Biomedical subjects
Publications and source records attributed to K McCormick.
A 12-year-old girl had a severe genu valgum deformity and osteomalacia with hypophosphatemia, hypercalciuria, and modestly elevated levels of 1,25-dihydroxyvitamin D3 and intact parathyroid hormone. This patient seems to have a different type of hypophosphatemic osteomalacia from that previously described.
The Urinary Incontinence in Adults Guideline Panel facilitated the ready elucidation of its guideline's management recommendations through the use of an annotated algorithm approach. The algorithms created as part of this guideline differ from previous algorithms in two ways: (1) they employ systematic annotation to link explicitly the algorithms' recommendations to the literature, and (2) they contain patient counseling and decision nodes to depict the major preference-dependent decision or branch points in the algorithm. We believe that these two innovations can help ensure the clinical validity of guidelines' algorithms while preserving appropriate clinical flexibility and respecting patient preferences.
A significant proportion of women with epilepsy have an increase in their seizure frequency during pregnancy. Multiple factors may be involved in this phenomenon, but changes in antiepileptic drug (AED) concentration appear to be the most significant. AED concentration declines as pregnancy progresses, due primarily to dynamic changes in plasma protein binding. Total concentrations of all first-line AEDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) fall significantly during pregnancy, compared to baseline. Free or unbound drug concentrations, however, fall significantly only for phenobarbital. Valproate free concentrations actually increase by 25% by delivery. Women taking carbamazepine, phenytoin, or valproate may be relatively protected by adequate free concentrations of these compounds. When managing pregnant women with epilepsy, measurement of free AED concentrations and appropriate dose adjustment to maintain therapeutic ranges will permit more effective clinical management than using total concentration values.
Sex differences are known to exist in the metabolism and bioavailability of trichloroethylene (TCE). This study revealed that dermal penetration of [14C]TCE in vitro was twofold greater in untreated female than in untreated male Sprague-Dawley rats. Since testosterone has been shown to mediate a wide variety of sex differences, its role in dermal penetration of [14C]TCE was investigated. Penetration was measured by using an in vitro evaporation-penetration cell with a 10-hr collection period. Depriving male rats of testosterone (by castration) resulted in increased values for total penetration, area under the curve (AUC), and penetration slopes compared to those for male control animals. The values for male animals deprived of testosterone approached those found in the female control group. Administration of testosterone to female animals produced values for total penetration, AUC, and penetration slopes significantly lower than those of the female control group.
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In this study, recombinant human IL-1 alpha (rhIL-1 alpha) was used to protect normal and tumor-bearing BALB/c mice from the acute toxicity caused by lethal doses of cyclophosphamide (Cy) and 5-fluorouracil. Pretreatment of mice for 7 days with 10,000 U/day of rhIL-1 alpha protected 70 to 100% of mice from the acute death induced by lethal doses of both Cy (380 mg/kg) and 5-fluorouracil (250 mg/kg). In contrast, post-treatment of mice with single or multiple doses of rhIL-1 alpha was not chemoprotective. Pretreatment of mice with rhIL-1 alpha increased the acute LD90 of Cy from 380 mg/kg to greater than 500 mg/kg in normal mice, an LD90 dose-modifying effect of at least 1.25, was accompanied by a more rapid recovery from neutropenia and a less severe reduction in the number of bone marrow single lineage monocyte, myeloid, or myelomonocytic colonies. Some of the mice (10 to 50%) that were successfully protected by pretreatment with rhIL-1 alpha died after day 50. These mice consistently presented with extensive pulmonary inflammation and fibrosis at death. Mice bearing murine renal cancer (Renca) were also protected from the acute toxic effects of Cy (450 mg/kg) by pretreatment with rhIL-1 alpha. Renca-bearing mice pretreated with rhIL-1 alpha and either sublethal (300 mg/kg) or lethal (450 mg/kg) doses of Cy exhibited enhanced survival times over those of untreated Renca-bearing mice. Interestingly, the cause of death in Renca-bearing mice that ultimately failed treatment with rhIL-1 alpha plus 300 mg/kg Cy was recurrent tumor, whereas most mice treated with rhIL-1 alpha plus 450 mg/kg Cy had no detectable tumor, although several died from late pulmonary inflammation and fibrosis. Thus, the dose escalation of Cy in rhIL-1 alpha-pretreated mice results in greater antitumor effects of Cy. However, the dose escalation of some cytotoxic agents allowed by the use of myelostimulatory agents can result in late fatal complications not detected in acute toxicity testing.
Previous studies have shown that established murine renal cancer (Renca) can be successfully treated with the investigational drug flavone acetic acid (FAA) used in combination with recombinant interleukin 2 (IL-2). Additional experiments demonstrated that the in vivo administration of FAA rapidly induced the expression of the genes, as well as the biologically active proteins, for alpha- and beta-interferons (IFNs) as well as tumor necrosis factor alpha. Both IFN-alpha and IFN-gamma have been shown to have direct antiproliferative effects against some tumors, as well as being potent immunodulators for the induction of antitumor effector cells. Thus, the present study was designed to investigate the ability of IFN-alpha and/or IFN-gamma to mediate direct antiproliferative effects against Renca in vitro as well as to cause regression of Renca in vivo. The present study confirms that RAA and/or IL-2 are inactive against Renca in vitro, further suggesting an indirect mechanism for FAA-induced antitumor effects in vivo. However, the exposure of Renca in vitro to recombinant human IFN-alpha A/D, murine IFN-alpha or murine IFN-beta resulted in a dose dependent growth inhibition of Renca as assessed by the microculture tetrazolium dye incorporation assay. Very little growth inhibition was induced by recombinant murine IFN-gamma. Interestingly, IFN-alpha (100-1000 units/ml) when combined with very low doses of recombinant murine IFN-gamma (1-10 units/ml) yielded significantly more pronounced growth inhibition than either cytokine alone. This effect was most evident by 5 days of culture where combinations of 100-1000 units/ml recombinant human IFN-alpha A/D with 1-5 units/ml recombinant murine IFN-gamma yielded growth inhibition in the range of 45-99%. In order to determine whether the mechanisms for the antitumor activity of recombinant human IFN-alpha A/D and recombinant murine IFN-gamma was due to their direct antiproliferative effects, we also studied the efficacy of these combinations against i.p. Renca in athymic mice. In contrast to the potent antitumor effects observed in euthymic mice, the combination of IFN-alpha and IFN-gamma only slightly increased mean survival times in athymic mice and no long term survivors were obtained. Subsequent studies demonstrated that most mice (77%) cured of peritoneal Renca by recombinant human IFN-alpha A/D plus recombinant murine IFN-gamma were immune to rechallenge. Therefore the combination of IFN-alpha and IFN-gamma may directly inhibit the growth of Renca, but a major effect of IFNs in vivo must be to contribute to the induction of an anti-Renca immune response.
A path analysis model examined interrelationships among variables significantly associated with chronic dyspnea in chronic bronchitis and emphysema (CBE) and the relative influence of these variables on each other and on functional status and quality of life. Results from the 45 adults (mean age, 61) with moderate CBE disease severity showed that dyspnea severity has a sizable effect on functional status and quality of life. Disease severity was more strongly related to functional status than to quality of life. Depression and mastery had the strongest total effects on quality of life. Dyspnea severity had strong but separate effects on functional status and quality of life. From these preliminary results, it is suggested that a direct focus on psychologic interventions to ameliorate depression and improve mastery is likely to improve quality of life with some resultant positive effect on functional status.
Anticonvulsant levels decline as pregnancy progresses, even in the face of constant and, in some cases, increased dosages of medications. It has been suggested that this decline is responsible for the increase in seizure frequency seen in approximately one-third of the women with epilepsy who become pregnant. Changes in plasma protein binding may explain the declines in anticonvulsant concentrations during pregnancy. A prospective cohort study was designed to test this hypothesis. Carbamazepine, phenytoin and phenobarbital were studied. The mean total concentrations of all 3 drugs declined as pregnancy progressed, rising in the postpartum period. Free concentrations also declined, but did so significantly only for phenobarbital. The free fraction for all anticonvulsants studied rose significantly throughout pregnancy. Protein binding is significantly altered during pregnancy for all 3 drugs studied and appears to account for much of the decline in anticonvulsant concentrations seen in this condition. It is suggested that free rather than total drug concentrations be monitored in pregnant women with epilepsy.
Various staff behaviors in a nursing home were sampled seven times a day, 5 days a week over 37 months and were coded separately for LPNs, RNs, and NAs. The behavior most frequently observed was patient care, which occurred during 56.9% of the samples. We observed staff interacting with patients during 10.7% and with other staff during 19.5% of the samples. The LPNs displayed significantly more patient care behaviors and NAs significantly more nonwork behaviors than other nursing staff. RNs displayed the least nonwork behavior. We conclude that nursing staff devote most of their time to patient needs and relatively little time to nonproductive activities.
We developed a staff management system for maintaining treatment gains achieved on a specialized continence unit located in a geriatric nursing home. Geriatric assistants learned to use a prompted voiding procedure to maintain improved dryness for 4 elderly residents. The staff management system included self-monitoring and recording of prompted voiding activities and supervisory monitoring and feedback based on group performance of these activities. Results show that the system was effective in maintaining prompted voiding activities with corresponding maintenance of improved patient continence. However, a gradual decline in staff performance was noted 4 to 5 months after the initiation of the system. During a subsequent phase of the study, provision of individual feedback restored staff performance to previous levels. Results are discussed in relation to the practicality of prompted voiding interventions in nursing home environments and the applicability of staff management systems in this setting.
Nine epileptic women were followed prospectively through pregnancy on a monthly basis. At each visit, total and free serum valproic acid levels and albumin levels were obtained. Assays were done by gas-liquid chromatography, and free drug was separated by ultrafiltration. Despite an upward dose adjustment in four patients, total valproic acid levels declined as pregnancy proceeded, but free levels did not. Plasma free fractions and clearances increased, but intrinsic clearances, which were adjusted for changes in body weight, remained unchanged.
A unique permeabilized adipocyte model is described in which vigorous intracellular intermediary metabolism is preserved through both the pentose and glycolytic-Krebs pathways following saponin-induced pore formation in plasma membranes. Upon addition of appropriate cofactors, the cells metabolize both glucose and glucose 6-phosphate at rates which are severalfold greater than control (membrane-intact) cells. Saponin is shown to mediate these metabolic effects solely by creating membrane pores through which substrate influx occurs. This cell model provides an unprecedented opportunity to examine intermediary metabolism in situ because it permits the entry into the cytosol of previously restricted substrates, modifiers, and radiolabeled compounds. By circumventing the glucose transporter while, for the most part, preserving plasma membrane integrity, these metabolically active, porous adipocytes may permit the direct exploration of postinsulin receptor glucose metabolism by various hormones or drugs.
Although carnitine palmitoyltransferase (CPT) has received considerable attention, particularly its regulation by malonyl CoA, most studies have monitored the forward reaction, ie, the formation of acylcarnitine. We examined the opposite or reverse reaction, in which palmitoyl CoA is generated, in osmotically-disrupted rat hepatic mitochondria. Specifically, the effects of pH, fasting, and untreated recent-onset diabetes were investigated. As with the forward (f) reaction, the CPT reverse (r) velocity v pH curve was somewhat parabolic with a pH maximum at approximately 7.2 (except the CPT that was from the diabetic rats). However, as the pH rose, the CPT reverse and forward curves diverged due to a precipitous decline in the forward reaction. This discordance in rates in the alkaline range was apparent in all three groups of CPT but was most prominent in the diabetic preparation (for example, as the pH increased from 7.3 to 8.8, the respective declines in the f and r velocities were 74% and 2%). In addition, under our assay conditions the CPTr from diabetic rats not only had a higher velocity (55.4 +/- 1.4 nmol/min/mg protein) than that from the fed (32.1 +/- 3.1) or fasted (43.1 +/- 3.4) animals, but also the Vmax was found to be twofold greater, even though there was no difference in the Km for palmitoylcarnitine. In summary, diabetes affects the kinetics of the reverse reaction and, regardless of the animal's premortem condition, but more so in the diabetes, this reaction is less attenuated than the forward one as the pH rises.
1. The effect on fluid homoeostasis of walking 37 km on each of 4 consecutive relatively cool days was studied in six male subjects. The daily exercise intensity was consistent and was equivalent to 17(1)% [mean (SE)] of maximum oxygen uptake for these subjects. 2. The diet during the study consisted of a mainly carbohydrate breakfast, consumed immediately before each day's exercise, and unrestricted access to a normal mixed diet after completion of each day's exercise. Water was allowed ad libitum during the walk. Food and fluid intake were recorded. 3. Body weight remained constant over the 4-day walk. The difference between total daily fluid intake and the corresponding 24 h urine output was 1684 (250) ml, 1621 (522) ml, 1107 (252) ml and 1406 (208) ml, respectively, on each of the 4 exercise days. 4. There was a calculated increase of 21.3(6.6)% in plasma volume over the 4-day walk; the largest daily change [11.3(2.9)%] occurred during the walk on day 1. The increase in plasma volume was maintained for at least 4 days after completion of the walk. 5. From day 2, serum sodium concentration tended to increase during the exercise period and fell to the pre-exercise concentration during the overnight rest periods. The concentration of the other measured serum constituents remained relatively constant, and serum osmolality did not alter over the study period.
Twenty untrained male volunteers were required to run downhill for 45 minutes on a motor driven treadmill to induce muscle soreness. The volunteers took diclofenac or placebo before and for 72 hours after two runs 10 weeks apart, in a randomised double blind crossover design. Subjective soreness was assessed before and at intervals up to 72 hours after each run; venous blood samples, collected at the same time intervals, were used to estimate serum activities of creatine kinase, lactate dehydrogenase and aspartate aminotransferase and serum concentrations of creatinine and urea. Subjective soreness and the biochemical parameters increased after both runs, although the serum enzyme response to the second run was reduced. Diclofenac had no influence on the serum biochemical response to downhill running. Although overall soreness was not affected by diclofenac, individual soreness measurements were reduced by diclofenac at the first period of the study. These results suggest that diclofenac does not influence muscle damage, but may slightly reduce the associated soreness.
Six healthy men walked 37 km (23 miles) per day over a 3-lap course for each of 4 consecutive days. Subjects were allowed breakfast and an unrestricted diet was consumed after completion of the walk, but no food was consumed during or between laps. At a later date the same subjects walked over the same course after an overnight fast and without breakfast. Completion time for each lap was 139 +/- 1 min (mean +/- SE) and exercise intensity was equivalent to 17 +/- 1% VO2max. Mean 24h energy intake was 14.5 +/- 0.8 MJ during the fed walk. Estimated daily energy expenditure was 12.0 MJ. Blood glucose concentration fell significantly on the first, third and fourth days of the fed walk, but no subject became hypoglycaemic. Glucose concentration did not fall during the fasted walk and was significantly higher pre-exercise and at the end of laps one and three when compared to the first day of the fed walk. Blood alanine concentration fell significantly after the end of the first lap of each day of the fed walk but not during the fasted walk. Blood lactate levels did not change during the course of either walk. Plasma free fatty acid, glycerol and blood 3-hydroxybutyrate concentrations were unchanged during the passage of the first lap on each day of the fed walk, but all three had increased significantly by the end of the first lap of the fasted walk.(ABSTRACT TRUNCATED AT 250 WORDS)
A female infant displaying morphological and clinical abnormalities is described. She had severe developmental delay, intrauterine growth retardation, and failure to thrive. Her features included an elfin facies, body and facial hirsutism, buttonlike nipples and prominent clitoris and labia. Endocrinological evaluation revealed markedly elevated serum gonadotropin levels. An LHRH stimulation test showed no LH response to LHRH but a rapid and pronounced FSH response. The patient died at 13 months following a respiratory infection. Postmortem examination revealed normal pituitary histology but an unusual pancreatic histology characterized by total absence of acinar cells. This patient had features suggestive of several clinical syndromes including leprechaunism, Shwachman syndrome, and Johanson-Blizzard syndrome, none of which, was completely satisfied. It is concluded that the infant may represent an atypical case of leprechaunism or a previously undescribed syndrome.