The hard choice facing Australian GPs.
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Australia↗
Biomedical subjects
S Cohen
Publications and source records attributed to S Cohen.
Prolonged leaching time of peptide antibiotics from acrylic bone cement.
The leaching time of antibiotics in growth inhibitory concentrations from polyacrylic bone cements was determined using Escherichia coli, methicillin resistant Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, and Pseudomonas aeruginosa as target bacteria. The leaching time of the peptide antibiotics vancomycin and polymyxin B nonapeptide was considerably longer than that of gentamicin, novobiocin, and erythromycin. Among the nonpeptide antibiotics, the leaching time of novobiocin lasted longer than did that of gentamicin. The acylated parent polymyxin B antibiotic leached for a considerably shorter period than did the deacylated polymyxin B nonapeptide derivative, suggesting that the lipids impede the leaching process from the cement. Cement beads impregnated with polymyxin B nonapeptide and introduced into the tibia of three rabbits receiving oral novobiocin protected bone infection against a challenge of Pseudomonas aeruginosa that otherwise caused infection in tibias containing gentamicin impregnated cement beads. The peptide antibiotics alone or in combination with other antibiotics (polymyxin B nonapeptide and novobiocin) impregnated in cements for orthopaedic procedures may provide longer periods of protection against a wide range of bacterial pathogens.
Acrylates↗
Telomeric repeats on small polydisperse circular DNA (spcDNA) and genomic instability.
Small polydisperse circular DNA (spcDNA) is a heterogeneous population of extrachromosomal circular molecules present in a large variety of eukaryotic cells. Elevated amounts of total spcDNA are related to endogenous and induced genomic instability in rodent and human cells. We suggested spcDNA as a novel marker for genomic instability, and speculated that spcDNA might serve as a mutator. In this study, we examine the presence of telomeric sequences on spcDNA. We report for the first time the appearance of telomeric repeats in spcDNA molecules (tel-spcDNA) in rodent and human cells. Restriction enzyme analysis indicates that tel-spcDNA molecules harbor mostly, if not exclusively, telomeric repeats. In rodent cells, tel-spcDNA levels are higher in transformed than in normal cells and are enhanced by treatment with carcinogen. Tel-spcDNA is also detected in some human tumors and cell lines, but not in others. We suggest, that its levels in human cells may be primarily related to the amount of the chromosomal telomeric sequences. Tel-spcDNA may serve as a unique mutator, through specific mechanisms related to the telomeric repeats, which distinguish it from the total heterogeneous spcDNA population. It may affect telomere dynamics and genomic instability by clastogenic events, alterations of telomere size and sequestration of telomeric proteins.
Animals↗
Nucleolar localization of mouse mammary tumor virus proteins in T-cell lymphomas.
To characterize novel proteins expressed in lymphoma cells, monoclonal antibodies (MAbs) were raised against variant S49 mouse lymphoma cells. Immunoperoxidase analysis with a specific MAb, named M-66, revealed nuclear localization with prominent staining in the nucleoli of both tumorigenic (T-63) cells and nontumorigenic, immunogenic (T-25-Adh) cells. Weak signals were also observed in the cytoplasm and plasma membrane of both cells. Western blot analysis with M-66 antibody revealed a 14-kDa protein in nuclear extracts of both T-25-Adh and T-63 cells. An additional nuclear 21-kDa protein was evident only in T-63 cells. M-66 identified several clones from a T-25-Adh cDNA expression library. These clones demonstrated extensive homology (approximately 95% identity throughout their length) to the mouse mammary tumor virus (MMTV) env and LTR regions. Extensive amino acid sequence homology (approximately 90% identity) between the clones and the env protein was observed. M-66 identified the 14-kDa protein in another MMTV bearing T-cell lymphoma, EL-4. Immunoperoxidase analysis of EL-4 cells with M-66 also revealed prominent nucleolar staining. MMTV-negative cells and MMTV-positive cells of nonlymphocytic origin were devoid of both 14- and 21-kDa proteins. Moreover, an anti-MMTV gp52 (env) antibody precipitated the 21-kDa protein in T-63 cells. We thus suggest that MMTV bearing T-cell lymphomas express nucleolar proteins translated from the env region of MMTV.
Amino Acid Sequence↗
Psychologic stress, immunity, and cancer.
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Humans↗
Protein phosphorylation associated with epipodophyllotoxin-induced apoptosis of lymphoid cells: role of a serine/threonine protein kinase.
We have previously shown that apoptosis induced in thymocytes by dexamethasone or teniposide (VM-26) could be inhibited by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) and sangivamycin, both relatively specific inhibitors for protein kinase C, but not by N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004), a more specific inhibitor for cAMP-dependent protein kinases. Apoptosis in this model system was not blocked by EGTA and no increase in cytosolic Ca2+ was observed during apoptosis induced by either dexamethasone or VM-26, suggesting that this kinase was Ca2+-independent. In the present study, we demonstrate that addition of 10 microM sangivamycin to thymocyte cultures up to 2 h after addition of either inducer resulted in virtually complete inhibition of apoptosis. Addition of 10 microM sangivamycin at 3 or 4 h after addition of inducer resulted in partial inhibition of apoptosis. Computerized image analysis of two-dimensional PAGE analyses of whole-cell lysates demonstrated that treatment of mouse thymocytes with VM-26 resulted in a limited number of de novo phosphorylation events within 1 h of treatment. The most prominent phosphorylation events associated with VM-26-induced apoptosis were that two intracellular protein species (Protein 1: m.w. = 22.9 kDa, pI, 5.11; and Protein 2: m.w. = 22.9 kDa, pI, 4.98). Similar phosphorylation events were seen in cells treated with dexamethasone. Finally, Western blot analysis suggests that de novo protein phosphorylation induced by VM-26 is on serine/threonine residues. These results provide further evidence that the mechanism of VM-26-induced apoptosis of murine thymocytes involves the action of one or more serine/threonine kinases.
Animals↗
U.S. Environmental Protection Agency's revised cancer guidelines for carcinogen risk assessment.
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Animals↗
Effects of N-propargyl-1-(R)aminoindan (rasagiline) in models of motor and cognition disorders.
N-propargyl-1-(R)aminoindan (rasagiline) is a new and selective irreversible MAO-B inhibitor, currently being considered as the mesylate salt for potential therapy in certain neurological disorders. It has been studied in animal models of cognition and motor dysfunction. Its ability to restore normal motor activity was determined in models of acute drug-induced dopaminergic dysfunction: Its effects in improving cognition and memory deficits was studied in adult and senescent rats that had been exposed to prolonged hypoxia, then subjected to the passive and active avoidance tests. In alpha-methyl-p-tyrosine (alpha-MpT)-induced hypokinesia (100-120 mg/kg, i.p.) pretreatment with rasagiline at 2.5 mg/kg i.p. restored motor activity to control level. But pretreatment with reserpine abolished the protective effect of rasagiline. Rasagiline at 0.5 mg/kg/day was protective against alpha-MpT also in hypoxia-lesioned rats. In haloperidol-induced catalepsy in rats (1.5 mg/kg, s.c.) or mice (4-6 mg/kg s.c.), rasagiline improved recovery of normal locomotion, gait and coordination at 0.4-2.4 mg/kg i.p. and 1.8-1.5 mg/kg i.p., respectively. In amphetamine-induced stereotypy (0.6 mg/kg s.c., rasagiline potentiated this effect at 1.5 mg/kg i.p. In hypoxia-induced impairment of memory and learning, rasagiline at 0.32-0.5 mg/kg/day per os improved performance of adult rats in passive and active avoidance, and of senescent rats in active avoidance. Selegiline was either ineffective or less effective at equivalent doses. Racemic N-propargyl-1-aminoindan (AGN-1135), besides being of lower potency, had a different dose-dependency than rasagiline in antagonizing haloperidol-induced catalepsy or alpha-MpT-induced hypokinesia. 1-(R)aminoindan ((R)AI), a metabolite of rasagiline, in relatively high doses produced effects that were distinct in certain respects from those of rasagiline.
Aging↗
Assessment of T2- and T1-weighted MRI brain lesion load in patients with subcortical vascular encephalopathy.
Previous cross-sectional studies in patients with subcortical vascular encephalopathy (SVE) have shown little or no correlation between brain lesion load and clinical disability, which could be due to the low specificity of T2-weighted MRI. Recent studies have indicated that T1-weighted MRI may be more specific than T2-weighted MRI for severe tissue destruction. We studied 37 patients with a diagnosis of SVE and 11 normal controls with standardised T1- and T2-weighted MRI. All patients underwent detailed clinical assessment including a neuropsychological test battery and computerised gait analysis. Both the T2- and T1-weighted total MRI lesion loads different between patients and controls different, particularly T1. The ratio of T2-/T1-weighted lesion load was lower in controls than in patients. There was no overall correlation of T1- or T2-weighted lesion load with clinical disability, but group comparison of patients with severe and mild clinical deficits showed different lesion loads. We suggest that T1- and T2-weighted MRI lesion loads demonstrate relevant structural abnormality in patients with SVE.
Aged↗
Sparing by rasagiline (TVP-1012) of cholinergic functions and behavior in the postnatal anoxia rat.
Rasagiline (N-propargyl-1(R)aminoindan) is a selective and potent MAO-B inhibitor currently under development as the mesylate salt (TVP-1012) for the treatment of various neurologic disorders. Preliminary work in adult and senescent rats, either normal or hypoxia-lesioned, showed that chronic rasagiline treatment improved performance in memory and learning tasks, suggesting some beneficial effect on central cholinergic function. We have now used the postnatal anoxia-lesioned rat as a model of cholinergic dysfunction. In the neonatal rat, anoxia strongly affects the cholinergic system, which has not yet reached full maturation at this state of life. Rasagiline mesylate was administered from day 1 to completion of the study (day 60), first through nursing mother milk until weaning (day 21), then in drinking water, at the rate of 0.5 mg/kg/day. Drug access to the CNS was verified by analysis of MAO activity in brain (at 21 days). Treatment improved the juvenile hyperactivity syndrome associated with anoxia (at day 28). It improved performance in the passive avoidance test to normal control level (at day 40). It improved spatial memory performance in the Morris water maze to normal control level (at day 50). The untreated anoxia group failed in these tasks and was significantly inferior to either the normal control and rasagiline-treated anoxia groups. Determination of ChAT activity in the caudate and hippocampus of rats from each of these groups gave the following results (pmol ACh/mg protein/min). Caudate: normal control, 588 +/- 56; anoxia, 398 +/- 54; rasagiline-treated anoxia, 536 +/- 35. Hippocampus: normal control, 380 +/- 31; anoxia, 275 +/- 47; rasagiline-treated anoxia, 325 +/- 35. Results are mean +/- SD from each of seven to nine different donors in a group. Thus, improvement in memory and learning tasks of the rasagiline-treated anoxia group finds correspondence in the activity of the cholinergic marker ChAT in two brain regions that have prominent cholinergic innervation.
Animals↗
Comparison of various in vitro susceptibility methods for testing Stenotrophomonas maltophilia.
A total of 57 clinical isolates were screened by disk diffusion for a related pharmacodynamic study. Testing was performed using National Committee for Clinical Laboratory Standards guidelines, except that results were interpreted at 16 to 18 h and 48 h. Of the 57 isolates, 19 were randomly chosen for additional comparative susceptibility testing of five methods (disk diffusion, Etest, Alamar colorimetric broth microdilution, Vitek, and MicroScan) and an in-house broth microdilution method. The two diffusion methods (disk and Etest) had the closest correlation. The commercial broth microdilution methods and the in-house microdilution method generated inconsistent results for all agents except trimethoprim-sulfamethoxazole. Vitek compared poorly with both diffusion and microbroth dilution methods. The most significant discrepancies were evident with all methods when the incubation period was extended to 48 h. When results were interpreted at 48 h, the incidence of resistance for all bactericidal agents was approximately double the resistance observed at 16 to 18 h. The bacteriostatic agents, trimethoprim-sulfamethoxazole and doxycycline, demonstrated the greatest in vitro activity and were least influenced by extended incubation with diffusion methods. Because correlative in vivo and in vitro studies have not revealed an effective therapeutic regimen for serious S. maltophilia infections, susceptibility results with all testing methods should be interpreted with caution when choosing therapy for patients with life-threatening infections. Susceptibility testing for this heterogeneous group remains controversial and routine testing, with the possible exception of doxycycline (or minocycline) and trimethoprim-sulfamethoxazole, should be avoided. Our data support that if testing is done with bactericidal agents, consideration should be given to interpretation after 48-h incubation.
Anti-Bacterial Agents↗
Types of stressors that increase susceptibility to the common cold in healthy adults.
Two-hundred seventy-six volunteers completed a life stressor interview and psychological questionnaires and provided blood and urine samples. They were then inoculated with common cold viruses and monitored for the onset of disease. Although severe acute stressful life events (less than 1 month long) were not associated with developing colds, severe chronic stressors (1 month or longer) were associated with a substantial increase in risk of disease. This relation was attributable primarily to under- or unemployment and to enduring interpersonal difficulties with family or friends. The association between chronic stressors and susceptibility to colds could not be fully explained by differences among stressed and nonstressed persons in social network characteristics, personality, health practices, or prechallenge endocrine or immune measures.
Adolescent↗
Effect of exogenous adenosine and its monophosphate on the contractile response to acetylcholine in the human isolated detrusor muscle strips.
1. Adenosine (0.1-1 mM) or its 5'-monophosphate (5'-AMP) induced a concentration-dependent relaxation of tension caused by acetylcholine (0.2 microM) in human urinary bladder detrusor strips. 2. This effect was antagonized concentration dependently by theophylline at an apparent pA2 value of about 5. 3. Maximum relaxation by adenosine or 5'-AMP never exceeded 50% and 80%, respectively, of acetylcholine-induced tension. Relaxation by some beta2-adrenoceptor agonists (0.1-0.2 mM) or norepinephrine was limited to about 50% of maximum. 4. The responses to adenosine and terbutaline were additive, causing full relaxation, and suggesting mobilization of distinct mechanisms underlying muscle relaxation.
Acetylcholine↗
Middle cerebral artery occlusion in the rat: consistent protocol for a model of stroke.
Variability in the effects of the intraluminal suture method of middle cerebral artery occlusion (MCAO) in the rat has been a common and disadvantageous finding. Therefore, we systematically investigated the effects of suture type and rat strain on outcome. First, the clinical and neuropathological effects of permanent MCAO with either an uncoated or a silicone-coated nylon suture were studied over 7 days in Sprague-Dawley rats (n = 36 for each type of suture). Outcome was less severe with the uncoated compared with the silicone-coated suture (e.g. total cerebral infarct volume at 24 h before any fatalities was 119.9 +/- 79.8 mm3, cf. 183.0 +/- 36.5 mm3, n = 12 for each, P < 0.05; and overall mortality rate was 12.5% cf. 33%, respectively), but much more variable (coefficient of variation was 66.6% cf. 19.9%, respectively). Second, being more consistent in its effects, the silicone-coated suture was further studied in Wistar and Fischer-344 rats (n = 12 for each). Seventy-five per cent of the Wistar's died prematurely from gross hemispheric oedema. Motor deficit and extent of infarction in the Fischer-344 rats were both significantly greater compared with Sprague-Dawley rats (e.g. total cerebral infarct volume at 24 h in the former was 253.6 +/- 25.4 mm3, n = 11, P < 0.05), and more consistent (coefficient of variation was only 10.0%). It was concluded that the silicone-coated suture and the Fischer-344 rats strain produced the most consistent results and their novel combination provides a reliable acute stroke model.
Animals↗
Prechallenge antibodies moderate disease expression in adults experimentally exposed to rhinovirus strain hanks.
This double-blind study determined the influence of serum neutralizing antibody titers on the rate of infection and magnitude of disease expression after experimental exposure of adult volunteers to rhinovirus strain Hanks (RV-H). A total of 133 healthy volunteers were tested for antibody status, cloistered for a 6-day period, and challenged with RV-H at the end of the first cloister day. On these days, response to viral challenge is assessed with symptom diaries and physical examinations. The low-titer infected group was significantly different from the intermediate-titer infected and the uninfected groups in terms of postchallenge nasal and throat symptoms, expelled secretion weights, nasal mucociliary clearance rates, and frequency of negative middle ear pressures. A similar trend held for the infected high-titer vs. low-titer group comparisons. These data show that high homotypic serum neutralizing antibody titers are associated with protection from infection and lessened signs and symptoms following experimental RV-H exposure.
Adult↗
Study of a needleless intermittent intravenous-access system for peripheral infusions: analysis of staff, patient, and institutional outcomes.
OBJECTIVE: To assess the effect on staff- and patient-related complications of a needleless intermittent intravenous access system with a reflux valve for peripheral infusions. DESIGN: A 6-month cross-over clinical trial (phase I, 13 weeks; phase II, 12 weeks) of a needleless intermittent intravenous access system (NL; study device) compared to a conventional heparin-lock system (CHL, control device) was performed during 1991 on 16 medical and surgical units. A random selection of patients was assessed for local intravenous-site complications; all patients were assessed for the development of nosocomial bacteremia and device-related complications. Staff were assessed for percutaneous injuries and participated in completion of product evaluations. A cost analysis of the study compared to the control device was performed. SETTING: A 1,100-bed, teaching, referral medical center. PATIENTS AND STAFF PARTICIPANTS: 594 patients during 602 patient admissions, comprising a random sample of all patients with a study or control device inserted within a previous 24-hour period on study and control units, were assessed for local complications. The 16 units included adult inpatient general medicine, surgical, and subspecialty units. Pediatrics, obstetrics-gynecology, and intensive-care units were excluded. All patients on study and control units were assessed for development of nosocomial bacteremia and device-related complications. All staff who utilized, manipulated, or may have been exposed to sharps on study and control units were assessed for percutaneous injuries. Nursing staff completed product evaluations. INTERVENTION: The study device, a needleless intermittent intravenous access system with a reflux valve, was compared to the control device, a conventional heparin lock, for peripheral infusions. RESULTS: During the study, 35 percutaneous injuries were reported. Eight injuries were CHL-related; no NL-related injuries were reported (P=.007). An evaluation of 602 patient admissions, 1,134 intermittent access devices, and 2,268 observed indwelling device days demonstrated more pain at the insertion site for CHL than NL; however, no differences in objective signs of phlebitis were noted. Of 773 episodes of positive blood cultures on study and control units, 6 (0.8%) were device-related (assessed by blinded investigator), with no difference between NL and CHL. Complications, including difficulty with infusion (P<.001) and disconnection of intravenous tubing from device (P<.001), were reported more frequently with CHL than with NL. Of nursing staff responding to a product evaluation survey, 95.2% preferred the study over control device. The projected annual incremental cost to our institution for hospitalwide implementation of NL for intermittent access for peripheral infusions was estimated at $82,845, or $230 per 1,000 patient days. CONCLUSIONS: A needleless intermittent intravenous access system with a reflux valve for peripheral infusions is effective in reducing percutaneous injuries to staff and is not associated with an increase in either insertion-site complications or nosocomial bacteremia. Institutions should consider these data, available institutional resources, and institution-specific data regarding the frequency and risk of intermittent access-device-related injuries and other types of sharps injuries in their staff when selecting the above or other safety devices.
Anticoagulants↗
Bupivacaine 0.01% and/or epinephrine 0.5 microg/ml improve epidural fentanyl analgesia after cesarean section.
BACKGROUND: The authors studied the addition of bupivacaine and epinephrine, separately and together, to epidural fentanyl to determine whether this improved postcesarean analgesia and reduced the incidence of side effects. METHODS: After elective cesarean section, 100 parturient patients who received fentanyl (3 microg/ml) epidurally for 48 h were allocated randomly in a double-blinded manner to four groups to receive, in addition to the study solution, 0.01% bupivacaine, 0.5 microg/ml epinephrine, both, or neither. A neurologic assessment of breast-fed neonates was made at 2 and 48 h of life. Plasma fentanyl concentrations were determined in a subset of patients at intervals after treatment. RESULTS: Patients receiving fentanyl alone made more attempts at patient-controlled analgesia (P < 0.01), required a greater total dose of fentanyl (P < 0.01), reported more pain (P < 0.003) and less satisfaction (P < 0.003), and had more nausea and urinary retention (P < 0.05) than all other groups. Patients who received bupivacaine with or without epinephrine had better overall satisfaction scores than those who did not receive bupivacaine (P < 0.001), and they required less fentanyl (P < 0.02) than patients who received fentanyl with only epinephrine. Motor blockade or orthostatic hypotension did not develop in any patient, and all patients could ambulate without difficulty. Neurobehavioral scores, which were similar among all neonates, were within the normal range. Plasma concentrations of fentanyl increased after epinephrine-containing solutions were discontinued. CONCLUSIONS: During the conditions of this study, the addition of epinephrine and bupivacaine to a 3-microg/ml epidural fentanyl solution for postcesarean section pain relief provided superior analgesia compared with fentanyl alone or fentanyl with epinephrine. Whether increasing the concentration of fentanyl alone might improve the efficacy of fentanyl remains unclear.
Adult↗
The total volar forearm musculocutaneous free flap for reconstruction of extended forequarter amputations.
Forequarter amputation is performed for resection of large, invasive tumors of the shoulder girdle region. A substantial defect can usually be closed with local or regional flaps; however, a subset of the forequarter amputation group has emerged at this institution with more complex issues. These patients have extensively more invasive posterior tumors, some with chest wall/rib invasion. Local/regional flaps in these situations are inadequate, and free tissue transfer is the only viable option. The forequarter specimen can sometimes be used as a donor site, thereby eliminating the usual donor site morbidity. Variations of the total forearm free flap have been sparsely described in the literature--the majority being case reports of either pure fasciocutaneous or "filet of forearm" flaps. We report a series of 4 patients treated over a 5 year period at this institution using the previously undescribed total volar forearm musculocutaneous free flap based on the brachial artery and its venae comitantes. This flap includes the entire musculature of the volar forearm with fasciocutaneous extensions on either side of the musculocutaneous unit. All potentially ischemic dorsal musculature is discarded, leaving a flap that has central bulk and a relatively large dimension. The entire flap remains extremely well vascularized, and a substantial surface area of as much as 45 x 25 cm can be attained. A pedicle as long as 20 cm can be dissected as far proximally in the arm as is oncologically safe. A single artery and vein are anastomosed to either the intrathoracic or neck vessels. All four flaps survived completely with uncomplicated wound healing. The total volar forearm musculocutaneous flap is extremely well vascularized and highly reliable. The flap as described provides the ideal combination of large surface area, muscle bulk, and long vascular pedicle. It can be dissected rapidly to minimize ischemic time and could therefore be applicable to traumatic forequarter amputations. It has become the flap of choice for reconstruction of extended oncological forequarter amputation defects.
Adult↗