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PubMed1994

Drug therapy in the neonatal foal.

The neonatal period in foals refers to the first 7 days of postnatal life. The effects of drugs (pharmacologic agents) may be different in neonatal foals, particularly during the first 3 days of postnatal life, from those in older foals and adult horses. The changed drug effects decrease as the physiologic processes that affect absorption, distribution, and elimination (metabolism and excretion) of drugs mature. Dosage regimens should take into account the altered pharmacokinetic profiles of drugs, and because of wide individual variation, the response to therapy should be closely monitored for signs of toxicity. In conjunction with the prudent use of drugs, good nursing care and the provision of supportive therapy are critical in the management of neonatal foal diseases. Over-crowding imposes stress upon young foals and predisposes them to an increased incidence of bacterial and parasitic infections. The collection of specimens for precise microbiologic diagnosis and correction of deficits in serum immunoglobulins should precede antimicrobial therapy. Although E. coli is by far the most common cause of bacterial infections in neonatal foals, other bacterial pathogens of unpredictable susceptibility often cause infection. The selection of an antimicrobial drug for specific therapy should be based on both the microbiologic (quantitative susceptibility) and pharmacologic (pharmacokinetic) properties of the drug. The use of an antimicrobial drug or combination of drugs that will produce a bactericidal effect is highly desirable. Whenever possible, a parenteral preparation that can be administered intravenously should be chosen. The bioavailability and selectivity of action of pharmacologic agents are influenced by the dosage form and route of administration. Diazepam is the sedative drug of choice for neonatal foals. Cimetidine, an H2-receptor antagonist, may be indicated in foals diagnosed to have gastric ulcers; hepatic microsomal oxidative metabolism of drugs administered concurrently with cimetidine is decreased. Nonsteroidal anti-inflammatory drugs (flunixin, phenylbutazone) have a higher incidence of toxicity in foals and, when indicated, should be used at lower dosage than in adult horses. Even though it is highly important to maintain hydration status and electrolyte balance, intravenous infusion should always be performed slowly. Immature renal function decreases the ability of the neonatal animal to excrete excess fluid. The use of drugs in neonatal foals requires greater precision in dosage, more attention to the route and rate of administration, and close monitoring of pharmacologic effects.

Animals↗

PubMed2003

Natural freeze-tolerance in hatchling painted turtles?

Hatchlings of the North American painted turtle (Family Emydidae: Chrysemys picta) typically spend their first winter of life inside a shallow, subterranean hibernaculum (the natal nest) where life-threatening conditions of ice and cold commonly occur. Although a popular opinion holds that neonates exploit a tolerance for freezing to survive the rigors of winter, hatchlings are more likely to withstand exposure to ice and cold by avoiding freezing altogether-and to do so without the benefit of an antifreeze. In the interval between hatching by turtles in late summer and the onset of wintery weather in November or December, the integument of the animals becomes highly resistant to the penetration of ice into body compartments from surrounding soil, and the turtles also purge their bodies of catalysts for the formation of ice. These two adjustments, taken together, enable the animals to supercool to temperatures below those that they routinely experience in nature. However, cardiac function in hatchlings is diminished at subzero temperatures, thereby compromising the delivery of oxygen to peripheral tissues and eliciting an increase in reliance by those tissues on anaerobic metabolism for the provision of ATP. The resulting increase in production of lactic acid may disrupt acid/base balance and lead to death even in animals that remain unfrozen. Although an ability to undergo supercooling may be key to survival by overwintering turtles in northerly populations, a similar capacity to resist inoculation and undergo supercooling characterizes animals from a population near the southern limit of distribution, where winters are relatively benign. Thus, the suite of characters enabling hatchlings to withstand exposure to ice and cold may have been acquired prior to the northward dispersal of the species at the end of the Pleistocene, and the characters may not have originated as adaptations specifically to the challenges of winter.

Acclimatization↗

PubMed2005

Impact of high- and low-intensity targeted exercise training on the type of substrate utilization in obese boys submitted to a hypocaloric diet.

BACKGROUND: We assessed the effect of two programs combining a hypocaloric diet with low-intensity (LI) or high-intensity (HI) exercise training, during two months, on substrate utilization at exercise in obese children. METHODS: Fifteen obese boys participated in a combined program of exercise and caloric restriction-induced weight loss (diet starting two weeks before the training program). The maximal fat oxidation point (Lipox max) was determined to individualize exercise training. Training consisted of cycling at either LI (Lipox max) for seven children or HI (Lipoxmax+40% Lipox max) for eight children. RESULTS: All children exhibited a decrease in weight (LI: -5.2 kg +/- 0.7 (P<0.01), HI: -7 kg +/- 0.7 (P<0.01)). While in the LI group, both fat and CHO oxidation were unchanged after training, HI group oxidize less fat and more CHO after training when exercising at 20% and 30% Wmax th (P = 0.02). DISCUSSION: While a LI exercise training program maintains (but does not improve) the ability to oxidize fat at exercise, HI training actually shifts towards CHO the balance of substrate oxidation during exercise. Thus, a low intensity training protocol seems to counteract to some extent the decline in lipid oxidation at exercise that occurs after a hypocaloric diet, and is thus likely to be synergistic to diet in the weight lowering strategy.

Adipose Tissue↗

PubMed2006

Attitudes toward parenthood and awareness of fertility among postgraduate students in Sweden.

BACKGROUND: Postponing childbirth is becoming increasingly common in Western countries, especially among women with higher education. OBJECTIVE: The aim of the present study was to investigate female and male postgraduate students' attitudes toward parenthood, their intentions to have children, perceived obstacles to having or raising children during postgraduate studies, and their awareness of fertility issues. METHODS: A 52-question survey was mailed to randomly selected postgraduate students attending a Swedish university. The questionnaire was developed based on earlier research by, and the professional experience of, the authors. Three pilot studies were conducted to test the questionnaire's reliability and validity. The t, x2, and Mann-Whitney U tests were used, as appropriate, to analyze responses. RESULTS: Two hundred female and 200 male postgraduate students aged<or=40 years received questionnaires. The response rate was 71% (n=141) among women and 58% (n=116) among men. Most childless respondents had positive attitudes toward parenthood and wanted to have 2 or 3 children, and a majority of women wanted to have their last child after age 35. Compared with men, women were more pessimistic about the effects of parenthood on their postgraduate studies, and perceived more problems related to balancing work and family life. One of 4 respondents overestimated a woman's ability to become pregnant between 35 and 40 years of age, and about half had overly optimistic perceptions of the chances to have a baby by means of in vitro fertilization. CONCLUSIONS: Most postgraduate students wanted to have children in the future. More women than men perceived that having children while completing postgraduate studies was or would be difficult, and that parenthood would negatively affect their status in the labor market. Because many female postgraduate students intend to have children at an age when female fecundity is decreased, information on fertility issues would help them make informed decisions regarding family planning.

Adult↗

PubMed1995

Three-dimensional quantitative structure-activity relationships of dioxins and dioxin-like compounds: model validation and Ah receptor characterization.

In the present study we have utilized comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship paradigm, to explore the physico-chemical requirements for binding to the Ah (dioxin) receptor. Recent developments by Gillner et al. [(1993) Mol. Pharmacol. 44, 336-345] prompted us to review and revise our previous CoMFA/QSAR model [Waller, C. L., and McKinney, J. D. (1992) J. Med. Chem. 36, 3660-3666] to include a structurally-diverse training set of Ah receptor ligands ranging in size from naphthalene to indolo[3,2-b]carbazole nuclei. An exhaustive validation process utilizing external test sets and hierarchical cluster analysis routines was employed during model construction and is discussed herein. The limitations of the approach presented herein are discussed with respect to predictive ability of the CoMFA/QSAR models, which is demonstrated to be dependent on a balance between structural diversity and redundancy in the molecules comprising the training set. The results of our modified CoMFA/QSAR model are consistent with and unify all previously established structure-activity relationships established for less structurally-diverse training sets of Ah receptor ligands. As a result of the more complete nature of the series of molecules under examination in the present study, the CoMFA/QSAR steric and electrostatic field contour plots as well as the essential and excluded volume plots provide for a more detailed characterization of the molecular binding domain of the Ah receptor. The implications of the CoMFA/QSAR model presented herein are explored with respect to quantitative hazard identification of potential toxicants.

Binding Sites↗

PubMed2002

Pathophysiologic basis for normouricosuric uric acid nephrolithiasis.

BACKGROUND: Low urinary pH is the commonest and by far the most important factor in uric acid nephrolithiasis but the reason(s) for this defect is (are) unknown. Patients with uric acid nephrolithaisis have normal acid-base parameters according conventional clinical tests. METHODS: We studied steady-state plasma and urinary parameters of acid-base balance in subjects with normouricosuric pure uric acid stones. We also tested the ability of these subjects to excrete ammonium in response to an acute acid load. We compared these parameters in patients with pure uric acid stones to patients with mixed uric acid/calcium oxalate stones, pure calcium stones, and normal volunteers. RESULTS: Pure uric acid stone formers have a much higher incidence of either diabetes or glucose intolerance. After equilibration to a control diet, patients with uric acid stones have lower urinary pH and they excrete less of their acid as ammonium. This is compensated by higher titratable acidity and hypocitraturia. Despite their low baseline urinary pH, uric acid stone formers further acidify their urine after an acid load because of a severely impaired ammonia excretory response. Their characteristics are significantly different from normal volunteers and pure calcium stone formers. Patients with mixed uric acid/calcium stones exhibit intermediate characteristics. CONCLUSION: We propose that certain patients with normouricosuric uric acid nephrolithiasis have a renal acidification disease. The primary defect lies in renal ammonium excretion, which may be linked to the insulin-resistant state. Although net acid excretion is maintained at the expense of increased titratable acidity and to some degree hypocitraturia, the compromise is acid urine pH and may result in uric acid nephrolithiasis.

Adult↗

PubMed2002

G protein-coupled receptor kinase 4 gene variants in human essential hypertension.

Essential hypertension has a heritability as high as 30-50%, but its genetic cause(s) has not been determined despite intensive investigation. The renal dopaminergic system exerts a pivotal role in maintaining fluid and electrolyte balance and participates in the pathogenesis of genetic hypertension. In genetic hypertension, the ability of dopamine and D(1)-like agonists to increase urinary sodium excretion is impaired. A defective coupling between the D(1) dopamine receptor and the G protein/effector enzyme complex in the proximal tubule of the kidney is the cause of the impaired renal dopaminergic action in genetic rodent and human essential hypertension. We now report that, in human essential hypertension, single nucleotide polymorphisms of a G protein-coupled receptor kinase, GRK4gamma, increase G protein-coupled receptor kinase (GRK) activity and cause the serine phosphorylation and uncoupling of the D(1) receptor from its G protein/effector enzyme complex in the renal proximal tubule and in transfected Chinese hamster ovary cells. Moreover, expressing GRK4gammaA142V but not the wild-type gene in transgenic mice produces hypertension and impairs the diuretic and natriuretic but not the hypotensive effects of D(1)-like agonist stimulation. These findings provide a mechanism for the D(1) receptor coupling defect in the kidney and may explain the inability of the kidney to properly excrete sodium in genetic hypertension.

Animals↗

PubMed2002

Protein SV-IV promotes nitric oxide production not associated with apoptosis in murine macrophages.

SV-IV (seminal vesicle protein no. 4) is a potent immunomodulatory and anti-inflammatory secretory protein (Mr 9758) produced in large amounts by the rat seminal vesicle epithelium. Here we show that this protein possesses the ability to upregulate in J774 macrophages the expression of the gene coding for the inducible nitric oxide synthase (iNOS). The increase in NO production consequent on the marked enhancement of iNOS activity was not associated with apoptotic damage of the SV-IV-treated cells. In the same experimental model, however, LPS induced upregulation of iNOS coupled with an increase in NO production and marked apoptotic death. Differences in the ability of SV-IV and LPS to control the life/ death signal balance in target cells via trans-membrane activation of apoptotic (mediated by TNF-alpha and NO/iNOS system) and anti-apoptotic (mediated by bcl-2, c-myc, etc.) pathways are suggested to be the basis of the apoptotic fate of the experimentally treated cells. In addition, considering the important role played by NO in the process of mammalian reproduction, SV-IV may be involved in the fine tuning of NO concentration in the female genital tract mucosa via an SV-IV-mediated control of iNOS gene expression in local macrophages.

Animals↗

PubMed1993

Interferon gamma inhibits interleukin 10 production by monocytes.

Interleukin 10 (IL-10) was first described for its ability to inhibit interferon gamma (IFN-gamma) production. Herein, we studied the balance between IFN-gamma and IL-10 production by human peripheral blood mononuclear cells (PBMC) in response to Staphylococcus aureus Cowan (SAC) or lipopolysaccharide (LPS). Monocyte depletion reduced IL-10 production by 90% and resulted in an increased IFN-gamma production. Addition of anti-IL-10 antibody to PBMC cultures also strongly increased IFN-gamma production. In contrast, among various cytokines, only IFN-gamma strongly reduced IL-10 synthesis by SAC- or LPS-activated PBMC and monocytes. Thus, IFN-gamma has proinflammatory effects through the combination of two mechanisms: (a) induction of early tumor necrosis factor alpha (TNF-alpha) and IL-1 beta synthesis; and (b) inhibition of the delayed production of IL-10, an inhibitor of TNF-alpha and IL-1 beta synthesis. Taken together, the present data indicate that IFN-gamma and IL-10 antagonize each other's production and function.

Cells, Cultured↗

PubMed1981

Relationship of the xylose absorption status of children in Bangladesh to their absorption of macronutrients from local diets.

We compared the results of xylose absorption tests from 31 asymptomatic Bangladeshi children with their ability to absorb macronutrients from cereal-vegetable diets, as determined by metabolic balance studies. The xylose test results ranged from 9.8 to 37.0% excretion of the ingested dose, with more than half of the values less than 20% excretion. Nevertheless, the apparent absorption of macronutrients during 7-day balance studies ranged from 89.8 to 97.7% of intake for carbohydrate, 81.7 to 98.7% for fat, and 47.3 to 78.9% for nitrogen. There was a statistically significant correlation between the xylose test results and apparent carbohydrate absorption for one diet group only (r = 0.76, p less than 0.05), but not between the xylose results and other indicators of intestinal function of nutrition status. We conclude that diminished absorption of xylose, which is commonly recognized among asymptomatic residents of the tropics, does not necessarily indicate impaired absorption of macronutrients from the customary diet. Therefore, tropical enteropathy may not have major nutritional significance for those individuals with manifestations of the syndrome.

Bangladesh↗

PubMed2002

Alternative metabolic pathways for energy supply and resistance to apoptosis in Fanconi anaemia.

Deregulation of control of the apoptotic process in Fanconi anaemia (FA) appears to be one of the main features of this disease at the cellular level. We show here that FA cells are resistant to treatments with rhodamine-1,2,3 and doxycycline, which both interfere with mitochondrial functionality by different mechanisms. In contrast, normal lymphoblastoid cells are severely affected by these treatments, which result in acute ATP depletion and a significant enhancement of the fraction of cells undergoing apoptotic cell death. FA cells are very sensitive to the action of 2-deoxy-D-glucose (2dG) and iodoacetic acid (IAA), two inhibitors of glycolytic metabolism. The ability of FA cells to sustain metabolic insults interfering with energy production and balance may be linked with the pathological manifestations of the disease, including susceptibility to acute myeloid leukemia. These findings suggest that FA genes may be involved in a pathway that mediates a protective response to stress. We suggest that a peculiar metabolic regulation in FA cells could explain both defective apoptosis and susceptibility to oxidative stress.

Adenosine Triphosphate↗

PubMed2003

Testability of preschoolers on stereotests used to screen vision disorders.

OBJECTIVE: The purpose was to determine whether preschool children aged 3 years 0 months through 3 years 6 months could be tested with the Random Dot E, Stereo Smile, and Randot Preschool stereoacuity tests, which are random dot stereotests marketed for use with preschoolers. METHODS: A total of 118 children from five Vision In Preschoolers Study Clinical Centers participated. Strabismic children, as determined by the cover test at distance and near, were excluded from this study. Stereopsis was tested on each child using each of the three tests in a variable, balanced order. A child's testability for each test was determined by the ability to complete the nonstereo task (pretest) and the gross stereo task for each stereotest. Proportions of children able to perform each test were compared using statistical methods accommodating multiple measurements per child. RESULTS: Testability of children on the pretest was greater for the Stereo Smile test (91%) than for the Random Dot E test (81%; p = 0.007) or the Randot Preschool test (71%; p < 0.0001) and greater for the Random Dot E test than for the Randot Preschool test (p = 0.02). For all children, testability on the gross stereo task was greater for the Stereo Smile (77%; p < 0.0001) and Random Dot E (74%; p = 0.005) tests than for the Randot Preschool test (56%) but did not differ significantly between the Stereo Smile and Random Dot E tests (p = 0.19). There were no significant differences among the proportion of children able to complete the gross stereo task among those who were testable on the pretest (p > 0.12, all comparisons). CONCLUSIONS: Among preschoolers aged 3 years 0 months through 3 years 6 months, testability differs significantly across the three commercially available random dot stereotests evaluated. The results suggest that two-choice procedures increase testability of young preschoolers.

Amblyopia↗

PubMed2001

Improved in vitro quantification of the force exerted by the papillary muscle on the left ventricular wall: three-dimensional force vector measurement system.

Recent developments indicate that the forces acting on the papillary muscles can be a measure of the severity of mitral valve regurgitation. Pathological conditions, such as ischemic heart disease, cause changes in the geometry of the left ventricle and the mitral valve annulus, often resulting in displacement of the papillary muscles relative to the annulus. This can lead to increased tension in the chordae tendineae. This increased tension is transferred to the leaflets, and can disturb the coaptation pattern of the mitral valve. The force balance on the individual components governs the function of the mitral valve. The ability to measure changes in the force distribution from normal to pathological conditions may give insight into the mechanisms of mitral valve insufficiency. A unique in vitro model has been developed that allows quantification of the papillary muscle spatial position and quantification of the three-dimensional force vector applied to the left ventricular wall by the papillary muscles. This system allows for the quantification of the global force exerted on the posterior left ventricular wall from the papillary muscles during simulation of normal and diseased conditions.

Animals↗

PubMed1975

Relationship of serum beta-glucuronidase and lysozyme to pathogenesis of tularemia in immune and nonimmune rats.

A temporal study is reported of the febrile responses, tissue bacterial contents, and serum concentration of the lysosomal enzymes, beta-glucuronidase and lysozyme, in nonimmune rats inoculated with virulent or attenuated strains of Francisella tularensis, and in immune rats challenged with either a high or low dose of virulent organisms. The level of serum beta-glucuronidase appears to be an indicator of hepatocyte damage, whereas serum lysozyme correlates with the appearance, frequency, and severity of pyogranulomatous lesions. Survival of nonimmune rats after a challenge with either virulent or attenuated organisms appears to depend on a balance between dose of bacterial inoculum, celerity of irreversible pathologic events, and the ability of the reticuloendothelial and immune systems to collaboratively mount a response to limit or prevent dissemination of the infection. In immune rats, infection of parenchymal hepatic cells does not occur after a low dose (10-4) virulent challenge. Infection of parenchymal hepatic cells, however, does occur in immunized rats when the challenge dose is sufficiently large (10-8) so as to overcome the capacity of the reticuloendothelial to clear opsonized organisms.

Animals↗

PubMed1993

Induction of murine T-helper-cell responses to the filarial nematode Brugia malayi.

The purpose of this study was to examine the murine T-helper-cell (Th) cytokine response to the human filarial parasite Brugia malayi. In the first 14 days following intraperitoneal inoculation of live microfilariae into BALB/c mice, filarial antigen-driven splenic lymphoid cells produced gamma interferon (IFN-gamma) and little or no interleukin-5 (IL-5). After this time, IL-5 production increased (to 10 to 12 ng per 5 x 10(6) cells) coincident with a marked diminution in IFN-gamma generation. A single subcutaneous immunization with soluble microfilarial antigens also induced an IFN-gamma but no IL-5 response, whereas immunization three times elicited a predominant Th2-like reaction characterized by IL-4 and IL-5 production by CD4+ lymph node lymphocytes and a 10-fold increase in serum immunoglobulin E. The importance of IL-10 in establishing the balance between parasite-specific Th1 and Th2 responses was demonstrated by the ability of neutralizing monoclonal antibody to this cytokine to increase IFN-gamma production by splenic and lymph node cells from mice chronically exposed to live microfilariae or immunized multiple times with soluble filarial antigens.

Animals↗

PubMed2005

Genetic requirements for potassium ion-dependent colony spreading in Bacillus subtilis.

Undomesticated strains of Bacillus subtilis exhibit extensive colony spreading on certain soft agarose media: first the formation of dendritic clusters of cells, followed by spreading (pellicle-like) growth to cover the entire surface. These phases of colonization are dependent on the level of potassium ion (K(+)) but independent of flagella, as verified with a mutant with a hag gene replacement; this latter finding highlights the importance of sliding motility in colony spreading. Exploring the K(+) requirement, directed mutagenesis of the higher-affinity K(+) transporter KtrAB, but not the lower-affinity transporter KtrCD, was found to inhibit surface colonization unless sufficient KCl was added. To identify other genes involved in K(+)-dependent colony spreading, transposon insertion mutants in wild-type strain 3610 were screened. Disruption of genes for pyrimidine (pyrB) or purine (purD, purF, purH, purL, purM) biosynthetic pathways abolished the K(+)-dependent spreading phase. Consistent with a requirement for functional nucleic acid biosynthesis, disruption of purine synthesis with the folic acid antagonist sulfamethoxazole also inhibited spreading. Other transposon insertions disrupted acetoin biosynthesis (the alsS gene), acidifying the growth medium, glutamine synthetase (the glnA gene), and two surfactin biosynthetic genes (srfAA, srfAB). This work identified four classes of surface colonization mutants with defective (i) potassium transport, (ii) surfactin formation, (iii) growth rate or yield, or (iv) pH control. Overall, the ability of B. subtilis to colonize surfaces by spreading is highly dependent on balanced nucleotide biosynthesis and nutrient assimilation, which require sufficient K(+) ions, as well as growth conditions that promote sliding motility.

Acetoin↗

PubMed1989

Interrelationship of brain edema, motor deficits, and memory impairment in rats exposed to focal ischemia.

We investigated the relations of brain edema, ion shifts, motor performance, and memory impairment using a focal ischemia model in rats. Cortical infarction was produced by ligation of the middle cerebral artery and the ipsilateral common carotid artery combined with temporary occlusion of the contralateral common carotid artery for 1 hour. Water content and sodium, potassium, and calcium concentrations were measured until Day 14 after the ischemic insult. Significant edema formation was observed; it peaked on Day 3 (p less than 0.001) and then declined. The tissue sodium concentration changed in a manner similar to that of water content, but the tissue potassium concentration changed in an opposite fashion. Massive accumulation of calcium was detected as early as Day 1 after ischemia (almost four times the normal level). The increased calcium concentration was sustained even up to Day 14. Motor performance examinations performed on Day 3, including inclined plane, balance beam, and prehensile tests, demonstrated significantly reduced (p less than 0.001) motor ability that did recover even by Day 7. Passive avoidance learning was carried out on Day 2, followed by a memory retention test on Day 3. Significant memory dysfunction was observed in ischemic compared with sham-operated rats (p less than 0.001). A high correlation coefficient (r = 0.91, p less than 0.01, n = 13) was obtained between water content and calcium concentration on Day 3. Both the total motor score and the degree of disturbance of the passive avoidance reaction also correlated well with water content.

Animals↗

PubMed2004

Family caring strategies in neutropenia.

Aggressive chemotherapy protocols result in neutropenia in approximately half of all patients receiving chemotherapy. Thus, neutropenia continues to be a significant and potentially life-threatening side effect of treatment, even with use of colony-stimulating factors. Families of patients with neutropenia often provide the primary healing environment because most chemotherapy protocols are managed on an outpatient basis. To learn about the family's experience of managing chemotherapy-induced neutropenia (CIN), a grounded-theory methodology was used to analyze data from seven families. The central theme revealed by these families was "turbulent waiting with intensified connections." This meant that when families had a sense of greater vulnerability in response to the waiting after diagnosis of CIN, they connected intensely with each other and healthcare providers. Families reported that connections with nurses became more significant when neutropenia interrupted chemotherapy. Families also developed family caring strategies to manage this period of waiting for the chemotherapy to resume. These strategies included family inquiry, family vigilance, and family balancing. Nurses need to be aware of approaches to support the family's ability to manage CIN. Interventions and approaches constructed from the perspective of a family-professional partnership will enhance the family cancer experience as well as ongoing family growth and function.

Adaptation, Psychological↗