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Biomedical subjects

Hart G W Lidov

Publications and source records attributed to Hart G W Lidov.

12 recordsLinked to original sources
PubMed2006

Aprotinin improves cerebral protection: evidence from a survival porcine model.

OBJECTIVE: Aprotinin is a serine protease inhibitor used during cardiac surgery to reduce blood loss and preserve platelet function. It has also been shown to reduce leukocyte activation during and after cardiopulmonary bypass. The goal of the study was to test the hypothesis that aprotinin could reduce cerebral injury after low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest. METHODS: Sixteen piglets (mean weight, 13.6 +/- 1.3 kg) were randomly assigned to receive aprotinin or placebo (8 animals per group) before a 120-minute period of deep hypothermic circulatory arrest (15 degrees C) or 25 mL x kg(-1) x min(-1) low-flow cardiopulmonary bypass (25 degrees C or 34 degrees C). Piglets had a cranial window placed over the parietal cerebral cortex for direct examination of the microcirculation by means of intravital microscopy. Rhodamine-stained leukocytes were observed in postcapillary venules, with analysis for adhesion and rolling. Plasma was labeled with fluorescein isothiocyanate-dextran for assessment of functional capillary density. Neurologic and histologic scores were used as the primary outcome measures. RESULTS: During rewarming, the mean number of both rolling and adherent leukocytes was significantly lower after aprotinin administration (P < .05). At 5 and 15 minutes of rewarming, functional capillary density recovered faster with aprotinin treatment (P < .05). Functional outcome (neurologic deficit score) on postoperative day 1 was significantly improved in aprotinin-treated piglets (P < .05). CONCLUSIONS: Aprotinin reduces inflammation and improves neurologic outcome after a prolonged period of deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass.

Animals↗
PubMed2005

Variations in gene expression among different types of human skeletal muscle.

There is a consistent variation in the response of different skeletal muscle groups to mutations in genes known to cause muscular dystrophy, yet these muscles appear histologically similar. To better understand these phenotypic differences, we analyzed gene expression patterns in control muscle specimens obtained from four sites at autopsy: deltoid, quadriceps, gastrocnemius, and tibialis anterior (TA). A total of 35 muscle samples from nine individuals (four pediatric and five geriatric) were studied. Factors potentially influencing gene expression in the different samples included individuality, age, muscle type, gender, cause of death, postmortem interval, and ethnicity. The first three factors, in decreasing order, were found to have a significant impact on the stratification of muscle specimens. A novel analytic method, using a second round of normalization, was used to elicit differences between muscle types. This approach may be extended to a broader survey, potentially elucidating a molecular classification of the skeletal muscles.

Adolescent↗
PubMed2005

Specific bypass conditions determine safe minimum flow rate.

BACKGROUND: The purpose of this study is to define a safe minimum flow rate for specific bypass conditions using continuous monitoring with near-infrared spectroscopy and direct observation of the cerebral microcirculation. METHODS: Two series of experiments (n = 72 in each) were conducted in which piglets were cooled to a temperature of 15 degrees, 25 degrees, or 34 degrees C on cardiopulmonary bypass with hematocrit 20% or 30%, pH-stat management in all, followed by 1 or 2 hours of reduced flow (10, 25, or 50 mL.kg(-1).min(-1)). Animals in series one had a cranial window placed over the parietal cortex to evaluate the microcirculation with intravital microscopy. Plasma was labeled with fluorescein-isothiocyanate-dextran for assessment of functional capillary density (FCD) and microvascular diameter. In series two, near-infrared spectroscopy was utilized to detect tissue oxygenation index (TOI). Outcome measures included histologic and neurologic injury scores. RESULTS: The TOI during low flow and FCD during rewarming and after weaning from cardiopulmonary bypass were associated with neurologic injury. Failure of FCD to return to baseline during rewarming predicted worse functional and histologic outcome (p < 0.001). Regression analysis indicated that temperature and low-flow rate were multivariable predictors of TOI and FCD during rewarming (p < 0.001). CONCLUSIONS: Tissue oxygen index derived from near-infrared spectroscopy is a useful real-time monitor for detecting inadequate cerebral perfusion during cardiopulmonary bypass. Minimal safe pump flow rate varies according to the conditions of bypass: using pH stat management and with an hematocrit of either 20% or 30%, a flow rate as low as 10 mL.kg(-1).min(-1) is safe for as long as 2 hours at a temperature of 15 degrees C. However, under the same conditions at 34 degrees C, a flow rate of 10 mL.kg(-1).min(-1) is very likely to be associated with neurologic injury.

Animals↗
PubMed2005

Tissue oxygenation index is a useful monitor of histologic and neurologic outcome after cardiopulmonary bypass in piglets.

OBJECTIVE: Tissue oxygenation index is a novel monitoring indicator derived by near-infrared spectroscopy. We hypothesized that tissue oxygenation index could predict a minimum safe flow rate for specific bypass conditions. METHODS: Thirty-six piglets (age, 43 +/- 5 days; weight, 9.0 +/- 1.1 kg) underwent cardiopulmonary bypass with cerebral near-infrared spectroscopy (NIRO-300; Hamamatsu Photonics K.K., Hamamatsu City, Japan). Animals were cooled for 40 minutes to 15 degrees C, 25 degrees C, or 34 degrees C (pH-stat, hematocrit value of 20% or 30%, and pump flow of 100 mL . kg -1 . min -1), followed by low-flow perfusion (10, 25, or 50 mL . kg -1 . min -1) for 2 hours. Neurologic and behavioral evaluations were determined for 4 days. The brain was then fixed for histologic assessment. Tissue oxygenation index was defined as the average signal during low-flow bypass. RESULTS: Animals with an average tissue oxygenation index of less than 55% showed cerebral injury, whereas animals with an index of greater than 55% showed minimal or no evidence of injury. Correlations were found between average tissue oxygenation index and histologic score (Spearman rho = -0.65, P < .001) and neurologic deficit score (Pearson r = -0.50, P = .002) on the first postoperative day. Temperature (P < .001), flow rate (P < .001), and hematocrit value (P = .002) were multivariable predictors of tissue oxygenation index, as determined by means of multivariable analysis of variance. CONCLUSION: Tissue oxygenation index is a useful monitor for defining the minimum safe flow rate during cardiopulmonary bypass. An index value of less than 55% is a strong predictor of neurologic injury.

Animals↗
PubMed2004

IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.

Animals↗
PubMed2004

Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency.

Limb girdle muscular dystrophy type 2B and Miyoshi myopathy are clinically distinct forms of muscular dystrophy that arise from defects in the dysferlin gene. Here, we report two novel lines of dysferlin-deficient mice obtained by (a) gene targeting and (b) identification of an inbred strain, A/J, bearing a retrotransposon insertion in the dysferlin gene. The mutations in these mice were located at the 3' and 5' ends of the dysferlin gene. Both lines of mice lacked dysferlin and developed a progressive muscular dystrophy with histopathological and ultrastructural features that closely resemble the human disease. Vital staining with Evans blue dye revealed loss of sarcolemmal integrity in both lines of mice, similar to that seen in mdx and caveolin-3 deficient mice. However, in contrast to the latter group of animals, the dysferlin-deficient mice have an intact dystrophin glycoprotein complex and normal levels of caveolin-3. Our findings indicate that muscle membrane disruption and myofiber degeneration in dysferlinopathy were directly mediated by the loss of dysferlin via a new pathogenic mechanism in muscular dystrophies. We also show that the mutation in the A/J mice arose between the late 1970s and the early 1980s, and had become fixed in the production breeding stocks. Therefore, all studies involving the A/J mice or mice derived from A/J, including recombinant inbred, recombinant congenic and chromosome substitution strains, should take into account the dysferlin defect in these strains. These new dysferlin-deficient mice should be useful for elucidating the pathogenic pathway in dysferlinopathy and for developing therapeutic strategies.

Animals↗
PubMed2004

Interaction of temperature with hematocrit level and pH determines safe duration of hypothermic circulatory arrest.

OBJECTIVE: Previous studies have demonstrated that both hematocrit level and pH influence the protection afforded by deep hypothermic circulatory arrest. The current study examines how temperature modulates the effect of hematocrit level and pH in determining a safe duration of circulatory arrest. The study also builds on previous work investigating the utility of near-infrared spectroscopy as a real-time monitor of cerebral protection during circulatory arrest. METHODS: Seventy-six piglets (9.3 +/- 1.2 kg) underwent circulatory arrest under varying conditions with continuous monitoring by means of near-infrared spectroscopy (hematocrit level of 20% or 30%; pH-stat or alpha-stat strategy; temperature of 15 degrees C or 25 degrees C; arrest time of 60, 80, or 100 minutes). Neurologic recovery was evaluated daily by a veterinarian, and the brain was fixed in situ on postoperative day 4 to be examined on the basis of histologic score in a blinded fashion. RESULTS: Multivariable analysis of total histologic score revealed that higher temperature, lower hematocrit level, more alkaline pH, and longer hypothermic circulatory arrest duration were predictive of more severe damage to the brain (P <.01). Regression modeling revealed that higher temperature exacerbated the disadvantage of a lower hematocrit level and longer arrest times but not pH strategy. Normalized oxyhemoglobin nadir time, derived from near-infrared spectroscopy, was positively correlated with neurologic recovery on the fourth postoperative day and with total histologic injury score (P <.0001). CONCLUSION: Hematocrit level and pH, as well as temperature, determine the safe duration of hypothermic circulatory arrest. Near-infrared spectroscopy is a useful real-time monitor of safe duration of circulatory arrest.

Animals↗
PubMed2004

Higher bypass temperature correlates with increased white cell activation in the cerebral microcirculation.

OBJECTIVE: Cardiopulmonary bypass induces a systemic inflammatory response, which in turn promotes a cascade of leukocyte and endothelial cell activity. We investigated whether differences in bypass temperature and flow rate affect endothelial cell and leukocyte adhesion in the cerebral microcirculation. METHODS: Thirty-six piglets (13.0 +/- 1.1 kg) had a cranial window placed over the parietal cortex to evaluate the microcirculation by means of intravital microscopy. Animals were cooled to a temperature of 15 degrees C, 25 degrees C, or 34 degrees C on cardiopulmonary bypass with hematocrit levels of 20% or 30% by using pH-stat management, followed by 60 minutes of reduced flow (10, 25, or 50 mL.kg(-1).min(-1)). Rhodamine staining was used to observe adherent and rolling leukocytes in postcapillary venules. RESULTS: Higher bypass temperature correlated with significantly more adherent and rolling leukocytes during the full 60 minutes of low-flow bypass (P <.05). Poisson regression revealed more adherent leukocytes at 34 degrees C than at 15 degrees C and at a flow rate of 10 mL.kg(-1).min(-1) compared with a flow rate of 50 mL.kg(-1).min(-1). There was an inverse correlation between flow rate and the number of adherent and rolling leukocytes at 30, 45, and 60 minutes of low-flow bypass (P <.05). Temperature was a multivariable predictor of histologic score, with greater neurologic damage found after bypass at 34 degrees C (P <.01). CONCLUSIONS: Leukocyte activation in cerebral microcirculation is increased with higher temperature and lower flow rate, suggesting that these variables influence the inflammatory response during cardiopulmonary bypass.

Animals↗
PubMed2003

Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle.

The nemaline myopathies (NMs) are a clinically and genetically heterogeneous group of disorders characterized by nemaline rods and skeletal muscle weakness. Mutations in five sarcomeric thin filament genes have been identified. However, the molecular consequences of these mutations are unknown. Using Affymetrix oligonucleotide microarrays, we have analyzed the expression patterns of >21,000 genes and expressed sequence tags in skeletal muscles of 12 NM patients and 21 controls. Multiple complementary approaches were used for data analysis, including geometric fold analysis, two-tailed unequal variance t test, hierarchical clustering, relevance network, and nearest-neighbor analysis. We report the identification of high satellite cell populations in NM and the significant down-regulation of transcripts for key enzymes of glucose and glycogen metabolism as well as a possible regulator of fatty acid metabolism, UCP3. Interestingly, transcript level changes of multiple genes suggest possible changes in Ca(2+) homeostasis. The increased expression of multiple structural proteins was consistent with increased fibrosis. This comprehensive study of downstream molecular consequences of NM gene mutations provides insights in the cellular events leading to the NM phenotype.

Adult↗
PubMed2003

Diagnostic value of electromyography and muscle biopsy in arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC), a clinical syndrome characterized by multiple congenital joint contractures, frequently is caused by lesions in the peripheral nervous system. Two standard tests for the evaluation of the motor unit are nerve conduction studies/electromyography (NCS/EMG) and muscle biopsy. We reviewed the diagnostic value of these two studies in the evaluation of AMC over a 23-year period, analyzing 38 patients with AMC who had NCS/EMG, muscle biopsy, or both. Final diagnoses were classified as neurogenic (8 patients), myopathic (10 patients), "other" (12 patients), or unknown (8 patients). Neither test alone had consistently high sensitivities, positive predictive values, or specificities. However, when NCS/EMG and muscle biopsy were concordant for neurogenic or myopathic findings, they were more accurate than either test alone, especially for neurogenic diseases. Test results were most commonly discordant in patients with "other" or unknown diagnoses. These findings suggest that when the clinical evaluation indicates a specific syndromic, developmental, or exogenous cause, NCS/EMG and muscle biopsy are not helpful and may not need to be performed. When the history, examination, and genetic evaluation are unrevealing, NCS/EMG and muscle biopsy together provide valuable diagnostic information.

Arthrogryposis↗
PubMed2002

Combination of alpha-stat strategy and hemodilution exacerbates neurologic injury in a survival piglet model with deep hypothermic circulatory arrest.

BACKGROUND: The optimal pH strategy and hematocrit during cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA) remain controversial. We studied the interaction of pH strategy and hematocrit and their combined impact on cerebral oxygenation and neurological outcome in a survival piglet model including monitoring by near-infrared spectroscopy (NIRS). METHODS: Thirty-six piglets (9.2+/-1.1 kg) underwent DHCA under varying conditions with continuous monitoring by NIRS (pH-stat or alpha-stat strategy, hematocrit 20% or 30%, DHCA time 60, 80, or 100 minutes). Neurological recovery was evaluated daily. The brain was fixed in situ on postoperative day 4 and a histological score (HS) for neurological injury was assessed. RESULTS: Oxygenated hemoglobin (HbO2) and total hemoglobin signals detected by NIRS were significantly lower with alpha-stat strategy during cooling (p < 0.001), suggesting insufficient cerebral blood supply and oxygenation. HbO2 declined to a plateau (nadir) during DHCA. Time to nadir was significantly shorter in lower hematocrit groups (p < 0.01). Significantly delayed neurologic recovery was seen with alpha-stat strategy compared with pH-stat (p < 0.05). The alpha-stat group had a worse histological score compared with those assigned to pH-stat (p < 0.001). Neurologic impairment was estimated to be over 10 times more likely for animals randomized to alpha-stat compared with pH-stat strategy (odds ratio = 10.7, 95% confidence interval = 3.8 to 25.2). CONCLUSIONS: Combination of alpha-stat strategy and lower hematocrit exacerbates neurological injury after DHCA. The mechanism of injury is inadequate cerebral oxygenation during cooling and a longer plateau period of minimal O2 extraction during DHCA.

Animals↗