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Biomedical subjects

M Hodges

Publications and source records attributed to M Hodges.

At least 19 recordsLinked to original sources
PubMed2003

Do neurotoxic lesions in rostral medullary nuclei induce/accentuate hypoventilation during NREM sleep?

Experimentally induced neuronal dysfunction in respiratory regions of the rostral medulla decrease breathing more in anesthetized mammals than in awake mammals. Sleep is similar to anesthesia in that excitatory inputs to respiratory neurons are reduced compared to the awake state; thus, we hypothesized that neurotoxic lesions in rostral medullary nuclei would, relative to wakefulness (WK), induce and/or accentuate hypoventilation during non-rapid eye movement (NREM) sleep. To test the hypothesis, goats were studied between 21:00 h and 03:00 h: (1) before and 30 days after chronically implanting microtubules bilaterally into the rostral medulla and, (2) 9-15 h and 2-17 days after unilateral injections of 100 nl to 1 microl, 50 mM ibotenic acid into the vestibular, gigantocellularis reticularis, or facial nuclei, or the retrotrapezoid nucleus/parapyramidal region. Arterial blood was repeatedly sampled in all studies during WK, and NREM and rapid eye movement (REM) sleep states. There was no significant (P>0.10) change in Pa(CO(2)) between WK and NREM sleep (and REM sleep when sufficient data were obtained) before or after implantation of microtubules and in studies after creating the neurotoxic lesions. Breathing frequency also did not significantly (P>0.10) differ between states in any of the studies. The data thus did not support the hypothesis. We speculate that in goats efficient compensatory mechanisms maintain Pa(CO(2)) homeostasis during normal sleep and the same and/or other mechanisms maintain homeostasis when excitatory drive is further reduced by lesions in rostral medullary nuclei.

Animals↗
PubMed2003

Perturbations in three medullary nuclei enhance fractionated breathing in awake goats.

Our aim was to determine the frequency and characteristics of a fractionated pattern of diaphragm and upper airway muscle activity and airflow during wakefulness and sleep in adult goats. A fractionated breath (FBr) was defined as three or more brief (40-150 ms) interruptions in the diaphragm activity not associated with multiple swallows, eructation, mastication, or movement. During a FBr, the discharge pattern in the diaphragm and upper airway muscles showed complete cycles of inspiration and expiration. Whereas the interval between peak diaphragm activity of the breath preceding the FBr to the first diaphragm peak of the FBr was 15-20% less than the average interval of the preceding five control breaths, the breath-to-breath interval of the five breaths after a FBr did not differ from the control breaths before the FBr event. In normal goats, FBr was evident in only 4 of 18 (22%) awake goats and in only one of these goats during non-rapid eye movement sleep. In 35 goats with implanted microtubules in the medulla, FBr were present in 14 (40%) goats. In these goats with FBr, 78% (11 of 14) had one or more implantations into or near the facial, vestibular, or raphe nuclei. The effect of perturbations in these nuclei is probably nonspecific, because injections into these nuclei with mock cerebrospinal fluid or excitatory amino acid-receptor agonist or antagonist produced both increases and decreases in the frequency of the FBr while not altering their characteristics. Finally, a swallow occurred at the termination or during the first breath after 60% of the FBr. We speculate that the FBr manifest 1) the disruption of a neuronal network, which coordinates breathing and other functions (such as swallowing), utilizing the same anatomic structures, and/or 2) transient changes in synaptic inputs that increase the rate of the normal respiratory rhythm generator or allow an ectopic, anomalous generator to become dominant.

Animals↗
PubMed2002

Manipulating PEPC levels in plants.

This review examines the current understanding of the structural, functional and regulatory properties of C4 and C3 forms of higher plant phosphoenolpyruvate carboxylase. The emphasis is on the interactive metabolic and post-translational controls acting on the enzyme in the physiological context of C4 photosynthesis and the anaplerotic pathway. A brief overview is given concerning the recent developments of PEPC-based genetic engineering of C3 plants with the aim of improving photosynthetic performance in normal and limiting environmental conditions. So far, in spite of achieving a considerable increase in PEPC levels, more work needs to be done with respect to the correct dosage and location before that goal is reached. Some unpublished results on the transformation of maize with a sorghum C4 PEPC cDNA are also presented. They show that it is possible to increase photosynthetic PEPC levels in this C4 plant and that the modification in enzyme content has a pleiotropic physiological impact and, notably, an improved water use efficiency when water is limited.

Biomass↗
PubMed2002

Effects of carotid and aortic chemoreceptor denervation in newborn piglets.

The objective of the present study was to test the hypothesis that in neonatal piglets there would be no hypoventilation after sham denervation or aortic denervation (AOD) alone, but there would be transient hypoventilation after carotid body denervation (CBD) and the hypoventilation would be greatest after combined carotid and aortic denervation (CBD+AOD). There was a significant (P < 0.05) hypoventilation in CBD and CBD+AOD piglets denervated at 5, 15, and 25 days of age. The hypoventilation in CBD+AOD piglets denervated at 5 days of age was greater (P < 0.05) than that of all other groups. Conversely, sham-denervated and AOD piglets did not hypoventilate after denervation. Injections of sodium cyanide showed that aortic chemoreceptors were a site of recovery of peripheral chemosensitivity after CBD. This aortic sodium cyanide response was abolished by prior injection of a serotonin 5a receptor blocker. Residual peripheral chemosensitivity after CBD+AOD was localized to the left ventricle. We conclude that 1) aortic chemoreceptors contribute to eupneic breathing in piglets that were carotid denervated at 5 days of age and 2) there are multiple sites of residual peripheral chemosensitivity after CBD.

Animals↗
PubMed2002

Contributions from rostral medullary nuclei to coordination of swallowing and breathing in awake goats.

The purpose of this study was to determine whether neurons in the facial (FN), gigantocellularis reticularis (RGN), and vestibular (VN) nuclei contribute to the regulation of breathing, swallowing, and the coordination of these two functions. Microtubules were chronically implanted bilaterally in goats. Two weeks later during wakefulness, 100-nl unilateral injections were made of mock cerebral spinal fluid or an excitatory amino acid receptor agonist or antagonists. When the agonist, N-methyl-D-aspartic acid, was injected into any nuclei, breathing and swallowing increased transiently (15-30%; P < 0.05), whereas only injections of the antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-(f)quinoxaline into VN increased swallowing (20%; P < 0.05). The phase of breathing in which the swallows occurred was not altered by any injections. However, more importantly, injections of the agonist and the antagonists significantly altered (P < 0.05) by 5-50% the respiratory phase-dependent timing and tidal volume effect of swallows on breathing relative to mock cerebral spinal fluid injections. In addition, these effects were not uniform for all three nuclei. We conclude that the FN, RGN, and VN are part of a neural circuit in the rostral medulla that regulates and/or modulates breathing, swallowing, and their coordination in the awake state.

2-Amino-5-phosphonovalerate↗
PubMed2001

A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients.

The efficacy, safety, and tolerability of voriconazole and fluconazole were compared in 391 immunocompromised patients with mycology- and biopsy-proven esophageal candidiasis. Primary efficacy analysis (256 patients) of esophageal treatment as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole. The 95% confidence interval for the difference in success rates ranged from -1.0% to 7.5%. The overall safety and tolerability of both antifungals were acceptable. Fewer patients discontinued voriconazole treatment because of insufficient clinical response (4 patients [2.0%] vs. 5 patients [2.6%]). More patients discontinued voriconazole than fluconazole treatment because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). The most frequent adverse events (23%) with voriconazole were mild, transient visual disturbances. Voriconazole (200 mg, b.i.d.) was shown to be at least as effective as fluconazole in the treatment of biopsy-proven esophageal candidiasis in immunocompromised patients.

Adolescent↗
PubMed2001

Assessment of QT dispersion as a prognostic marker for sudden death in a regional nonreferred hypertrophic cardiomyopathy cohort.

In a consecutive, prospectively assessed and unselected hypertrophic cardiomyopathy (HC) cohort closely resembling the true disease state, QTc dispersion (and QTc) on the 12-lead electrocardiogram did not prove to be a reliable predictor of HC-related sudden death. Therefore, QT dispersion would not appear to be useful in devising future risk stratification strategies for predicting sudden death in HC.

Adult↗
PubMed2001

Utility of current risk stratification tests for predicting major arrhythmic events after myocardial infarction.

OBJECTIVES: We surveyed the literature to estimate prediction values for five common tests for risk of major arrhythmic events (MAEs) after myocardial infarction. We then determined feasibility of a staged risk stratification using combinations of noninvasive tests, reserving an electrophysiologic study (EPS) as the final test. BACKGROUND: Improved approaches are needed for identifying those patients at highest risk for subsequent MAE and candidates for implantable cardioverter-defibrillators. METHODS: We located 44 reports for which values of MAE incidence and predictive accuracy could be inferred: signal-averaged electrocardiography; heart rate variability; severe ventricular arrhythmia on ambulatory electrocardiography; left ventricular ejection fraction; and EPS. A meta-analysis of reports used receiver-operating characteristic curves to estimate mean values for sensitivity and specificity for each test and 95% confidence limits. We then simulated a clinical situation in which risk was estimated by combining tests in three stages. RESULTS: Test sensitivities ranged from 42.8% to 62.4%; specificities from 77.4% to 85.8%. A three-stage stratification yielded a low-risk group (80.0% with a two-year MAE risk of 2.9%), a high-risk group (11.8% with a 41.4% risk) and an unstratified group (8.2% with an 8.9% risk equivalent to a two-year incidence of 7.9%). CONCLUSIONS: Sensitivities and specificities for the five tests were relatively similar. No one test was satisfactory alone for predicting risk. Combinations of tests in stages allowed us to stratify 91.8% of patients as either high-risk or low-risk. These data suggest that a large prospective study to develop a robust prediction model is feasible and desirable.

Death, Sudden, Cardiac↗
PubMed2001

Multiple rostral medullary nuclei can influence breathing in awake goats.

The purpose of this study was to determine the effect on breathing of neuronal dysfunction in the retrotrapezoid (RTN), facial (FN), gigantocellularis reticularis (RGN), or vestibular (VN) nuclei of adult awake goats. Microtubules were chronically implanted to induce neuronal dysfunction by microinjection of an excitatory amino acid (EAA) receptor antagonist or a neurotoxin. The EAA receptor antagonist had minimal effect on eupneic breathing, but 8--10 days after injection of the neurotoxin, 7 of 10 goats hypoventilated (arterial PCO(2) increased 3.2 +/- 0.7 Torr). Overall there were no significant (P > 0.10) effects of the EAA receptor antagonist on CO(2) sensitivity. However, for all nuclei, > or =66% of the antagonist injections altered CO(2) sensitivity by more than the normal 12.7 +/- 1.6% day-to-day variation. These changes were not uniform, inasmuch as the antagonist increased (RTN, n = 2; FN, n = 7; RGN, n = 6; VN, n = 1) or decreased (RTN, n = 2; RGN, n = 3; VN, n = 2) CO(2) sensitivity. Ten days after injection of the neurotoxin into the FN (n = 3) or RGN (n = 5), CO(2) sensitivity was also reduced. Neuronal dysfunction also did not have a uniform effect on the exercise arterial PCO(2) response, and there was no correlation between effects on CO(2) sensitivity and the exercise hyperpnea. We conclude that there is a heterogeneous population of neurons in these rostral medullary nuclei (or adjacent tissue) that can affect breathing in the awake state, possibly through chemoreception or chemoreceptor-related mechanisms.

2-Amino-5-phosphonovalerate↗
PubMed2000

Anthelminthic treatment and haemoglobin concentrations during pregnancy.

A longitudinal study was conducted in Sierra Leone to measure the impact of a single dose anthelminthic (400 mg albendazole) and daily iron-folate supplements (36 g iron and 5 mg folate) on haemoglobin (HG) concentration during pregnancy. After controlling for baseline Hb concentration and season, anthelmintic treatment reduced the decline in haemoglobin concentration between the first and third trimesters by 6.6 g/L (p=0.0034) relative to the control. The corresponding value for iron-folate supplements was 13.7 g/L(p<0.0001) [corrected]. These findings indicate that anthelminthic treatment should be included in strategies to control maternal anaemia in Sierra Leone.

Adolescent↗
PubMed2000

A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree.

Malignant hyperthermia (MH) is a pharmacogenetic disorder that predisposes to a sometimes fatal hypermetabolic reaction to halogenated anaesthetics. MH is considered to originate from abnormal regulation of skeletal muscle Ca(2+) release. Current diagnosis of MH susceptibility (MHS) relies on in vitro contracture testing (IVCT) of skeletal muscle. The ryanodine receptor (RYR1) encoding the major Ca(2+) release channel in the skeletal muscle sarcoplasmic reticulum has been shown to be mutated in a number of MH pedigrees. The large Maori pedigree reported here is the largest MHS pedigree investigated to date and comprises five probands who experienced clinical episodes of MH and 130 members diagnosed by the IVCT. Sequencing of the 15 117 bp RYR1 cDNA in a MHS individual from this pedigree identified a novel C14477T transition that results in a Thr4826 to Ile substitution in the C-terminal region/transmembrane loop of the skeletal muscle ryanodine receptor. This is the first mutation in the RyR1 C-terminal region associated solely with MHS. Although linkage analysis showed strong linkage (max LOD, 11.103 at theta = 0.133) between the mutation and MHS in the pedigree using the standardized European IVCT phenotyping protocol, 22 MHS recombinants were observed. The relationship between the IVCT response and genotype was explored and showed that as IVCT diagnostic cut-off points were made increasingly stringent, the number of MHS discordants decreased with complete concordance between the presence or absence of the C14477T mutation and MHS and MH normal phenotypes, respectively, using a cut-off of 1.2 g tension at 2.0 mM caffeine and 1.8 g tension at 2.0% halothane. Many MHS pedigrees investigated have been excluded from linkage to the RYR1 gene on the basis of a small number of recombinants; however, the linkage analysis reported here suggests that other recombinant families excluded from linkage to the RYR1 gene may actually demonstrate linkage as the number of members tested within the pedigrees increases. The high number of discordants observed using the standardized diagnostic cut-off points is likely to reflect the presence of a second MHS susceptibility locus in the pedigree.

Amino Acid Sequence↗
PubMed2000

Disruption of a novel imprinted zinc-finger gene, ZNF215, in Beckwith-Wiedemann syndrome.

The genetics of Beckwith-Wiedemann syndrome (BWS) is complex and is thought to involve multiple genes. It is known that three regions on chromosome 11p15 (BWSCR1, BWSCR2, and BWSCR3) may play a role in the development of BWS. BWSCR2 is defined by two BWS breakpoints. Here we describe the cloning and sequence analysis of 73 kb containing BWSCR2. Within this region, we detected a novel zinc-finger gene, ZNF215. We show that two of its five alternatively spliced transcripts are disrupted by both BWSCR2 breakpoints. Parts of the 3' end of these splice forms are transcribed from the antisense strand of a second zinc-finger gene, ZNF214. We show that ZNF215 is imprinted in a tissue-specific manner.

Alleles↗
PubMed1999

Sildenafil citrate (Viagra) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of sildenafil in men with broad-spectrum erectile dysfunction (ED), with reference to age-matched healthy control subjects. METHODS: One hundred eleven patients were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, 12-week, flexible-dose study. Efficacy assessments included the International Index of Erectile Function (IIEF), a global assessment question, and patient event log data. In a separate, nontreatment study, 109 control subjects also completed the IIEF. RESULTS: Mean IIEF scores at baseline were significantly lower for patients with ED than for control subjects without a history of ED. After treatment, mean IIEF scores for patients receiving sildenafil approached values observed in control subjects and were significantly higher than mean scores for patients receiving placebo (P<0.01). Responses to the global assessment question and patient log data corroborated the IIEF results. Sildenafil was well tolerated, with no discontinuations because of adverse events. CONCLUSIONS: The results indicate that sildenafil, an effective oral therapy for the treatment of broad-spectrum ED, is associated with a near normalization of patient erectile function.

Adult↗
PubMed1999

Are isocitrate dehydrogenases and 2-oxoglutarate involved in the regulation of glutamate synthesis?

In plants, nitrogen assimilation into amino acids relies on the availability of the reduced form of nitrogen, ammonium. The glutamine synthetase-glutamate synthase pathway, which requires carbon skeletons in the form of 2-oxoglutarate, achieves this. To date, the exact enzymatic origin of 2-oxoglutarate for plant ammonium assimilation is unknown. Isocitrate dehydrogenases synthesize 2-oxoglutarate. Recent efforts have concentrated on evaluating the involvement of different isocitrate dehydrogenases, distinguished by co-factor specificity and sub-cellular localization. Furthermore, several observations indicate that 2-oxoglutarate is likely to be a metabolic signal that regulates the coordination of carbon:nitrogen metabolism. This is discussed in the context of recent advances in bacterial signalling processes.

Journal Article↗
PubMed1999

The experience of life-threatening illness: patients' and their loved ones' perspectives.

BACKGROUND: Little is known about the actual concerns of patients and families regarding their health care during life-threatening illness and at end of life. Previous research with these groups has focused on their reaction to concerns of the medical community, eg, advance directives, decision making, and pain and symptom management. OBJECTIVE: To elicit and listen attentively to the actual experiences and major concerns of persons with life-threatening illness, personal/family caregivers, and bereaved individuals regarding their health care and interactions with healthcare system. DESIGN: Thirty-three focus groups were convened to involve 3 categories of individuals: persons with life-threatening illness (n = 77), personal/family caregivers (n = 70), and bereaved persons (n = 81). Three focus groups, 1 of each kind, were held in 11 cities across the United States. Verbatim transcripts were coded and analyzed to identify themes. RESULTS: (1) Persons with life-threatening illnesses indicated that health professionals focus on medical and physical interventions, give too little information, appear uncomfortable talking about death, and do not include family members in conversations. (2) Caregivers reported exhaustion. They said that doctors do not appreciate the impact of the illness on their lives and rarely consult them, although all treatment decisions affect them. (3) Bereaved persons emphasized the loved ones' comfort in the last days of life. They wished that physicians would tell families when the end is near and avoid interrupting the process of dying with medical and often futile tasks. "I'm sorry" is sufficient initially to express the physician's condolences, but families appreciate contact weeks later. CONCLUSIONS: Many sources of dissatisfaction with care among persons with life-threatening illness and their families are interpersonal in nature. The physician's respectful presence and demonstration of caring are highly desired, significant interventions for those who cannot be cured of illness and for their loved ones. Making healthcare professionals aware of these concerns may itself bring about some changes in daily practice. Further research is needed to test the most useful skills and behaviors of healthcare professionals in caring for persons with life-threatening illness and their loved ones.

Journal Article↗
PubMed1999

A human p57(KIP2) transgene is not activated by passage through the maternal mouse germline.

Genomic imprinting results in expression of some autosomal genes from one parental allele only. Human chromosome 11p15, and the syntenic region on mouse distal chromosome 7, contain several imprinted genes, including p57 (KIP2) ( CDKN1C ) and IGF2. These two genes, which are separated by >700 kb, are both implicated in the pathogenesis of Beckwith-Wiedemann syndrome. We have shown previously that an Igf2/H19 transgene is expressed appropriately and can imprint at ectopic chromosomal locations. To investigate the p57 (KIP2) region, we similarly tested the imprinting and function of a 38 kb human genomic fragment containing the p57 (KIP2) gene in transgenic mice. This transgene showed appropriate tissue-specific expression and transgene copy number-dependent expression at ectopic sites. However, the levels of expression are reminiscent of that found for the paternal allele in humans (10%). There was no change in expression levels when the transgene was inherited from the maternal germline. These results suggest that the cis -elements required for enhanced expression of the maternally inherited p57 (KIP2) allele lie at a distance from the gene. This finding has important implications for the role of this gene in the human disease, in particular with respect to the translocation breakpoints identified in some patients.

Animals↗