Comments on fluid intake, renal solute, and water balance in infancy.
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Drinking↗
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Results for “Balance ability”
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Role of ARC NPY neurons in energy homeostasis.
Neuropeptide Y (NPY) is one of the most abundant and widely distributed neurotransmitters in the mammalian brain and appears to be an important regulatory peptide in both the central and peripheral nervous systems. The arcuate nucleus (ARC) is the major site of expression for NPY within neurons in the hypothalamus. The most noticeable effect of NPY is the stimulation of feeding. To date, six NPY receptor subtypes have been cloned and pharmacologically characterized, and there is evidence for further NPY receptor subtypes. The recent isolation and cloning of a rat NPY receptor with the required pharmacology for the feeding response, called the Y(5) receptor, has led to the suggestion that this is the "feeding" receptor. There is, however, still controversy as to whether the Y(5) receptor represents the true "feeding" receptor, since selective Y(1) receptor antagonists are capable of antagonizing NPY-induced hyperphagia. It also is possible that another, as yet unidentified, NPY receptor subtype(s) may mediate the effects of NPY on energy balance. The potency and behavioral specificity of NPY on feeding and its ability to induce obesity, together with the evidence that ARC-NPY neurons operate homeostatically to counteract energy deficits, all suggest that the ARC-PVN projection is important in regulating energy balance. The next few years will tell us whether or not these important physiological lessons will be successfully translated into a safe and effective form of therapy for human obesity.
Journal Article↗
Striking a balance: modulation of the actin cytoskeleton by Salmonella.
Salmonella spp. have evolved the ability to enter into cells that are normally nonphagocytic. The internalization process is the result of a remarkable interaction between the bacteria and the host cells. Immediately on contact, Salmonella delivers a number of bacterial effector proteins into the host cell cytosol through the function of a specialized organelle termed the type III secretion system. Initially, two of the delivered proteins, SopE and SopB, stimulate the small GTP-binding proteins Cdc42 and Rac. SopE is an exchange factor for these GTPases, and SopB is an inositol polyphosphate phosphatase. Stimulation of Cdc42 and Rac leads to marked actin cytoskeleton rearrangements, which are further enhanced by SipA, a Salmonella protein also delivered into the host cell by the type III secretion system. SipA lowers the critical concentration of G-actin, stabilizes F-actin at the site of bacterial entry, and increases the bundling activity of the host-cell protein T-plastin (fimbrin). The cellular responses stimulated by Salmonella are short-lived; therefore, immediately after bacterial entry, the cell regains its normal architecture. Remarkably, this process is mediated by SptP, another target of the type III secretion system. SptP exert its function by serving as a GTPase-activating protein for Cdc42 and Rac, turning these G proteins off after their stimulation by the bacterial effectors SopE and SopB. The balanced interaction of Salmonella with host cells constitutes a remarkable example of the sophisticated nature of a pathogen/host relationship shaped by evolution through a longstanding coexistence.
Actins↗
Specialist surgical training in Papua New Guinea: the outcomes after 10 years.
Surgical training commenced in 1975, the year that Papua New Guinea (PNG) gained independence. The training involves a 4-year programme leading to a Master of Medicine (MMed), awarded by the University of Papua New Guinea. In the past 30 years just over 50 general surgeons have graduated. There have also been 9 graduates in the area of ear nose and throat, 10 in ophthalmology and 2 in oral surgery. The subspecialization of general surgeons began in 1994 with four trainees, two orthopaedic, one head and neck and one urological. The model used was to develop specialist skills over 2-3 years only qualified (MMed) general surgeons so that their ability to carry out general surgical procedures and work in a remote hospital was not lost. The different specialties required different balances of in-country and out-of-country training depending on the local ability to provide training in PNG. An important sponsor has been the PNG National Department of Health, which has funded the training posts by using existing general surgical positions and covering the loss of manpower while surgeons are training overseas, sometimes for up to 2 years. Medical education and tertiary health service projects, funded by Aus-Aid, have also contributed significantly to the teaching and training. These projects have provided visiting specialists to teach and hospital attachments for national surgeons to train in Australasia. Various individual surgeons and their specialist societies in Australasia have also provided invaluable support. Three surgeons have been recipients of the Rowan Nicks scholarship. Twelve surgeons have been awarded a specialist diploma and a further five are in training. The posting of national specialist surgeons to Port Moresby has resulted in all modules of the General surgery MMed programme being taught by Papua New Guineans, which would have been hard to imagine back in 1993. The MMed is now a sustainable programme and can be provided without external support. National surgeons carry out a wide range of specialist procedures, formerly carried out only by visiting teams. They are also able to make outreach visits within PNG and specialist visits to neighbouring Pacific Island countries.
Australia↗
Antepartum care in the twenty-first century.
Major factors impacting on antepartum care in the twenty-first century were reviewed in this article, including the impact of managed care and collaborative health care teams, the malpractice crisis, antepartum visits and the quality of care, increased use of the Internet and computer technology, the increasing age of childbearing, advances in genetic and prenatal diagnosis, the importance of evidence-based medicine, the goals of Healthy People 2010 [11], the Safe Mother Initiative, and the use of complementary and alternative medicine. Recommendations for antepartum care in the twenty-first century include; the formation of integrated collaborative health care teams to deal with the effects of managed care; development of a more sensitive health care system to assist all parties involved with medical malpractice; increased expertise in the use of the Internet and computer technology; acknowledging and preparing for the increased population of older gravidas; becoming aware of advances in genetic and prenatal diagnosis; increasing the ability to critically evaluate research and incorporate well-founded study findings into clinical practice; incorporating the goals of Healthy People 2010 [11] when providing care to antepartum patients; contributing resources and manpower to the Safe Mother Initiative to decrease maternal mortality in developing countries; becoming knowledgeable, obtaining adequate training, and utilizing or performing evidence-based studies to validate the use of complementary and alternative medicine in antepartum practice; and finally to find a balance between the factors impacting on prenatal care and the ability to continue to provide safe, high-quality, continuous, sensitive, and humane antepartum care.
Complementary Therapies↗
Preservation of the right atrial appendage improves reduced plasma atrial natriuretic peptide levels after the maze procedure.
OBJECTIVES: The present study was conducted to determine whether preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and whether the increase of plasma atrial natriuretic peptides improves the ability of the kidneys to excrete the fluid load after the operation. METHODS: We evaluated 42 patients who underwent the maze procedure. The right atrial appendage was preserved in 22 patients but not in 20. Blood samples were obtained before and after the operation for measurement of atrial natriuretic peptides. To evaluate the influence of atrial natriuretic peptides on the ability of the kidneys, we also measured body weight, fluid balance, and the doses of furosemide and dopamine administered after the operation. RESULTS: The restoration to sinus rhythm at 1 month after was comparable in the two groups. Plasma atrial natriuretic peptide levels significantly increased after the operation in patients in whom the right atrial appendage was preserved (1 day after: 23.4 +/- 17.8 vs 3 days after: 42.7 +/- 23.6 and 7 days after: 36.3 +/- 23.7 pg/mL, P <.05) but not in patients in whom the right atrial appendage was not preserved (1 day after: 20.0 +/- 19.6, 3 days after: 28.5 +/- 19.3, and 7 days after: 23.0 +/- 16.1 pg/mL). Furthermore, plasma atrial natriuretic peptide levels were significantly lower in patients in whom the right atrial appendage was not preserved than in patients in whom the right atrial appendage was preserved at 3 and 7 days after the operation. The fluid balance during the first 7 days of the postoperative period was comparable in the two groups, although the total dose of dopamine used in the same period was significantly smaller in patients in whom the right atrial appendage was preserved than in patients in whom the right atrial appendage was not preserved (155.3 +/- 119.0 vs 244.9 +/- 129.0 microg/kg, P <.05). CONCLUSIONS: The present study showed that preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and that increased plasma atrial natriuretic peptides may improve the ability of the kidneys to excrete the fluid load after the operation.
Atrial Appendage↗
Tail loss and thermoregulation in the common lizard Zootoca vivipara.
Tail autotomy in lizards is an adaptive strategy that has evolved to reduce the risk of predation. Since tail loss reduces body mass and moving ability-which in turn are expected to influence thermal balance-there is potential for a trade-off between tail autotomy and thermoregulation. To test this hypothesis, we studied a common lizard (Zootoca vivipara) population at high latitude, inhabiting a high-cost thermal environment. Z. vivipara is a small, non-territorial lizard known as a very accurate thermoregulator. We made two predictions: (1) the reduced body weight due to tail loss results in faster heating rate (a benefit), and (2) the reduction in locomotor ability after tail loss induces a shift to the use of thermally poorer microhabitats (a cost), thus decreasing the field body temperatures of active lizards. We did not find any effect of tail loss on heating rate in laboratory experiments conducted under different thermal conditions. Likewise, no significant relationship between tail condition and field body temperatures, or between tail condition and thermal microhabitat use, were detected. Thus, our results suggest that tail autotomy does not influence the accuracy of thermoregulation in small-bodied lizards.
Animals↗
A postmigrational switch among skin-derived dendritic cells to a macrophage-like phenotype is predetermined by the intracutaneous cytokine balance.
Migration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83(+) DC to immature CD14(+) macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.
Biomarkers↗
Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet.
The pivotal issue of transplant rejection diagnosis and management is design, conduct, and analysis of clinical trials. The historical experience with clinical trials of major immunosuppressive drugs (cyclosporine and especially tacrolimus) is examined in this article. Cyclosporine was a turning point in transplantation, providing an extraordinary improvement over previous therapies. Additionally, early investigational experience with tacrolimus was shown to be important in rescue from cyclosporine failure. Experience with tacrolimus in liver recipients for primary therapy led to understanding that the side effect profile was similar to cyclosporine and that the important side effects of tacrolimus (toxicity and diabetes) could be lessened by altering the drug dose. Early dosing regimens were determined by attempts to balance the toxicities (representing a dose ceiling) against rejection (for minimum dosing). Drug levels became understandable and trough levels could be used to guide therapy. However, when the multicenter liver trial was implemented, high starting doses were included in the protocol design, ignoring information obtained with drug level monitoring. Disregard for this information led to a distortion of the potential value of tacrolimus. Historical controls from the Pittsburgh experience suggested that tacrolimus was a critical immunosuppressant, and the randomized trial against cyclosporine confirmed the drug's ability to compete. The multicenter liver trial, however, was not balanced across treatment arms for other immunosuppressive agents (ie, higher doses of prednisone from center to center, additional induction protocols at various centers). Additionally, analysis of study results differed across continents, and the role of tacrolimus in cyclosporine rescue was not examined thoroughly. When tacrolimus was proposed for use in extrahepatic organ transplantation, again the Pittsburgh experience, as well as experience from other single centers, was determined inadequate evidence of efficacy, and randomized trials were required by the FDA. The fact that multicenter trials in transplantation have historically been poorly designed or analyzed weighed against the dramatic improvements shown from historically controlled studies or single-center trials should lead to question of the regulatory requirement for multicenter randomized trials for all organ types.
Cyclosporine↗
Is insulin resistance the principal cause of type 2 diabetes?
The data presented from these recent studies raise serious doubt concerning the commonly held view that insulin resistance is the principal cause of type 2 diabetes: first of all they provide evidence that insulin resistance may not be the primary genetic factor for type 2 diabetes; secondly, they demonstrate that at least under certain circumstances insulin resistance is not essential for diabetes to occur, and then finally, they indicate that insulin resistance may not be the predominant factor determining the degree of hyperglycaemia. Although these studies suggest that the role of insulin resistance relative to that of beta-cell dysfunction in the pathogenesis of type 2 diabetes has been generally overestimated, one should not be left with the impression that insulin resistance is not important. It is certainly an important factor in determining the degree of hyperglycaemia or glucose intolerance present at a given level of beta-cell function. The improvement in glycaemic control after weight loss which lessens insulin resistance or after the administration of pharmacologic agents that improve insulin sensitivity clearly argue that insulin resistance is important in this regard. In addition to influencing the severity of glucose intolerance, insulin resistance is probably also important in determining the time of onset of diabetes. It may do this simply by altering the balance between the body's demand for insulin and the ability of the pancreas to provide insulin. It might adversely affect beta-cell function in addition to increasing the demand for insulin. This concept is schematically represented in figure 3. It is well established that beta-cell function normally deteriorates as a function of age [41]. Although the prevalence of type 2 diabetes increases as a function of age, this by itself obviously does not result in diabetes in the great majority of people. In such individuals their insulin sensitivity is sufficient to maintain the balance between the supply and demand for insulin above the threshold for developing diabetes. Theoretically one may postulate three other situations originating with a genetic beta-cell defect: some people may start off life with normal beta-cell function but experience a genetically determined accelerated deterioration; some people may start off life with reduced beta-cell function (e.g. less beta-cell s); still others may start off with reduced beta-cell function and have an accelerated rate of deterioration. In each of the above situations, at any given level of beta-cell function, the degree of insulin resistance present would alter the threshold for developing impaired glucose tolerance and ultimately type 2 diabetes; in other words, the greater the insulin resistance, the lower the threshold, the earlier the onset and the more severe the diabetes will be. It follows therefore that efforts to diminish insulin resistance and to preserve beta-cell function should both be beneficial. Weight loss and increased physical activity, both of which reduceinsulin resistance, have been shown to prevent progression of people with impaired glucose tolerance to diabetes. Whether this is simply due to shifting the balance between insulin requirements and insulin availability or whether it also involves an improvement in beta-cell function and/or prevention of its deterioration remains to be clarified. Furthermore, it is not known whether pharmacologic agents which improve insulin sensitivity have similar effects.
Diabetes Mellitus↗
Balance, mobility and gaze stability deficits remain following surgical removal of vestibular schwannoma (acoustic neuroma): an observational study.
QUESTION: Are there residual deficits in balance, mobility, and gaze stability after surgical removal of vestibular schwannoma? DESIGN: Observational study. PARTICIPANTS: Twelve people with a mean age of 52 years who had undergone surgical removal of vestibular schwannoma at least three months previously and had not undergone vestibular rehabilitation. Twelve age- and gender-matched healthy people who acted as controls. OUTCOME MEASURES: Handicap due to dizziness, balance, mobility, and gaze stability was measured. RESULTS: Handicap due to dizziness was moderate for the clinical group. They swayed significantly more than the controls in comfortable stance: firm surface eyes open and visual conflict (p < 0.05); foam surface eyes closed (p < 0.05) and visual conflict (p < 0.05); and feet together: firm surface, eyes closed (p < 0.05), foam surface, eyes open (p < 0.05) and eyes closed (p < 0.01). They displayed a higher rate of failure for timed stance and gaze stability (p < 0.05) than the controls. Step Test (p < 0.01), Tandem Walk Test (p < 0.05) and Dynamic Gait Index (p < 0.01) scores were also significantly reduced compared with controls. There was a significant correlation between handicap due to dizziness and the inability to maintain balance in single limb and tandem stance (r = 0.68, p = 0.02) and the ability to maintain gaze stability during passive head movement (r = 0.78; p = 0.02). CONCLUSION: A prospective study is required to evaluate vestibular rehabilitation to ameliorate dizziness and to improve balance, mobility, and gaze stability for this clinical group.
Adult↗
Secreted apolipoprotein E reduces macrophage-mediated LDL oxidation in an isoform-dependent way.
As an inflammatory cell, the macrophage produces various oxidizing agents, such as free radical species. These can modify LDL as a secondary effect and doing so may favor atherogenic processes. Any molecule able to counteract these reactions would be of much benefit, especially if secreted by the macrophage itself at the lesion site. Such is the case for apolipoprotein E (apoE), which has been shown to exert antioxidant properties in some studies, mostly in relation to Alzheimer's disease. In this study, we assessed the antioxidant potential of the various isoforms of apoE (E2, E3, and E4) using a metal-induced LDL oxidation system with exogenous recombinant apoE and an in vitro model of macrophage-mediated LDL oxidation. We found that all three isoforms had an antioxidant capacity. However, whereas apoE2 was the most protective isoform in the cell-free system, the opposite was observed in apoE-transfected J774 macrophages. In the latter model, cellular cholesterol efflux was found to be more important with apoE2, possibly explaining the larger quantity of oxidative indices observed in the medium. It is proposed that the antioxidant property of apoE results from a balance between direct apoE antioxidant capacities, such as the ability to trap free radicals, and potentially pro-oxidative indirect events associated with cholesterol efflux from cells. Our observations add to the therapeutic potential of apoE. However, they also suggest the need for more experiments in order to achieve careful selection of the apoE isoform to be targeted, especially in the perspective of apoE transgene use.
Animals↗
Use of clinical risk factors in elderly women with low bone mineral density to identify women at higher risk of hip fracture: The EPIDOS prospective study.
Elderly women with very low bone mineral density (BMD) ( T-score </= -3.5) have a risk of hip fracture more than two times higher than the average risk of women of the same age. Using data from the EPIDOS prospective study, we have shown that by measuring BMD on the 50% of women who have the lowest weight, it is possible to identify the majority of these women at higher risk. In the present analysis, we assessed whether the use of clinical risk factors, in the subset of women selected for osteodensitometry and with moderately low BMD ( T-score between -3.5 and -2.5), allows the identification of another subgroup of women with a risk 2 times higher than average and, thereby, increases the efficiency of selective BMD screening. We then assessed the discriminant value for hip fracture of the overall screening strategy (i.e., use of weight to select women for osteodensitometry, then use of clinical risk factors to enhance the predictive value of BMD), and compared it with the value of BMD used as a population screening tool. In total, 6933 EPIDOS participants, aged 75 years or above, were included in this analysis. Using Cox regression models, we first determined which baseline factors were most predictive of hip fracture among the 1588 women with weight below median (selection criteria for osteodensitometry in the proposed strategy) and T-score between -3.5 and -2.5. Based on the relative risk (RR) estimates from the final risk function, we calculated an individual risk score for hip fracture. We assessed the incidence of hip fracture for each value of the score, and determined the cutoff to identify women with a risk about 2 times higher than the average risk in this elderly cohort. The overall screening strategy (i.e., selective BMD measurement based on weight, followed by clinical fracture risk assessment) identifies two subgroups of higher risk women: a group with very low BMD ( T-score </= -3.5), and another group with moderately low BMD ( T-score between -3.5 and -2.5) but a high fracture risk score. We calculated the total number of women classified as being at high risk, and assessed the overall sensitivity and specificity of this strategy to identify elderly women who will suffer a hip fracture. Among women with weight below median and T-score between -3.5 and -2.5, the factors most predictive of the risk of hip fracture were age, history of fall, ability to do the tandem walk (test of dynamic balance), gait speed and visual acuity. A simple additive score based on these factors (except visual acuity) allows a high-risk group (risk about 2 times higher than average) to be clearly distinguished from a low-risk group (risk below average). Overall, the proposed strategy identifies approximately 15% of the women in the cohort as being at high risk, i.e., 543 women with T-score </= -3.5 and 503 women with -3.5 < T-score </= -2.5 and a high fracture risk score. The sensitivity for hip fracture is equal to 37% and the specificity to 85%, which is equivalent to the discriminant value of BMD as a population screening tool. In elderly women, the use of a simple clinical risk score, in women with previous BMD values, allows the number of high-risk women identified to be increased. Overall, the proposed screening strategy (use of weight to select women for osteodensitometry, and then use of clinical risk factors to enhance the predictive value of BMD) has the same discriminant value for hip fracture as BMD used as a population screening tool.
Aged↗
Walking stability and sensorimotor function in older people with diabetic peripheral neuropathy.
OBJECTIVE: To evaluate, in older people with diabetic peripheral neuropathy (DPN) and in age-matched controls, acceleration patterns of the head and pelvis when walking to determine the effect of lower-limb sensory loss on walking stability. DESIGN: Case-control study. SETTING: Falls and balance laboratory in Australia. PARTICIPANTS: Thirty persons with diabetes mellitus (age range, 55-91 y) and 30 age-matched controls. INTERVENTIONS: Acceleration patterns of the head and pelvis were measured while participants walked on a level surface and an irregular walkway. Participants also underwent tests of vision, sensation, strength, reaction time, and balance. MAIN OUTCOME MEASURES: Temporospatial gait parameters and variables derived from acceleration signals. RESULTS: Participants with DPN had reduced walking speed, cadence, and step length, and less rhythmic acceleration patterns at the head and pelvis compared with controls. These differences were particularly evident when participants walked on the irregular surface. Participants with DPN also had impaired peripheral sensation, reaction time, and balance. CONCLUSIONS: Older people with DPN have an impaired ability to stabilize their body when walking on irregular surfaces, even if they adopt a more conservative gait pattern. These results provide further insights into the role of peripheral sensory input in the control of gait stability, and suggest possible mechanisms underlying the increased risk of falling in older people with diabetic neuropathy.
Acceleration↗
Hsp90 functions to balance the phosphorylation state of Akt during C2C12 myoblast differentiation.
The function of the 90-kDa heat shock protein (Hsp90) is essential for the regulation of a myriad of signal transduction cascades that control all facets of a cell's physiology. Akt (PKB) is an Hsp90-dependent serine-threonine kinase that plays critical roles in the regulation of muscle cell physiology, including roles in the regulation of muscle differentiation and anti-apoptotic responses that modulate cell survival. In this report, we have examined the role of Hsp90 in regulating the activity of Akt in differentiating C2C12 myoblasts. While long-term treatment of differentiating C2C12 cells with the Hsp90 inhibitor geldanamycin led to the depletion of cellular Akt levels, pulse-chase analysis indicated that geldanamycin primarily enhanced the turnover rate of newly synthesized Akt. Hsp90 maintained an interaction with mature Akt, while Cdc37, Hsp90's kinase-specific co-chaperone, was lost from the chaperone complex upon Akt maturation. Geldanamycin partially disrupted the interaction of Cdc37 with Akt, but had a much less significant effect on the interaction of Hsp90 with Akt. Surprisingly, short-term treatment of differentiating C2C12 with geldanamycin increased the phosphorylation of Akt on Ser473, an effect mimicked by treatment of C2C12 cells with okadaic acid or the Hsp90 inhibitor novobiocin. Furthermore, Akt was found to interact directly with catalytic subunit of protein phosphatase 2A (PP2Ac) in C2C12 cells, and this interaction was not disrupted by geldanamycin. Thus, our findings indicate that Hsp90 functions to balance the phosphorylation state of Akt by modulating the ability of Akt to be dephosphorylated by PP2Ac during C2C12 myoblast differentiation.
Animals↗
Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: a study on process parameters and in vitro performances.
Currently, delayed/pulsatile release and colon delivery represent topics of remarkable interest. The present paper deals with the study and development of an oral dosage form devised to release drugs following a programmed time period after administration or, when opportune design modifications are introduced, to target the colon. The system is composed of a drug-containing core and a hydrophilic swellable polymeric coating capable of delaying drug release through slow interaction with aqueous fluids. An optional external gastroresistant film is applied to overcome gastric emptying variability, thus allowing colon delivery to be pursued according to the time-dependent approach. The aim of this work was to evaluate different hydroxypropyl methylcellulose (HPMC) viscosity grades as possible materials for the attainment of the system retarding hydrophilic layer. Both the relevant suitability for application onto tablet cores by aqueous spray-coating in fluid bed and capability of delaying drug release for a programmable period were explored and compared. Methocel E50 was found to afford the best balance among different important items, i.e. process time, retarding ability, dimensions of the coated units and possibility of finely tuning the delay duration. Further results pointed out the robustness of Methocel E50-based systems, which have shown to be practically unaffected by the concentration of the employed coating solution and the pH of the release medium, as well as only poorly influenced by ionic strength, at least with regard to values encompassed in the physiological range for gastrointestinal fluids.
Administration, Oral↗
Behavior in mice with targeted disruption of single genes.
The use of mice with targeted deletion, or knockout, of specific genes provides a relatively new approach to establish the molecular bases of behavior. As with all ablation studies, the interpretation of behavioral data may be limited by the technique. For example, indirect effects of the missing gene may affect behavior, rather than the missing gene per se. Also, because the missing gene might affect many developmental processes throughout ontogeny and because up-regulation or compensatory mechanisms may be activated in knockouts, behavioral data from mice with targeted gene deletions should be interpreted with caution. The development of conditional knockouts, in which a specific gene can be inactivated any time during ontogeny, should allow investigators to avoid these conceptual shortcomings associated with behavioral data from knockouts in the near future. The behavioral alterations reported in knockout mice are reviewed here. Many dramatic changes in complex motivated behaviors including aggression, sexual, ingestive, and parental behaviors, have been reported for knockouts. There have also been many reports of alterations in sensorimotor abilities and spontaneous activity, as well as impairments in balance, coordination, and gait. Impaired learning and memory have also been reported for mice with targeted disruption of specific genes. Taken together, the use of knockouts will provide an important new tool to understand the mechanisms underlying behavior.
Animals↗
An overview of inhibitors of Na(+)/H(+) exchanger.
The Na(+)/H(+) exchanger (NHE) is involved in intracellular pH homeostasis of many mammalian cell types. To date seven NHE isoforms (NHE1-NHE7) have been identified. NHE1 is the most predominant isoform expressed in heart where it contributes to cardiomyocyte pH homeostasis. Although the NHE activation is essential for the restoration of physiological pH, hyperactivation of NHE1 during ischemia-reperfusion episodes disrupts the intracellular ion balance, leading to cardiac dysfunction and damage. Beside its ability to inhibit a conductive Na(+) channel and the Na(+)/Ca(++) exchanger, amiloride was the first drug described as NHE inhibitor. Double substitution of the nitrogen of the 5-amino group of amiloride gave DMA, EIPA, MIBA and HMA. Later, several acylguanidines were prepared to selectively inhibit NHE1. The replacement of the pyrazine ring of amiloride by a pyridine ring or by a phenyl increased the potency and the NHE selectivity. The simultaneous replacement of the pyrazine ring by a phenyl, of the 6-chloro by a sulfomethyl led to drugs such as HOE-694, cariporide, eniporide and BIIB-513 which also selectively inhibited NHE1. In the last decade several bicyclic guanidines were prepared: zoniporide, MS-31038, SM-20220, SM-20550, SMP-300, KB-R9032, BMS-284640, T-162559, TY-12533, S-3226 or SL-591227. Extensive pre-clinical studies indicated that NHE inhibitors afford substantial protection in different animal models of myocardial ischemia (MI) and reperfusion, but the results of clinical trials involving eniporide and cariporide were mixed.
Animals↗