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Biomedical subjects

K Russell

Publications and source records attributed to K Russell.

At least 55 records · Page 3Linked to original sources
PubMed1998

Attenuation of skeletal muscle wasting with recombinant human growth hormone secreted from a tissue-engineered bioartificial muscle.

Skeletal muscle wasting is a significant problem in elderly and debilitated patients. Growth hormone (GH) is an anabolic growth factor for skeletal muscle but is difficult to deliver in a therapeutic manner by injection owing to its in vivo instability. A novel method is presented for the sustained secretion of recombinant human GH (rhGH) from genetically modified skeletal muscle implants, which reduces host muscle wasting. Proliferating murine C2C12 skeletal myoblasts stably transduced with the rhGH gene were tissue engineered in vitro into bioartificial muscles (C2-BAMs) containing organized postmitotic myofibers secreting 3-5 microg of rhGH/day in vitro. When implanted subcutaneously into syngeneic mice, C2-BAMs delivered a sustained physiologic dose of 2.5 to 11.3 ng of rhGH per milliliter of serum. rhGH synthesized and secreted by the myofibers was in the 22-kDa monomeric form and was biologically active, based on downregulation of a GH-sensitive protein synthesized in the liver. Skeletal muscle disuse atrophy was induced in mice by hindlimb unloading, causing the fast plantaris and slow soleus muscles to atrophy by 21 to 35% ( < 0.02). This atrophy was significantly attenuated 41 to 55% (p < 0.02) in animals that received C2-BAM implants, but not in animals receiving daily injections of purified rhGH (1 mg/kg/day). These data support the concept that delivery of rhGH from BAMs may be efficacious in treating muscle-wasting disorders.

Animals↗
PubMed1998

Matrices of paired substitutions show the effects of tRNA D/T loop sequence on Drosophila RNase P and 3'-tRNase processing.

Drosophila RNase P and 3'-tRNase endonucleolytically process the 5' and 3' ends of tRNA precursors. We examined the processing kinetics of normal substrates and the inhibitory effect of the tRNA product on both processing reactions. The product is not a good RNase P inhibitor, with a KI approximately 7 times greater than the substrate KM of approximately 200 nM and is a better inhibitor of 3'-tRNase, with a KI approximately two times the KM of approximately 80 nM. We generated matrices of substitutions at positions G18/U55 and G19/C56 (two contiguous universally conserved D/T loop base pairs) in Drosophila tRNAHis precursors. More than half the variants display a significant reduction in their ability to be processed by RNase P and 3'-tRNase. Minimal substrates with deleted D and anticodon stems could be processed by RNase P and 3'-tRNase much like full-length substrates, indicating that D/T loop contacts and D arm/enzyme contacts are not required by either enzyme. Selected tRNAs that were poor substrates for one or both enzymes were further analyzed using Michaelis-Menten kinetics and by structure probing. Processing reductions arise principally due to an increase in KM with relatively little change in Vmax, consistent with the remote location of the sequence and structure changes from the processing site for both enzymes. Local changes in variant tRNA susceptibility to RNase T1 and RNase A did not coincide with processing disabilities.

Animals↗
PubMed1998

Reconstruction of nasal defects with implant-retained nasal prostheses.

Predictable biomechanical retention of nasal prostheses can now be achieved using Brånemark osseointegrated implants. These prostheses are tissue compatible, simple in design and easy to place, can be worn independently of spectacles and can in the majority of cases be provided soon after surgical excision. We have treated 14 patients (30 implants) 8 of whom had the implants placed at the time of surgical excision of the tumour. The longest survival so far has been 62 months (mean 38 months). Craniofacial osseointegration changes patients' perceptions of a nasal prosthesis and improves quality of life. Initial reconstructive surgery after radical nasal excision should be limited to reconstruction of the upper lip and preparation of the surgical defect for an implant-retained prosthesis.

Female↗
PubMed1998

Adrenal function in preterm infants: ACTH may not be the sole regulator of the fetal zone.

The fetal zone of the adrenal gland is known to persist after preterm birth, but there is uncertainty as to how long adrenal fetal zone steroid production continues and how it is regulated. The purpose of this study was to test two hypotheses. First, that the urinary excretion of 3beta-OH-5-ene steroids persists until term, and then declines, as it does in full-term infants. Second, that the persistence of the fetal zone is due to continuing ACTH stimulation. A longitudinal observational study was undertaken in 22 preterm infants of 24-31-wk gestation. Sequential measurements were made of urinary 3beta-OH-5-ene steroids (fetal zone steroid metabolites), plasma dehydroepiandrosterone sulfate (DHEAS), and ACTH. Excretion of urinary 3beta-OH-5-ene steroids was 1500-2000 microg kg(-1) d(-1), persisting until term, and declining abruptly at approximately 42 wk postconceptional age (PCA), to levels comparable to term infants at the same PCA. Median plasma ACTH levels rose from <7.6 pg mL(-1) at 25-wk PCA to 34.5 pg mL(-1) at 46-wk PCA. Urinary 3beta-OH-5-ene steroids were highest when ACTH levels were lowest, and were declining when ACTH was rising. In four infants given dexamethasone, urinary excretion of 3beta-OH-5-ene steroids and plasma DHEAS were not suppressed fully, when plasma ACTH and cortisol, and urinary cortisol metabolites were. These data suggest that ACTH is not the sole regulator of the adrenal fetal zone steroid synthesis and that involution of the fetal zone is related to gestation rather than birth.

Adrenal Glands↗
PubMed1998

Discriminative stimulus properties of nicotine at low doses: the effects of caffeine preload.

Discriminative stimulus properties of low nicotine doses administered in the form of chewing gum in combination with caffeine have been evaluated in humans, using established behavioural drug discrimination procedures. Twenty-one smokers who were also regular coffee drinkers were trained to discriminate 0 versus 1 mg nicotine chewing gum. Twenty subjects (11 men and nine women) were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 0.25, 0.5 and 1 mg was then examined. Subjects were randomly allocated to receive either 50 mg caffeine or placebo before testing. Nicotine-appropriate responding was linearly related to dose, demonstrating that smokers can accurately discriminate nicotine from placebo and between relatively small doses of nicotine. Nicotine-appropriate responding was high at the 0 mg nicotine dose in the caffeine group demonstrating a partial generalization. Subjective effects assessed concurrently with behavioural discrimination revealed that nicotine discrimination was guided by the interoceptive cues of 'sensations in mouth', 'taste', 'heart rate', 'stimulated', 'alert' 'jittery' and 'nausea'. Caffeine increased self-ratings of 'stimulated' and 'alert' (at the 0 mg nicotine dose) and 'jittery' at the 0.5 and 1.0 mg nicotine dose. Relationships between nicotine-appropriate responding and subjective feelings induced by caffeine suggested that feelings of 'stimulated' and 'alert' were guiding discrimination behaviour. These data are discussed in terms of interoceptive nicotine cues and their importance at different doses and after caffeine preload.

Adult↗
PubMed1997

Methods of correcting for multiple testing: operating characteristics.

We examine the operating characteristics of 17 methods for correcting p-values for multiple testing on synthetic data with known statistical properties. These methods are derived p-values only and not the raw data. With the test cases, we systematically varied the number of p-values, the proportion of false null hypotheses, the probability that a false null hypothesis would result in a p-value less than 5 per cent and the degree of correlation between p-values. We examined the effect of each of these factors on family-wise and false negative error rates and compared the false negative error rates of methods with an acceptable family-wise error. Only four methods were not bettered in this comparison. Unfortunately, however, a uniformly best method of those examined does not exist. A suggested strategy for examining corrections uses a succession of methods that are increasingly lax in family-wise error. A computer program for these corrections is available.

Clinical Trials as Topic↗
PubMed1997

Effect of the potassium channel opener ZM260384 on skeletal muscle function during restricted blood flow in the anaesthetized cat.

The aim of the present experiment was to determine whether the potassium channel opener 2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1, 4-benzoxazine-4-yl)pyridine-N-oxide (ZM260384) was capable of accelerating the decline in skeletal muscle function during restricted blood flow in vivo. Cats (3.0-4.5 kg body weight) were anaesthetized with alphaxalone-alphadalone and breathed spontaneously following tracheotomy. Isometric tension was measured in the extensor digitorum longus-anterior tibialis (EDL-TA) muscle group. Ischaemia was induced by perfusing the hindlimb with the animal's own blood at a rate of 12.5 ml min-1 using a roller pump and stimulating the common peroneal nerve to induce repetitive submaximal tetanic contractions in the EDL-TA. The number of stimulation voltage increments required each minute to maintain a constant level of submaximal mechanical output and the time to exhaustion were used as indices of the rate of tension decline. The rate of tension decline in the ischaemic EDL-TA in the presence of ZM260384 at 3 mg kg-1, a maximally hypotensive dose predicted to be within the dose range required to exert direct effects on skeletal muscle, was measured and compared with the rate of tension decline in the presence of ZM260384 at 0.03 mg kg-1, also maximally hypotensive dose but below the predicted dose range for skeletal muscle effects. The number of voltage increments per minute was 1.93 +/- 0.07 and 1.48 +/- 0.14 (P < 0.05) in the presence of 3 and 0.03 mg kg-1 ZM260384, respectively. Time to exhaustion was 17.5 +/- 4.2 and 7.2 +/- 0.8 min (P < 0.05) in the presence of 3 and 0.03 mg kg-1 ZM260384, respectively. Given that there was no difference between these two groups in any haemodynamic variable measured, the results of the present study suggest that ZM260384 (3 mg kg-1) increases the rate of isometric force loss in ischemic skeletal muscle in vivo.

Anesthesia↗
PubMed1996

N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides: KATP potassium channel openers. Modifications on the western region.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

Amides↗
PubMed1996

The effects of pharmacological modulation of KATP on the guinea-pig isolated diaphragm.

The purpose of the present study was to investigate the functional consequences of KATP modulation in the normal and the metabolically inhibited guinea-pig isolated diaphragm using the K+ channel openers cromakalim, pinacidil, RP49356 (N-methyl-2-(3-pyridil)-tetrahydrothiopyran-2-carbothiami de-1-oxide) and ZM260384 (2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine -4-yl)pyridine-N-oxide) and the K+ channel inhibitors glibenclamide, phentolamine and ciclazindol. All K+ channel openers accelerated the decline in function induced by intermittent tetanic contractions following metabolic inhibition and delayed the development of contracture. Cromakalim also improved the recovery of twitch tension following 10 min intermittent tetanic stimulation in the hypoxic guinea-pig diaphragm preparation. Of the K+ channel inhibitors tested, only ciclazindol, at the highest concentration tested (10 microM), significantly delayed the decline in tetanic tension following metabolic inhibition in the guinea-pig isolated diaphragm. None of the inhibitors significantly accelerated the development of contracture. All inhibitors however, antagonised the actions of the K+ channel opener, cromakalim. The results indicate that opening of KATP can accelerate the decline in function following metabolic inhibition in the guinea-pig isolated diaphragm. In the absence of K+ channel openers however, KATP does not appear to contribute to this decline under the conditions of the present study.

Adenosine Triphosphate↗
PubMed1996

Gross anatomic evidence of partitioning in the human fibularis longus and brevis muscles.

Evidence from a variety of studies suggests that many mammalian muscles are partitioned with respect to their architecture and innervation. Each of these specific muscle subvolumes is innervated by an individual muscle nerve branch, contains motor unit territories with a unique array of physiological attributes and has been known as a neuromuscular compartment or segment. This gross anatomic study investigated for evidence of neuromuscular segmentation in human fibularis (peroneus) longus and brevis muscles. Forty-three legs (24 left, 19 right) from embalmed adult cadavers were dissected. Any architectural segment within these muscles were identified. The specific innervation patterns of these muscles were also described. The fibularis longus muscle was consistently found to have connective tissue partitions that separated it into four parts: anterior superficial, anterior deep, posterior superficial, and posterior deep. The innervation pattern of this muscle was consistent with the segments defined by the connective tissue partitions. There were consistently four primary motor branches, each supplying a specific portion of the fibularis longus muscle. While a typical branching pattern was recognized, there was some variability as to the order of these branches as they originated. The fibularis brevis muscle was consistently found to have a central connective tissue partition that separated it into two portions: anterior and posterior. In 91% of the fibularis brevis muscles, there were two primary motor branches, one for each of the two segments of the muscle. In the other 9%, only one primary motor branch supplying the muscle could be identified.

Adult↗
PubMed1996

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study.

OBJECTIVES: To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer. METHODS: Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. RESULTS: Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. CONCLUSIONS: Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

Aged↗
PubMed1996

Activity of the adrenal fetal zone in preterm infants continues to term.

In term babies, steroids from the fetal zone of the adrenal gland decline in the blood and urine in the first few weeks after birth. In infants born prematurely, fetal zone steroids (3 beta-OH-5ene steroids) persist but it is not known for how long. The present study set out to address this by examining changes in the synthesis and metabolism of adrenal steroids with postconceptional age, using serial measurements of steroid metabolites in the urine. 21 preterm infants, median gestation 29 weeks (range 24-31 weeks) and median birth weight 933g were examined. 3 beta-OH-5ene steroids represented around 90% of the total steroids excreted until 2 weeks past term, falling to 55% by 12 weeks after term. 3 beta-OH-5ene steroids were excreted in the urine at levels of 1500-2000 micrograms kg-1 d-1, until 3-4 weeks past term, after which these urinary fetal zone steroid metabolites declined, falling to 500 micrograms kg-1 d-1 six weeks past term. We conclude that activity of the adrenal fetal zone in preterm infants continues to term, after which it diminishes. This suggests that it is gestation that determines fetal zone activity rather than birth.

Adrenal Cortex↗
PubMed1996

Genetic analysis of TAP2 in systemic lupus erythematosus patients from two ethnic groups.

The aim of this study was to determine whether the TAP2 (Transporter associated with Antigen Processing 2) locus is involved in susceptibility to systemic lupus erythematosus (SLE). We adopted the interethnic approach to overcome problems in the analysis resulting from linkage disequilibrium. The TAP2 gene polymorphisms of the codons corresponding to amino acid positions 379, 565 and 665 were investigated by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) in 186 patients (151 white Europeans, 35 Afrocaribbeans) and 183 controls (79 white Europeans, 104 Afrocaribbeans). In the European SLE patients, the frequency of the TAP2 type V-A-TA was marginally lower compared with the control group (31% vs 42%), with negative linkage disequilibrium between this TAP2 type and DR3 probably accounting for the difference. For the European SLE patients, we confirmed a significant association of DR3 with disease status [odds ratio = 4.16, 95% confidence interval (CI), 2.08-8.39] and in the patients with DR3 there was a significantly high frequency of the TAP2 type V-A-T-. In the Afrocaribbean SLE patients, any associations of disease status with TAP2 phenotype were the inverse of those in the European patients. Thus, in these patients the frequency of V-A-TA was higher than in controls (46% vs 26%, OR = 2.4, 95% CI 1.01-5.74), while the frequency of V-A-T- was lower (26% vs 40%, not significant). Despite possible sampling error, the lack of a difference in TAP2 status between cases and controls within ethnic groups and, if anything, an inverse association across ethnic groups, makes it unlikely that the TAP2 polymorphism studied here is of primary relevance to SLE susceptibility.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

The relationship of thoracic lymphadenopathy to pulmonary interstitial disease in diffuse and limited systemic sclerosis: CT findings.

OBJECTIVE: Mediastinal lymphadenopathy is frequently associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). This study compared the extent of lymphadenopathy in diffuse and limited SSc with the presence and type of ILD found on CT scans. SUBJECTS AND METHODS: Seventy-three patients with diffuse and limited SSc underwent thoracic CT. The presence of lymphadenopathy was correlated with the frequency and type of ILD. RESULTS: Fifty-eight percent (18/31) of patients with diffuse cutaneous SSc and 40% (17/42) of patients with limited cutaneous SSc had lymphadenopathy. A significant relationship was found between lymphadenopathy and the presence of interstitial disease (p = .0002). Seventy-two percent (18/25) of patients with a ground-glass parenchymal pattern of interstitial disease and 74% (14/19) of patients with a honeycomb pattern had lymphadenopathy. CONCLUSION: Lymphadenopathy is prevalent in patients with SSc and ILD regardless of clinical subtype or interstitial pattern. Lymphadenopathy appears to increase as a function of the profusion rather than the morphology of ILD.

Female↗
PubMed1995

Calcium dependent K-channels in guinea pig and human urinary bladder.

This study provides evidence for the presence of large conductance Ca(2+)-dependent K-channels in guinea pig and human urinary bladder smooth muscle. A23187, a Ca(2+)-ionophore, increased charybdotoxin and iberiatoxin sensitive 42K efflux in human urinary bladder smooth muscle cells, suggesting that large conductance Ca(2+)-dependent K-channels are present in these cells. NS004, a large conductance Ca(2+)-dependent K-channel opener, relaxed guinea pig bladder strips precontracted with 15 mM KCl which is inhibited by iberiatoxin. In addition, NS004 also evoked an iberiatoxin sensitive increase in 86Rb/42K efflux in guinea pig and human urinary bladder smooth muscle cells, demonstrating that NS004 activates large conductance Ca(2+)-dependent K-channels to achieve its relaxation effect in the bladder.

Animals↗