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PubMed1992

Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria.

We report the finding of mitochondrial ATP-synthase deficiency in a child with persistent 3-methylglutaconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-HCO3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The excretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibroblasts was normal. The child had a hypertrophic cardiomyopathy and magnetic resonance images revealed hypoplasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neurologic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol x min-1 x (mg protein)-1, control range 223-673 nmol x min-1 x (mg protein)-1. The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addition of an uncoupler. Low Mg2+ ATPase activity was also demonstrated by histochemical methods. Morphologic examination revealed ultrastructural abnormalities of mitochondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences.

Acidosis, Lactic↗
PubMed2004

Inhibition of platelet function by hydroxyethyl starch solutions in chronic pain patients undergoing peridural anesthesia.

The use of hydroxyethyl starch (HES) solutions as a fluid replacement before peridural blockade may compromise blood coagulation, thus increasing the risk of neuraxial bleeding. In this prospective, double-blind, placebo-controlled, crossover study, we compared the influence of HES 130 (molecular weight in kilodalton), HES 200, and lactated Ringer's solution on platelet function and hemodynamics in chronic low back pain patients scheduled for peridural blockades. Patients received 3 test infusions of 10 mL/kg each administered IV for 30 min. Collagen/epinephrine and collagen/adenosine diphosphate were used as agonists for assessment of platelet function analyzer-closure times. Arterial blood pressure, heart rate, platelet counts, and hemoglobin levels were documented. Platelet function analyzer-closure times remained stable after lactated Ringer's solution but were significantly prolonged after HES. The platelet-inhibiting effect of HES 200 was more than that of HES 130. Hemodynamic stability was sufficiently maintained by all test infusions. In contrast to previous observations, a relevant antiplatelet effect of both low and medium molecular weight HES solutions was found in this study in chronic pain patients undergoing peridural anesthesia. Because hemostasiological competence is a prerequisite for safe neuraxial blockade, the decision of HES for intravascular fluid administration before blockade should be critically made.

Adult↗
PubMed1992

Metabolic factors in fatigue.

The supply of energy is of fundamental importance for the ability to sustain exercise. The maximal duration of exercise is negatively related to the relative intensity both during dynamic and static exercise. Since exercise intensity is linearly related to the rate of energy utilisation this suggests that energetic deficiency plays a major role in the aetiology of muscle fatigue. Characteristic metabolic changes in the muscle are generally observed at fatigue--the pattern being different after short term exercise (lactate accumulation and phosphocreatine depletion) from after prolonged exercise at moderate intensity (glycogen depletion). A common metabolic denominator at fatigue during these and many other conditions is a reduced capacity to generate ATP and is expressed by an increased catabolism of the adenine nucleotide pool in the muscle fibre. Transient increases in ADP are suggested to occur during energetic deficiency and may be the cause of fatigue. Experimental evidence from human studies demonstrate that near maximal power output can be attained during acidotic conditions. Decreases in muscle pH is therefore unlikely to affect the contractile machinery by a direct effect. However, acidosis may interfere with the energy supply possibly by reducing the glycolytic rate, and could by this mechanism be related to muscle fatigue.

AMP Deaminase↗
PubMed1989

Leukocytic infiltration of bovine mammary parenchymal tissue in response to Corynebacterium bovis colonization.

Morphological changes and local leukocyte response to prolonged Corynebacterium bovis colonization were studied in lactating bovine mammary glands. Morphometric analysis of parenchymal tissue demonstrated no adverse effects of colonization on the synthetic and secretory activity of mammary epithelium. Numbers of macrophages, lymphocytes, and plasma cells were higher in tissue from C. bovis-colonized quarters. However, there were no differences in numbers of neutrophils between colonized and uninfected quarters. Results suggest persistent C. bovis colonization may elicit effector cell populations in lactating mammary tissue where leukocyte concentrations tend to be lower.

Animals↗
PubMed1999

Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 x 10(9)/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 x 10(9)/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 10(9)/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 x 10(9)/L peripheral tumor cells (P = .0017). Due to massive side effects in the first patient treated with 375 mg/m(2) in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m(2) dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 x 375 mg/m(2) rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

Adult↗
PubMed2002

Breastfeeding, amenorrhea and contraceptive practice among postpartum women in Zibo, China.

This paper reports a hospital-based longitudinal study that was conducted in Zibo, China, in June 1996. The objective was to investigate the existing patterns of breastfeeding, amenorrhea and contraceptive use among postpartum women in urban areas of China. Information was obtained from 492 newly parturient women. Follow-up interviews were done at 42 days. 4 months and 1 year after delivery. The results showed that the full breastfeeding rate (including exclusive and almost exclusive breastfeeding) was 78% and 43% at 42 days and 4 months after delivery, respectively. The mean reported length of abstinence from sexual intercourse after delivery was 71 days. The mean reported time to menses resumption was 184 days. Ninety-three per cent of women had resumed sexual intercourse at 4 months after delivery. Seventy-three per cent of women were using contraceptive methods when they resumed sexual activity after delivery. After childbirth, the majority ofthe women interviewed used condoms within 3 months. Thereafter, most of them switched to intrauterine device (IUD)). Life table analysis shows that the continuation rates of full breastfeeding and amenorrhea at 4 months after delivery were 35% and 68%, respectively. This implies that if the full breastfeeding rate can be prolonged, it is feasible to use the lactational amenorrhea method (LAM) among Chinese postpartum women. The policy implications of this study are that quality care on contraceptive services and information for postpartum women in urban areas need to be improved further.

Adolescent↗
PubMed1990

Platelet activation may explain the storage lesion in platelet concentrates.

While the exact nature of the dysfunction of stored platelets is not known, it is generally agreed that the platelet's metabolic activity with lactate accumulation presents a significant impediment to prolonged storage. There is an increasing body of evidence that stored platelets have become activated in the preparation and handling of platelet concentrates. Changes in platelet function and structure in concentrates can be explained in terms of sequelae of activation, especially heightened metabolic activity and activation-specific changes in surface glycoproteins on stored platelets. With the use of inhibitors of platelet activation in the preparation of platelet concentrates, the loss of platelet function and integrity is less rapid and platelet metabolic rate is decreased during an extended storage period. Surface levels of glycoprotein Ib, normally decreased during prolonged storage of platelets, are well-preserved in the presence of activation inhibitors. When the use of inhibitors is combined with replacement of plasma with an artificial medium, platelets stored for up to 20 days appear to be metabolically and structurally intact and responsive to stimuli. In summary, platelet activation appears to play a major role in the generation of the storage lesion in platelet concentrates.

Blood Preservation↗
PubMed1994

Metabolic Control of Anaerobic Glycolysis (Overexpression of Lactate Dehydrogenase in Transgenic Tomato Roots Supports the Davies-Roberts Hypothesis and Points to a Critical Role for Lactate Secretion.

Roots of all plants examined so far have the potential for both ethanol and lactate fermentation. A short burst of lactate fermentation usually occurs when plant tissues are transferred from normoxic to anoxic conditions. According to the Davies-Roberts hypothesis, the consequent pH drop both initiates ethanol fermentation and blocks further production of lactate by inhibiting lactate dehydrogenase (LDH). However, the role of LDH in this pH control mechanism is still a matter of debate. To perturb the control system in a defined way, a barley LDH cDNA under the control of the cauliflower mosaic virus 35S promoter was introduced into tomato (Lycopersicon esculentum Mill. cv VFMT) using Agrobacterium rhizogenes. The transgenic root clones expressed up to 50 times the LDH activity of controls. The fermentative metabolism of these clones was compared using roots grown previously in normoxic conditions or roots given a 3-d hypoxic pretreatment. During the transition from normoxia to anoxia, lactate accumulation was no faster and no more extensive in transgenic roots than in controls. Similarly, during prolonged anoxia the flux of 14C from [U-14C] glucose to lactate and ethanol was not modified by the expression of the transgene. However, in both transgenic and control roots, hypoxic pretreatment increased the flux to lactate and promoted lactate export to the medium. These results show that LDH has a very low flux control coefficient for lactate fermentation, consistent with the Davies-Roberts hypothesis. Moreover, they suggest that lactate secretion exerts major control over long-term lactate glycolysis in vivo.

Journal Article↗
PubMed1999

Capillary refill and core-peripheral temperature gap as indicators of haemodynamic status in paediatric intensive care patients.

OBJECTIVES: Capillary refill time is an important diagnostic adjunct in the acute resuscitation phase of the shocked child. This study assesses its relation to commonly measured haemodynamic parameters in the postresuscitation phase when the child has reached the intensive care unit, and compares this with core-peripheral temperature gap. METHODS: Ninety standardised measurements of capillary refill time were made on 55 patients, who were divided into postcardiac surgery (n = 27), and general (n = 28), most of whom had septic shock (n = 24). A normal capillary refill time was defined as < or = 2 seconds. Measured haemodynamic variables included: cardiac index, central venous pressure, systemic vascular resistance index, stroke volume index (SVI), and blood lactate. Seventy measurements were made on patients while being treated with inotropes or vasodilators. RESULTS: Capillary refill time and temperature gap both correlated poorly with all haemodynamic variables among post-cardiac surgery children. For general patients, capillary refill time was related to SVI and lactate; temperature gap correlated poorly with all variables. General patients with a prolonged capillary refill time had a lower median SVI (28 v 38 ml/m2) but not a higher lactate (1.7 v 1.1 mmol/l). A capillary refill time of > or = 6 seconds had the best predictive value for a reduced SVI. CONCLUSION: Among ventilated, general intensive care patients, capillary refill time is related weakly to blood lactate and SVI. A normal value for capillary refill time of < or = 2 seconds has little predictive value and might be too conservative for this population; septic shock.

Body Temperature Regulation↗
PubMed1976

Origin, concentration and structural features of human mammary gland cells cultured from breast secretions.

This study traced the origin of cells observed in human breast secretion samples obtained during lactation and describes the appearance of these cells following prolonged maintenance in vitro. Human milk contains a large number of single vacuolated foam celsl and a small proportion of non-vacuolated epithelial cells in clusters. Foam cells are identified by their large size, the polarity of their cytoplasmic organelles, the variation in number and size of lipid vacuoles and the condensed chromatin of their eccentrically located nucleus. Both cell types originate by exfoliation from the mammary gland. This was established by comparing the structural characteristics of cells isolated from milk with those of the cuboidal cell linings of ducts and alveoli in lactating mammary tissue. Relatively pure populations of foam cells could be established from early lactation samples (3-7 days post/partum) while non-vacuolated epithelial cell clusters were more frequently cultured from late lactation specimens (1-10 days postweaning). Foam cells did not divide and lost cytoplasmic organization during prolonged culture. In contrast, non-vacuolated epithelium in clusters proliferated to form colonies of polygonal cells. These results, which imply that foam cells are an active form of the non-vacuolated mammary cells in clusters, call attention to one system for the study of the complex hormonal interactions necessary to induce and maintain lactation.

Animals↗
PubMed1986

Development of ovarian follicles during lactation in rats.

Ovarian follicular development was studied during lactation in rats. At an early stage of lactation (day 7) the ovaries showed only small follicles in agreement with the expected 'follicular quiescence' during lactation. However, at a more advanced stage of lactation (day 14), there were large follicles which were capable of ovulation in response to exogenous gonadotropins. Unilateral ovariectomy early during lactation (day 2) resulted in compensatory follicular development in the remaining ovary. However, doubling of the number of large follicles per ovary had not yet occurred by day 13. Unilateral ovariectomy caused a significant prolongation of the delay of embryonic implantation in pregnant lactating rats: this probably reflected delay of the development of sufficiently large numbers of oestrogen-producing follicles for this process. Unilateral ovariectomy did not affect the length of lactational pseudopregnancy. The findings indicate that 'follicular quiescence' during lactation in rats is limited to the very first period after parturition. This limitation may result from the relative ineffectiveness of suckling to suppress the secretion of FSH. In this respect, ovarian follicular development in rats differs from that in many other species, including primates and man.

Animals↗
PubMed1981

Therapeutic effect of phenylbutazone on experimental acute Escherichia coli endotoxemia in ponies.

Phenylbutazone (PBZ), a classic anti-inflammatory and prostaglandin-synthesis inhibitor drug, was used to determine the role of prostaglandins and other mediators on the development and perpetuation of the response to intraperitoneal Escherichia coli endotoxin administration. The PBZ (15 mg/kg of body weight) was administered IV 30 minutes after endotoxin administration and was repeated later at 6 and 12 hours at a dose of 10 mg/kg. A variety of evaluation measurements (hematologic, blood glucose, pyruvate, lactate and fibrinogen, serum beta-glucuronidase, prothrombin time, blood gases, hepatic glycogen, plasma esterase, capillary refill time, and rectal temperature) were utilized. Marked alterations were noted for all evaluators following endotoxin administration except for blood fibrinogen, prothrombin time, and plasma esterase activity. The PBZ therapy blocked the hemoconcentration, hyperglycemia, increased blood lactate, decreased bicarbonate, decreased blood pH, pyrexia, and prolonged capillary refill time responses associated with endotoxin administration. Despite the significant blocking effects of PBZ on endotoxin responses, the eventual survival rate was unaffected in these experiments.

Animals↗
PubMed2005

Recovery from parkinson syndrome and prolonged visually evoked potentials in hepatic encephalopathy.

The combination of Parkinson syndrome (PS) and prolonged visually evoked potentials (VEPs) in a single patient with hepatic encephalopathy (HE) has not been reported. A 52-year-old male with chronic HE developed PS in early 2001. Treatment with L-DOPA was only of minimal effect. In August 2001 he was admitted because of worsening PS and HE. There was anemia, hyperlipidaemia, markedly elevated liver-function-parameters, hyperammonemia, elevated resting-lactate, steatosis hepatis and hepatomegalia. VEPs showed markedly prolonged P100-latencies. Under L-DOPA, pramipexol, L-ornithin-L-aspartate, paromomycin-sulfate, and lactulose liver-function-parameters normalized and PS markedly improved. In February 2003, VEPs were normal. L-DOPA was discontinued by the patient in April 2003 and pramipexol in December 2003. Since then PS did not recur. This case shows that HE may go along with reversible PS and prolonged VEPs. Under adequate therapy liver-function-parameters and VEPs normalize and PS disappears.

Anti-Bacterial Agents↗
PubMed1991

Coronary vasodilator reserve. Comparison of the effects of papaverine and adenosine on coronary flow, ventricular function, and myocardial metabolism.

To evaluate coronary flow reserve during cardiac catheterization, intracoronary adenosine and papaverine have been used in the clinical setting. Although papaverine maximizes coronary blood flow, it induces several toxic side effects that reduce its desirability as a coronary dilator. This investigation was designed to compare the subselective intracoronary administration of papaverine with that of adenosine in an animal model. In dogs (n = 34), we studied the effects of each agent on hemodynamics, regional myocardial blood flow, contractility (sonomicrometric and echocardiographic), metabolism (coronary arterial and venous lactate and tissue high-energy phosphates), and electrocardiographic (ST and QT intervals) parameters. Barbiturate and morphine anesthesia/analgesia was induced, and a left thoracotomy was performed. An arterial shunt was created from the left carotid artery to the left anterior descending coronary artery. Two separate groups were studied: group 1 (n = 16) for regional myocardial blood flow and mechanical function and group 2 (n = 18) for biochemical measurements. Adenosine (67 +/- 2 micrograms/min) or papaverine (6 +/- 1 mg/min) was infused into the coronary shunt at a rate of 0.5 + 0.1 ml/min for a maximum duration of 3.5 minutes. Regional myocardial blood flows were determined at control (predrug) and maximal coronary flow using radiolabeled microspheres. All hemodynamic, wall motion, biochemical, and electrocardiographic parameters were also measured at these times. Both drugs produced comparable increases in total and regional coronary blood flows (adenosine, 1.21 +/- 0.15 to 4.83 +/- 0.36 ml/min/g; papaverine, 1.21 +/- 0.05 to 4.89 +/- 0.28 ml/min/g) upon infusion into the left anterior descending coronary artery. Papaverine produced significant (p less than 0.05) changes in subendocardial ST segment electrocardiogram (-2.5 mm), QT prolongation (8 +/- 2%), myocardial creatine phosphate (47% decrease), and coronary sinus serum lactate (277% increase) compared with control. In addition, intracoronary papaverine induced an abnormal contractile pattern. No significant changes in any of these parameters (i.e., ST segment, QT prolongation, myocardial creatine phosphate level, or lactate level) were observed with intracoronary adenosine infusions. We conclude that intracoronary adenosine is comparable to papaverine for maximizing coronary blood flow without the deleterious properties observed with intracoronary papaverine.

Adenosine↗
PubMed1995

1H NMR detection of lactate and alanine in perfused rat hearts during global and low pressure ischemia.

A spin-echo method is presented for obtaining high resolution, 13C coupled, proton spectra of lactate and alanine in intact, beating rat hearts. All hearts were depleted of glycogen prior to prolonged perfusion with either 10 mM unenriched glucose or [1-13C]glucose to restore glycogen. These two groups of hearts were then examined by 1H NMR during prolonged global (zero flow) or low pressure (low flow) ischemia. During global ischemia, lactate was derived from both glucose and glycogen, with endogenous glycogen contributing twice as much lactate as exogenous glucose. During low perfusion pressure ischemia, however, lactate was derived exclusively from exogenous glucose. The entire pool of lactate (both 12C and 13C) was visible by NMR in intact, glucose perfused hearts while alanine was not detected. However, upon adding 10 mM pyruvate to the perfusate, the entire alanine pool became NMR visible while some of the lactate became NMR invisible. These observations indicate that the NMR visibility of small, usually highly mobile metabolites such as alanine and lactate is not always 100% in intact hearts and that the NMR visibility of these molecules may depend upon which exogenous substrate is presented to the heart.

Alanine↗
PubMed1981

The effects of prolonged exercise on spinally injured subjects.

The effects of prolonged exercise on paraplegics have not been reported. Seven male paraplegic subjects with spinal lesions from T4 - T12 - L1 underwent an incremental wheelchair treadmill test to exhaustion. Heart rate (HR), VO2max, and VESTPD were recorded and calculated. One week later, subjects exercised in their wheelchairs at approximately 50% (mean = 52 +/- 2%) of VO2max for 60 min on a motorized treadmill. Approximately 10 ml venous blood was withdrawn both 10 min and immediately prior to the prolonged exercise, at 20, 40, and 60 min of the exercise period, and at 10 min post-exercise. Venous blood was analyzed for glucose, hemoglobin, lactate, Na+, K+, Cl-, and plasma protein. Hematocrit was recorded and plasma volume changes calculated VO2, VE, and HR were recorded at 17, 37, and 57 min of the prolonged exercise. The mean VO2max was 29.5 +/- 2.7 ml.kg-1.min-1, with a mean max VESTPD and HR of 61.86 +/- 4.98 1.min-1 and 174 +/- 4 b.min-1, respectively. The changes in VO2 and VE during the prolonged wheelchair exercise were not significant. Significant changes occurred in venous lactate and plasma glucose concentrations during prolonged wheelchair exercise. Plasma volume changes were similar to those seen in able-bodied subjects. A notable finding was the pre-exercise hemodilution. Present data indicate that paraplegics can exercise at approximately 50% VO2 for 60 min, producing responses similar to those in able-bodied subjects.

Adult↗
PubMed1986

Biochemistry of muscle fatigue.

Fatigue--or decrease in force generation--is a reduction of simultaneously attached cross-bridges in the force generating state. Two processes are necessary for the force generation: Firstly Ca++ release from the sarcoplasmic reticulum to the sarcoplasm and the binding of Ca++ by the troponin molecule and secondly the turnover of myosin-actin cross-bridges. These processes require energy in at least three different ATPase reactions and can consequently be inhibited when ATP hydrolysis is decreased, i.e. when ATP content is to low or when the reaction products (ADP, Pi and H+) reach inhibiting levels or when muscle pH has decreased to values inhibiting actomyosin ATPase activity (22). Low pH will also decrease Ca++ release and Ca++ affinity by troponin (23). In isometric contraction the force is well preserved as long as ADP phosphorylation can be provided by both PCr degradation and anaerobic glycolysis. When the PCr store is exhausted the force starts to decline and if muscle activation is maintained the force will continue to decrease along with falling glycolytic rate. ADP phosphorylation rate decreases successively and ATP content falls with an at least transient increase in ADP. The ATP decrease, apart from the minor increase in ADP, is balanced by an equimolar increase in IMP. Lactate accumulation produces an increasing acidity with muscle pH values down to 6.25. Early changes in free ADP content cannot be excluded as reason for the initial decrease in force production followed by more pronounced inhibition of ATPase activity during continued contraction due to both substrate lack and product inhibition together with pH effect on the excitation--contraction mechanism. In dynamic exercise with supramaximum work intensity the relation between fatigue development and metabolism is similar. In prolonged dynamic exercise relying on oxidative metabolism without lactate formation the point of fatigue is reached when the glycogen store is exhausted. Again ADP phosphorylation rate is decreased when the energy substrate is changed from carbohydrate to fat with lower maximum rate of ATP resynthesis.

Adenosine Triphosphate↗