and bicarbonate, and steady levels of lactate, whereas NaCl resulted in further declines of blood pH and bicarbonate, and rising blood lactate levels. Overall lactate production decreased during therapy with either regimen, but hepatic lactate extraction increased significantly with DCA, while it remained unchanged with NaCl. Tissue lactate levels in liver and skeletal muscle decreased significantly with DCA treatment but were unchanged with NaCl. Additionally, an increase in muscle intracellular pH was observed only in DCA treated dogs. A possible mechanism for the observed actions of DCA might be related to a significant increase in oxygen delivery to tissues. Such an effect was found with DCA administration, but was not observed with NaCl therapy. In conclusion, DCA therapy in hypoxic lactic acidosis has beneficial systemic effects compared with therapy with NaCl. DCA administration is accompanied by increases of blood pH and bicarbonate, a decrease in lactate production, and enhanced liver lactate extraction, and a lowering of tissue lactate levels.

Stabilizing Powers of Monetary Policy under Rational Expectations

The potential of monetary policy to stabilize fluctuations in output and employment is demonstrated in a stochastic rational expectations model in which firms choose, considering average profitability, to set prices in advance of the period when they apply to goods sold. This lead time in pricing decisions increases the fluctuations of output about the normal employment level. But proper use of a feedback monetary policy rule can reduce these fluctuations even though expectations are rational and people know the policy rule. It is noted that use of a rule-dictated policy sometimes requires the monetary authorities to penalize the economy in the short run for the sake of beneficial system effects of the rule upon the relevant steady-state distributions.