Insufficient Inhibition Research Articles

Glucose metabolism and the postprandial state.

Disturbances of postprandial glucose metabolism are now thought to contribute to cardiovascular disease. Postprandial glucose excursions can be affected by a number of factors, such as the types of carbohydrates ingested and the way they are metabolized. In Type 2 diabetes, factors that contribute to excessive postprandial glucose excursions include disruption of insulin secretion, insufficient inhibition of hepatic glucose production and defective glucose storage in muscle. A number of measures may attenuate excessive postprandial blood glucose excursions. These include a diet high in 'low glycaemic index' foods and treatment with drugs that improve or restore the hormonal response (e.g. the sulphonylureas and the newer beta-cell mediated insulinotropic drugs such as repaglinide), that improve insulin sensitivity or that delay gastric emptying.

From Gilles de la Tourette's Disease to Tourette Syndrome: A History

AbstractOver the past century researchers have attributed the symptoms that today are labeled as Tourette syndrome to various etiologies. Although most investigators have accepted Gilles de la Tourette's initial description of a symptom complex of tics and involuntary vocalizations, most have rejected his claim that “tic disease” resulted from hereditary degeneration. Subsequent investigators have offered an array of contradictory etiological explanations including viewing these symptoms as a subset of choreas, a result of insufficient inhibition, a failure to control infantile habits, a sequel to encephalitis and other infections, or the result of unconscious psychosexual childhood conflict. With the advent of effective pharmacologic treatments in the 1960s, psychiatrists, often urged on by the parents of afflicted children, began to insist that the disorder resulted from organic factors, most likely connected to transmission of the neurotransmitter dopamine and signaling in the basal ganglia. Since the 1970s, research has focused on a variety of possible organic substrates, but disputes over which symptoms to include in the syndrome's phenotype continue to constrain efforts to locate its etiology.

Quantification of human lithostathine S2-5 forms using the antibody to the N-terminal peptide region.

Lithostathine S2-5 inhibits in vitro crystal growth of CaCO3. We developed an antibody against the peptide region responsible for inhibitory effect to determine whether lithostathine S2-5 levels are different in the pancreatic juice of patients with and without chronic pancreatitis. The antibody against the synthetic peptide of the N-terminal end of lithostathine S2-5 detected lithostathine S2-5 but not lithostathine S1 or lithostathine extracted from pancreatic calculi. Lithostathine S2-5 was detected in samples of pancreatic juice protein by immunoblotting using the specific antibody. The concentration of lithostathine S2-5 was compared between control and chronic pancreatitis groups. The mean concentrations of lithostathine S2-5 were significantly (p=0.002) lower in chronic pancreatitis, 16.3 microg/mg of total protein, than in the control, 47.1 microg/mg of total protein. A decreased concentration of lithostathine S2-5 seems to increase the risk of stone formation in the ducts during the course of chronic pancreatitis because of insufficient inhibition of CaCO3 crystal growth.

Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro

It has been shown previously that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) such as compactin and lovastatin suppress human lymphocyte functions in vitro (Cuthbert and Lipsky, 1981; Cutts and Bankhurst, 1989). Although it is not fully understood what inhibitory role the HMG-CoA RIs perform in causing this suppression, we show in this study that a certain inhibition threshold (inhibition level > 90%) of lymphocytic HMG-CoA reductase is required for the HMG-CoA RIs to attain effective inhibitory action in human lymphocyte functions in vitro. Thus the inhibitory activity of simvastatin, a lipophilic inhibitor, on sterol synthesis (HMG-CoA reductase activity) in lymphocytes was as much as 430 times more potent than that of pravastatin sodium, a hydrophilic inhibitor (IC50; 0.013 μM and 5.6 μM, respectively), and although pravastatin sodium and simvastatin at concentration levels of 10 and 0.016 μM respectively, inhibited the sterol synthesis in just over 50%, they failed to inhibit the lymphocyte functions. Significant inhibition (P < 0.01) of lymphocyte functions, including lymphocyte proliferative responses to a variety of stimuli and activated natural killer cell cytotoxicity, was demonstrated only when greater than 90% of the sterol synthesis in lymphocytes was inhibited by either simvastatin or simvastatin sodium salt at concentrations above 2 μM. This simvastatin-induced inhibition of lymphocyte functions was almost completely reversed by the addition of a 1 mM solution of mevalonate. Although simvastatin at a lower clinical blood concentration of 0.016 μM failed to inhibit either lymphocyte functions or HMG-CoA reductase activity sufficiently, at this level it caused a significant increase in cyclosporin A-induced suppression of T-cell response. These results infer that insufficient inhibition (in the 50% region) of HMG-CoA reductase activity by a low clinical blood concentration of HMG-CoA RIs, could still render the lymphocytes susceptible to immunosuppressive treatments. Pravastatin sodium on the other hand, is inactive in inhibiting lymphocyte functions in vitro, and such inactivity can be explained solely of the basis of its failure to inhibit HMG-CoA reductase activity in lymphocytes sufficiently.

Diffusional transport mechanisms and biofilm nitrification characteristics influencing nitrite levels in nitrifying trickling filter effluents

The widely reported accumulation of nitrite during nitrification is studied in recirculating fish culture systems. Nitrite oxidation capacity was homogeneously distributed over the trickling filter, as opposed to the ammonia oxidation capacity, which decreased at an increasing filter depth. Under all circumstances tested, nitrite accumulation in the system was restricted to an elevated but stable nitrite concentration, indicating complete oxidation of the produced nitrite. For a specific trickling filter, a fixed ratio between nitrite and ammonia concentrations in the recirculating water was found. Nitrifying biofilms maintaining relatively low nitrite concentrations were characterized by a relatively high nitrite oxidizing capacity compared to ammonia oxidizing capacity, whereas biofilms with a relative low nitrite oxidation capacity induced high nitrite concentrations. The occurrence of high nitrite concentrations in trickling filter effluents can entirely be explained by diffusional transport mechanisms in combination with the characteristics of the biofilm. There is no argument that high levels of nitrite are caused by insufficient activity or inhibition of the nitrite oxidation process.

Thymidylate synthase and drug resistance.

Thymidylate synthase is an important target for both fluorinated pyrimidines and for new folate analogues. Resistance to 5-fluorouracil (5FU) can be related to insufficient inhibition of thymidylate synthase. The 5FU-nucleotide FdUMP induces inhibition of thymidylate synthase which is enhanced and retained for longer in the presence of increased folate pools, for which leucovorin is a precursor. In a murine model system, 5FU treatment caused a 4-fold induction of thymidylate synthase levels which may have contributed to resistance. Addition of leucovorin to this treatment prevented this induction and increased the antitumour effect 2-3-fold. In the clinical setting, 5FU administration to patients resulted in approximately 50% inhibition of TS after 48 h. The combination with leucovorin resulted in a more pronounced inhibition after 48 h (approximately 70%). A significant relationship was observed with outcome of treatment; when thymidylate synthase levels were high and inhibition was low, no response was observed. A separate study showed that low thymidylate synthase levels appeared to be an independent prognostic factor for adjuvant therapy.

Relationship between transfusion regimen and suppression of erythropoiesis in beta-thalassaemia major.

In the management of beta-thalassaemia major, different transfusion schemes are employed with baseline haemoglobin levels ranging from 8 to over 12 g/dl. We studied the relationship between transfusion regimen and suppression of erythropoiesis in 52 patients with beta-thalassaemia major whose mean pretransfusion haemoglobin levels ranged from 8.6 to 10.9 g/dl. Multiple, regression analysis showed that serum transferrin receptor was the parameter more closely related to mean pretransfusion haemoglobin (r = -0.77, P < 0.001). As measured through serum transferrin receptor, erythroid activity was 1-2 times normal for pretransfusion haemoglobin levels between 10 and 11 g/dl. 1-4 times normal for levels from 9 to 10 g/dl, and 2-6 times normal for levels from 8.6 to 9 g/dl. Mean pretransfusion haemoglobin was also inversely related to serum erythropoietin (r = -0.72, P < 0.001), whereas it showed no or a weak relationship with Hb F, reticulocyte count, or circulating nucleated red cell count. This study suggests that serum transferrin receptor is a reliable indicator of suppression of erythropoiesis in beta-thalassaemia major. On the basis of our findings, pretransfusion haemoglobin values of < or = 9 g/dl should be adopted with caution, because these levels can be associated with an insufficient inhibition of erythroid marrow expansion. However, a transfusion programme, with a baseline haemoglobin of 9-10 g/dl, may provide enough suppression of erythropoiesis and allow a reduction in blood consumption as compared with the classic hyper- or supertransfusion schemes. Since fixed haemoglobin levels may not be the best target for transfusion treatment in all thalassaemic patients, assay of serum transferrin receptor may be helpful for individualizing the transfusion regimens.

T lymphocytes and their cytokines in human immunodeficiency virus (HIV) infection: implications for associated neoplasias.

Infection with the human immunodeficiency virus (HIV) results in gradual immunosuppression due to the loss of CD4+ T cells. In the wake of immune system breakdown, infected individuals may acquire multiple opportunistic infections and develop certain malignancies which ultimately account for the vast majority of deaths in these persons. A limited number of malignancies are directly associated with HIV infection and suggest a common tie between these tumors. Inappropriate immune surveillance resulting in insufficient inhibition of virus replication and inadequate control of the growth of transformed cells may contribute to the development of malignancies in HIV-infected individuals. Alternatively, malignancies in HIV infection may be the consequence of immune dysregulation. Cellular immune responses mediated by antigen-specific cytotoxic T lymphocytes (CTL) are of particular importance for immunologic control of viral infections and substantial information has been gathered about theses cells in HIV infection. The goal of this review is therefore to summarize recent findings regarding the cellular immune response to HIV with a particular focus on cytokines released by HIV-specific CTL.

Comparison of Symptomatic and Asymptomatic Reinfarctions after Small Subcortical Stroke

We compared possible factors leading to symptomatic and asymptomatic reinfarcts in 207 patients an average of 2.1 years after their index atherothrombotic stroke presenting with small subcortical infarcts. Symptomatic reinfarcts were mostly small infarcts in the perforating artery regions associated with angiographic evidence of atherosclerosis of parent arteries (large-artery disease), a high hematocrit, elevated fibrinogen and Lp(a) levels. They occurred with insufficient inhibition of platelet aggregability in patients receiving antiplatelet medication. In contrast, many asymptomatic reinfarcts were small perforator infarcts not associated with large-artery disease or cortical infarcts, and occurred in the absence of hematologic risk markers, and in spite of sufficient inhibition of platelet aggregability.

The role of inhibition in a spreading-activation model of language production. I. The psycholinguistic perspective

Spreading-activation models of language production are only workable to the extent that they manage to solve the “heat death” problem, i.e., the danger that too many nodes in the network are overactive at the same time. Therefore, a delicate balance between activational and deactivational forces has to be struck. Of the three prevailing dampening mechanisms of decay, self-inhibition and other-inhibition, the latter has been selected for closer scrutiny. The key proposal of this two-part article is that activation-based models of language production cannot afford to do without an inhibitory component, in particular lateral inhibition among nodes of the same level. Psycholinguistic evidence is reviewed in an attempt to insulate inhibitory from excitatory mechanisms. Although it is difficult in normal adult language use to distinguish between the effects of excessive activation and insufficient inhibition, some patterns from language acquisition and aphasia can be shown to follow from inhibitory rather than excitatory problems, thus demonstrating the reality of inhibition. In a system of activational and deactivational forces, other-inhibition is claimed to have the excitatory mechanism of syntax as its natural opponent. It is finally argued that other-inhibition offers an explanation for some puzzling findings from the experimental literature.

Inhibition through negative priming with Stroop stimuli in schizophrenia.

Stroop stimuli were used to measure the negative priming effect in eight positive and 10 negative schizophrenics, 21 depressive and 35 healthy control subjects in order to test hypotheses of insufficient versus persistent cognitive inhibition in schizophrenia. Data show that schizophrenics do not increase their response times to suppressor Stroop items compared to identical but neutral Stroop stimuli because the insufficiency of their inhibitory processes weakens the distractor-suppression effect. However, pre-exposure of the lexical distractor can compensate for insufficient inhibitory mechanisms in positive but not negative schizophrenics, suggesting more severe deterioration in the latter. Depressed subjects showed a slower development of cognitive inhibition. The results suggest important differences in the temporal evolution of inhibitory processes, and are discussed in terms of Hemsley's (1977) and Frith's (1979) theories.

The effects of urinastatin on the plasma levels of granulocyte elastase during open heart surgery under simple deep hypothermia.

Changes in granulocyte elastase (GLE) and Beta-gluculonidase (Beta-gl) were observed during open heart surgeries which were performed under deep hypothermia with surface cooling. In addition, the effect of urinary trypsin inhibitor, urinastatin, on the activities of these enzymes was studied. The patients were divided into three groups, namely group U-I with intravenous injection of 6000 u.kg(-1) of urinastatin before cooling, group U-II administered with an additional 6000 u.kg(-1) after warming to 30 degrees C, and an untreated group (Group C). The plasma level of GLE increased significantly in the three groups compared with the level before cooling respectively. In the group U-II, the GLE level after the warming was lower than that in the control group. The serum level of Beta-gl increased significantly in the three groups at the end of rewarming (36 degrees C). The release of GLE from lysosomes in granulocytes was inhibited in the group U-II. The insufficient inhibition of GLE release in the group U-I is probably due to relatively short half-life of urinastatin. Therefore double administration of 6000 u.kg(-1), before and after the cooling, may be required to achieve the therapeutic effect. Consequently, urinastatin appears to be useful in open heart surgery under deep hypothermia with surface cooling.

Cellular physiology and pathophysiology of the parathyroid glands

This report provides insight into parathyroid gland physiology and the pathophysiology of hyperparathyroidism (HPT). Increases in the extracellular calcium concentration constitute the primary physiological signal for inhibition of parathyroid hormone (PTH) release. Transduction of the external signal into a cellular response involves activation of a cation receptor mechanism on the plasma membrane with rapid rise in the cytoplasmic calcium concentration of the cells. This recently discovered parathyroid calcium receptor has been characterized as a glycoprotein of unusually high molecular weight, which may play a key role in calcium homeostasis since it is also expressed in the kidney and placenta. Binding of external calcium to the receptor is associated with mobilization of intracellular calcium as well as calcium influx into the cells and phosphoinositol hydrolysis. These events rapidly interfere with the release process through essentially unknown mechanisms and probably also at sustained stimulation inhibit PTH gene transcription. The relative calcium insensitivity of the PTH release in HPT is associated with a deranged regulation of cytoplasmic calcium within pathological parathyroid cells. The molecular basis for this disturbance comprises down regulation of the cation receptor, whereby external calcium is translated into abnormally low levels of cytoplasmic calcium and insufficient inhibition of PTH release. Studies on expression of the functionally important cation sensing glycoprotein and its associated cellular signal systems may provide novel means for interference with the pathophysiological derangements of HPT.

経皮的声帯内注射の治療成績とその影響因子について

The result of transcutaneous intrafold injection and its influencing factors were studied for fifty five procedures in fifty two patients with unilateral recurrent nerve paralysis. Maximum phonation time, mean air flow rate and amplitude perturbation quotient of the voice were normalized or improved after the procedures more than 85%. In general assessment with functional and acoustic examinations, 76% of the procedures showed significant improvement. The paralysis after the thoracic surgery, right vocal fold paralysis and the paralysis complicated with sulcus vocalic tended to have insufficient improvement after injection. The most significant correlation to the result was shown in the degree of vocal fold augmentation immediately after injection. It was depend on the surgeon's technique and the patient's problems such as an anatomical abnormality of the larynx and an insufficient inhibition of the gag reflex.

Therapeutic Options in Severe Reflux Oesophagitis

Standard doses of H2-receptor antagonists are usually effective in milder forms of reflux oesophagitis, but these lower doses induce relatively low healing rates in more severe forms of the disease. In the patients with severe reflux oesophagitis, prokinetic or mucosa-protecting agents do not offer better results, whereas a combination of standard doses of H2-receptor antagonists with prokinetic or mucosa-protecting agents results in no or only marginally better results than obtained with H2-receptor antagonist mono-therapy. Several studies have shown that insufficient inhibition of gastric acid secretion is the major reason for the low healing rates obtained with standard doses of H2-receptor antagonists. It has recently been shown that higher doses of ranitidine increase the time the oesophageal pH is above 4 and induce higher healing rates in patients with severe reflux oesophagitis. Therefore, we now have three therapeutic options for patients with severe reflux oesophagitis: first, higher doses of hi...

POSTOPERATIVE GLUCOSE TOLERANCE DURING EXTRADURAL ANALGESIA

Thirteen patients undergoing lower abdominal gynaecological surgery were allocated to general anaesthesia (halothane and nitrous oxide) or general anaesthesia plus extradural analgesia (T8-S5). I.v. glucose tolerance tests were performed on the day before surgery and 8 h after skin incision. All patients having extradural analgesia (T8) were pain-free following surgery. Extradural analgesia blocked the hyperglycaemic response to surgery but not the late postoperative cortisol response, although values were significantly less than in the group receiving general anaesthesia alone. Impairment of glucose tolerance and of insulin response to the glucose load in the period after operation were not influenced by extradural analgesia and this may have resulted from insufficient inhibition of the stress-induced release of catecholamines or cortisol, or both, or from blockade of stimulatory efferent sympathetic pathways to pancreatic islets.

Epilepsy and schizophrenia: A neurochemical bridge

This paper reviews some of the evidence in the literature that suggests neurochemical processes by which the regulation of seizure threshold and the onset of schizophrenic-like symptoms are interrelated. For those patients who experience the alternation of seizures and acute psychoses the following working hypothesis is presented: The central dopaminergic synapse is described as a malfunctioning regulatory circuit. Insufficient feedback inhibition or lifting of the setpoint leads to an increased number of occupied receptors. This might cause schizophrenic-like symptoms. Insufficient release of feedback control or lowering of the setpoint leads to a decreased number of occupied receptors. This might increase seizure susceptibility. The neurochemical arguments in support of this hypothesis will be discussed in detail. The localization of the dopaminergic synapses involved in the development of schizophrenic-like symptoms is subject to speculation. The meso-limbic dopaminergic system has to be taken into consideration.

THE EFFECTS OF CARBON MONOXIDE INHIBITION ON ATP LEVEL AND THE RATE OF MITOSIS IN THE SEA URCHIN EGG

The requirements for ATP synthesis during the various phases of mitosis were investigated in the oxygen-requiring eggs of the sea urchin, Strongylocentrotus purpuratus. CO in the dark, a specific inhibitor of respiration, was used to inhibit ATP synthesis. The kinetics of respiratory inhibition were determined by analyzing ATP levels with the luciferin-luciferase assay. The kinetics of mitotic inhibition were determined by analysis of the rate of mitosis. It was found that CO inhibition resulted in a decrease in the normal ATP level. Coincident with this decrease was a decrease in the rate of mitosis which stops completely when the ATP drops below 50 per cent of the normal level. With the use of various degrees of CO inhibition, the rate of mitosis is shown to be related to the resultant ATP level. These results contradict the basic premise of the energy reservoir hypothesis, and also disagree with other reports that cells in mitosis are insensitive to inhibitors of energy metabolism. Data are presented which demonstrate that these conflicting reports result from insufficient inhibition of ATP synthesis. The above findings all indicate that mitosis depends on the continuous synthesis and utilization of ATP.