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A Gibson

Publications and source records attributed to A Gibson.

At least 19 recordsLinked to original sources
PubMed2002

Geographies of need and the new NHS: methodological issues in the definition and measurement of the health needs of local populations.

For a variety of purposes it is increasingly necessary to establish the health needs of local populations. Following a critique of existing proxies of need, this paper presents and evaluates an alternative which draws upon epidemiological evidence concerning the age, sex and social class distribution of morbidity in order to estimate the prevalence of specific conditions in designated populations. By way of demonstrating the insights to be gained through the use of these indicative prevalence rates, the paper considers the treatment of ischaemic heart disease in a sample of 539 practices and presents evidence regarding the significance of deprivation and rurality in determining health service use relative to needs.

Epidemiologic Methods↗
PubMed2002

ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency.

T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIV(mac251 (561)). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIV(mac251 (561)) or SIV(SME660). However, a significant delay in CD4+ T-cell loss was observed in Mamu-A*01-positive macaques in each group. Of interest, in the case of intravenous or intrarectal challenge with the chimeric SIV/HIV strains SHIV(89.6P) or SHIV(KU2), respectively, MHC-I Mamu-A*01-positive macaques did not significantly restrict primary viremia. The finding of the protective effect of the Mamu-A*01 molecule parallels the protective effect of the B*5701 HLA allele in HIV-1-infected humans and needs to be accounted for in the evaluation of vaccine efficacy against SIV challenge models.

Animals↗
PubMed2001

GTPase activity of dynamin and resulting conformation change are essential for endocytosis.

Dynamin is a large GTPase with a relative molecular mass of 96,000 (Mr 96K) that is involved in clathrin-mediated endocytosis and other vesicular trafficking processes. Although its function is apparently essential for scission of newly formed vesicles from the plasma membrane, the nature of dynamin's role in the scission process is still unclear. It has been proposed that dynamin is a regulator (similar to classical G proteins) of downstream effectors. Here we report the analysis of several point mutants of dynamin's GTPase effector (GED) and GTPase domains. We show that oligomerization and GTP binding alone, by dynamin, are not sufficient for endocytosis in vivo. Rather, efficient GTP hydrolysis and an associated conformational change are also required. These data argue that dynamin has a mechanochemical function in vesicle scission.

Amino Acid Sequence↗
PubMed2001

Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes.

Adaptor protein 180 (AP180) and its homolog, clathrin assembly lymphoid myeloid leukemia protein (CALM), are closely related proteins that play important roles in clathrin-mediated endocytosis. Here, we present the structure of the NH2-terminal domain of CALM bound to phosphatidylinositol-4,5- bisphosphate [PtdIns(4,5)P2] via a lysine-rich motif. This motif is found in other proteins predicted to have domains of similar structure (for example, Huntingtin interacting protein 1). The structure is in part similar to the epsin NH2-terminal (ENTH) domain, but epsin lacks the PtdIns(4,5)P2-binding site. Because AP180 could bind to PtdIns(4,5)P2 and clathrin simultaneously, it may serve to tether clathrin to the membrane. This was shown by using purified components and a budding assay on preformed lipid monolayers. In the presence of AP180, clathrin lattices formed on the monolayer. When AP2 was also present, coated pits were formed.

Adaptor Protein Complex 2↗
PubMed2001

Phosphodiesterase 5 inhibitors and nitrergic transmission-from zaprinast to sildenafil.

Phosphodiesterase 5 terminates the cellular actions of the second messenger molecule cyclic GMP; inhibitors of phosphodiesterase 5 will therefore increase and prolong the actions of endogenous substances that signal via the cyclic GMP pathway, including nitric oxide released as a neurotransmitter from nitrergic nerves. To date, the most widely used phosphodiesterase 5 inhibitors, zaprinast and sildenafil, have proved vital in the elucidation of the widespread role of cyclic GMP in nitrergic transmission and, specifically in the case of sildenafil, have provided a major breakthrough in the treatment of erectile dysfunction in men. Although still a matter of debate, early evidence indicates that sildenafil may also be of benefit in some forms of sexual dysfunction in women. The remarkable clinical success of sildenafil has prompted the search for further novel phosphodiesterase 5 inhibitors which might be used to enhance nitrergic function in other disease states.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Three-dimensional electrical impedance tomography of human brain activity.

Regional cerebral blood flow and blood volume changes that occur during human brain activity will change the local impedance of that cortical area, as blood has a lower impedance than that of brain. Theoretically, such impedance changes could be measured from scalp electrodes and reconstructed into images of the internal impedance of the head. Electrical Impedance Tomography (EIT) is a newly developed technique by which impedance measurements from the surface of an object are reconstructed into impedance images. It is fast, portable, inexpensive, and noninvasive, but has a relatively low spatial resolution. EIT images were recorded with scalp electrodes and an EIT system, specially optimized for recording brain function, in 39 adult human subjects during visual, somatosensory, or motor activity. Reproducible impedance changes of about 0.5% occurred in 51/52 recordings, which lasted from 6 s after the stimulus onset to 41 s after stimulus cessation. When these changes were reconstructed into impedance images, using a novel 3-D reconstruction algorithm, 19 data sets demonstrated significant impedance changes in the appropriate cortical region. This demonstrates, for the first time, that significant impedance changes, which could form the basis for a novel neuroimaging technology, may be recorded in human subjects with scalp electrodes. The final images contained spatial noise and strategies to reduce this in future work are presented.

Adolescent↗
PubMed2001

Biology of the anococcygeus muscle.

The anococcygeus is a smooth muscle tissue of the urogenital tract which, in the male, runs on to form the retractor penis. The motor innervation is classically sympathetic with noradrenaline as transmitter, but the relaxant parasympathetic transmitter has only recently been identified as nitric oxide. Indeed, the anococcygeus has provided an extremely useful model with which to probe the mechanisms underlying this novel nitrergic system, including the importance of physiological antioxidants in maintaining the potency of nitric oxide as a neurotransmitter. The cellular mechanisms of contraction and relaxation are slowly being clarified, with particular interest in the contribution of capacitative calcium entry and the guanylyl cyclase/cyclic GMP system. Many questions remain unanswered, however, including the precise physiological role of the muscle, the identity of substances released from subcellular vesicles of nitrergic nerves, the unusual sensitivity of the tissue to certain peptides (oxytocin and urotensin II), and the nature of store-operated channels through which calcium enters the cell to maintain contraction.

Animals↗
PubMed2001

Refractive changes following Nd:YAG capsulotomy.

PURPOSE: To investigate the effect of Nd:YAG capsulotomy on refractive changes and the need for a post-capsulotomy refraction. METHODS: Forty-two eyes with uncomplicated phacoemulsification and implant (AMO@Phacoflex II) were included. Autorefraction and subjective refraction were performed to get the best visual acuity before and after Nd:YAG capsulotomy. RESULTS: The spherical equivalent before the Nd:YAG capsulotomy was -0.61 +/- 0.90 and after the capsulotomy, -0.57 +/- 0.84. Using the paired Student's t-test there was no significant difference in the refraction following Nd:YAG capsulotomy. CONCLUSION: Routine refraction following Nd:YAG capsulotomy in patients who have had uncomplicated phacoemulsification using AMO@Phacoflex II intraocular lenses is not necessary.

Aged↗
PubMed2001

Inhibition of capacitative calcium entry is not obligatory for relaxation of the mouse anococcygeus by the NO/cyclic GMP signalling pathway.

1. The object of this study was to determine whether inhibition of capacitative calcium entry is essential for relaxation of the mouse anococcygeus via the NO/cyclic GMP signalling pathway. 2. In intact muscles, thapsigargin (Tg; 100 nM)-induced tone was relaxed by NO, sodium nitroprusside (SNP), 8-Br-cyclic GMP, and nitrergic field stimulation. The relaxations were similar in magnitude to those observed against carbachol (50 microM) tone and, with the exception of those to 8-Br-cyclic GMP, were reduced by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 microM). 3. In single smooth muscle cells, loaded with Fura-2, both carbachol and Tg produced sustained elevations in cytoplasmic calcium levels ([Ca2+]i). SNP inhibited the rise in [Ca2+]i produced by carbachol, an effect attenuated by ODQ. In contrast, neither SNP nor 8-Br-cyclic GMP reduced the elevated [Ca2+]i associated with Tg. 4. In beta-escin skinned preparations, NO had no effect on tone induced by calcium (1 microM in the presence of 100 microM GTP). Carbachol and Tg produced further increases in calcium/GTP-induced tone and, in both cases, this additional tone was relaxed by NO and 8-Br-cyclic GMP. 5. The results support the hypothesis that the NO/cyclic GMP pathway inhibits capacitative calcium entry by refilling the internal stores, since reduction in [Ca2+]i was not observed in the presence of Tg. However, as muscle relaxation was still observed, impairment of capacitative calcium entry cannot be considered obligatory for relaxation. Results from skinned tissues suggest that inhibition of calcium sensitization processes, perhaps associated with store-depletion, may be an important mechanism of NO/cyclic GMP-induced relaxation.

Animals↗
PubMed2001

Selective inhibition of thapsigargin-induced contraction and capacitative calcium entry in mouse anococcygeus by trifluoromethylphenylimidazole (TRIM).

This study examined the effects of trifluoromethylphenylimidazole (TRIM) on tone, and calcium entry, in mouse anococcygeus stimulated by either thapsigargin (Tg; 100 nM) which activates capacitative calcium entry (CCE), or high K (60 mM) which activates voltage-operated calcium channels. TRIM (1 - 333 microM) produced concentration-related relaxation of Tg-induced tone (EC(50), 42 microM) but was much less effective against high K. In single smooth muscle cells loaded with FURA-2, TRIM reduced the increase in fluorescence ratio produced by Tg but had no effect on that produced by high K. The relaxations of Tg-induced tone, and reduction in fluorescence ratio, were obtained in the presence of L-N(G)-nitroarginine and were thus independent of nitric oxide synthase inhibition; further, TRIM had no discernible effect on nitrergic responses. TRIM provides a novel drug for the selective inhibition of CCE and a template for the development of more potent inhibitors.

Animals↗
PubMed2001

An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A).

AIMS: The use of multiple probe substrates to evaluate the activity of drug metabolizing enzymes requires that there are no inter-substrate interactions. As part of a series of studies to develop a clinically useful collection of probe substrates that could be given alone or in any combination, we observed an interaction between midazolam (MDZ) and another component of the six-drug cocktail. Published data indicated that the interacting component was likely to be chlorzoxazone. This was investigated as part of a second study. The data relating to the interaction from both studies are reported here. METHODS: Both studies were performed in 16 healthy subjects. All treatments were given orally after an overnight fast. In study 1, which was performed to a four-period, open, crossover design, subjects received on separate occasions MDZ 5 mg, diclofenac 25 mg, a four drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg and chlorzoxazone 250 mg) and a six drug cocktail (caffeine 100 mg, mephenytoin 100 mg, debrisoquine 10 mg, chlorzoxazone 250 mg, diclofenac 25 mg and MDZ 5 mg). In study 2, which was performed to a two-period, open, crossover design, subjects received a five drug cocktail (as the six drug cocktail in the first study, but without chlorzoxazone and with diclofenac dose increased to 50 mg) and a six drug cocktail (as five drug cocktail, with chlorzoxazone 250 mg). In both studies, blood samples were taken for measurement of plasma MDZ and 1-hydroxy MDZ (1-OH MDZ) concentrations. In study 1, blood samples were taken up to 12 h post-dose while in study 2 a single sample was taken 2 h after dosing. In study 1, the potential interaction between MDZ and the other components of the six drug cocktail was assessed by comparing AUClast ratios (1-OH MDZ/MDZ) between the two treatments. Additionally, a single sampling timepoint of 2 h post-dose for determination of concentration, rather than AUC, ratios was established. The 2 h plasma concentration ratios from studies 1 and 2 were combined and a pooled analysis performed to compare ratios within each study (to determine the change in ratio when MDZ was dosed with and without chlorzoxazone) and between studies (to determine the consistency of the ratios when MDZ was given either as part of the two six drug cocktails or when given alone and as part of the five drug cocktail). RESULTS: In study 1, both the AUClast ratio and the 2 h post-dose plasma concentration ratio were reduced when MDZ was given as part of the six drug cocktail in comparison with those for MDZ alone. This was the result of an increase in MDZ, rather than decrease in 1-OH MDZ, concentrations and was considered to result from a reduction in first pass metabolism of MDZ. The geometric mean AUClast values (with 95% CI) for MDZ were 95.6 (79.0, 115.7) and 160.4 (133.6, 192.6) microg l(-1) h when given alone and as part of the six drug cocktail, respectively. The corresponding values for 1-OH MDZ were 789.6 (697.6, 893.6) and 791.4 (701.7, 892.6) microg l(-1) h. The ratio of adjusted geometric mean AUClast ratios for the two treatments was 1.82 (90% CI 1.48, 2.23, P < 0.001). The pooled plasma 1-OH MDZ/MDZ ratio data from both studies showed that the differences in MDZ metabolism observed in study 1 were replicated in study 2. The adjusted geometric mean 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the six drug cocktail were 7.79 and 4.59, respectively, for study 1 (ratio 1.70, 95% CI 1.36, 2.11, P < 0.001) and 7.64 and 4.60 for study 2 (ratio 1.66, 95% CI 1.34, 2.06, P < 0.001). These data indicate that when given orally chlorzoxazone interacts with MDZ, increasing plasma MDZ concentrations. In contrast, there was no difference between the plasma 1-OH MDZ/MDZ ratios when MDZ was given alone and as part of the five drug cocktail indicating that there were no interactions between MDZ and any of the other components of that cocktail. CONCLUSIONS: Chlorzoxazone appears to significantly influence the pharmacokinetics of oral MDZ, probably through inhibition of first pass metabolism by CYP3A in the GI tract. Data from these studies and literature evidence showing a further interaction between chlorzoxazone and CYP1A2 substrates and questions concerning the specificity of chlorzoxazone as a probe substrate for CYP2E1, indicate that the use of chlorzoxazone in multisubstrate probe cocktails should be avoided.

Administration, Oral↗
PubMed2001

Functional glucocorticoid receptors in the mesonephros of the ovine fetus.

BACKGROUND: At 27 days of gestation in the ovine fetus (term = 145 to 150 days), the only kidney is the mesonephros, and allantoic fluid represents fetal urine. The hypothesis tested in this study was that functional glucocorticoid receptors (GRs) are present in this early mesonephric kidney. METHODS: Pregnant ewes, between 26 and 30 days, were infused with saline, dexamethasone (0.48 mg/hour), cortisol (5 mg/hour), or aldosterone (10 microg/hour) for 48 hours and were then killed for collection of fetuses and fetal fluids. GR mRNA was measured by real-time polymerase chain reaction in whole fetuses, and the location of gene expression was determined by hybridization histochemistry. RESULTS: Significant changes in allantoic fluid composition were produced by the exposure of the fetus to maternally infused synthetic (dexamethasone) and natural (cortisol) glucocorticoids, over a period of two days, compared with fetuses of ewes infused with vehicle (isotonic saline; N = 8) or aldosterone (N = 8). Volume of fluid was unchanged by any treatment, but both dexamethasone (N = 10) and cortisol (N = 8) caused significant (P < 0.05) decreases in sodium and chloride concentrations and increases in concentrations of potassium, urea, glucose, and fructose. GR mRNA was detected in equivalent concentrations in the whole fetuses of saline, dexamethasone, and cortisol treatments. The GR mRNA levels were significantly decreased in the aldosterone group. By hybridization histochemistry, GR mRNA was detected in most of the tubular cells of the mesonephros. CONCLUSION: These results suggest that functional GRs are present in the early ovine mesonephros.

Allantois↗
PubMed2001

Solving the forward problem in electrical impedance tomography for the human head using IDEAS (integrated design engineering analysis software), a finite element modelling tool.

If electrical impedance tomography is to be used as a clinical tool, the image reconstruction algorithms must yield accurate images of impedance changes. One of the keys to producing an accurate reconstructed image is the inclusion of prior information regarding the physical geometry of the object. To achieve this, many researchers have created tools for solving the forward problem by means of finite element methods (FEMs). These tools are limited, allowing only a set number of meshes to be produced from the geometric information of the object. There is a clear need for geometrical accurate FEM models to improve the quality of the reconstructed images. We present a commercial tool called IDEAS, which can be used to create FEM meshes for these models. The application of this tool is demonstrated by using segmented data from the human head to model impedance changes inside the head.

Algorithms↗
PubMed2001

Electrical impedance tomography of human brain activity with a two-dimensional ring of scalp electrodes.

Previously, electrical impedance tomography (EIT) has been used to image impedance decreases in the exposed cortex of rabbits during brain activity. These are due to increased blood volume at the site of the stimulated cortex; as blood has a lower impedance than brain, the impedance decreases. During human brain activity similar blood flow changes have been detected using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). If blood volume also changes then the impedance of human cortex will change during brain activity; this could theoretically be imaged with EIT. EIT data were recorded from a ring of 16 scalp electrodes in 34 recordings in 19 adult volunteers before, during and after stimulation with (1) a visual stimulus produced by an 8 Hz oscillating checkerboard pattern or (2) sensory stimulation of the median nerve at the wrist by a 3 Hz electrical square wave stimulus. Reproducible impedance changes, with a similar timecourse to the stimulus, were seen in all experiments. Significant impedance changes were seen in 21 +/- 5% (n = 16, mean +/- SEM) and 19 +/- 3% (n = 18) of the electrode measurements for visual and somatosensory paradigms respectively. The reconstructed 2D EIT images showed reproducible impedance changes in the approximate region of the stimulated cortex in 7/16 visual and 5/18 somatosensory experiments. This demonstrates that reproducible impedance changes can be measured during human brain activity. The final images contained spatial noise; the reasons for this and strategies to reduce this in future are discussed.

Adult↗
PubMed2001

Validation of a 3D reconstruction algorithm for EIT of human brain function in a realistic head-shaped tank.

Previous work has demonstrated that electrical impedance tomography can be used to image human brain activity during evoked responses, but two-thirds of the reconstructed images fail to localize an impedance change to the expected stimulated cortical area. The localization failure may be caused by modelling the head as a homogenous sphere in the reconstruction algorithm. This assumption may lead to errors when used to reconstruct data obtained from the human head. In this study a 3D reconstruction algorithm, based on a model of the head as a homogenous sphere, was characterized by simulating the algorithm model, the head shape and the presence of the skull in saline-filled tanks. EIT images of a sponge, 14 cm3 volume with a resistivity contrast of 12%, were acquired in three different positions in tanks filled with 0.2% saline. In a hemispherical tank, 19 cm in diameter, the sponge was localized to within 3.4-10.7% of the tank diameter. In a head-shaped tank, the errors were between 3.1 and 13.3% without a skull and between 10.3 and 18.7% when a real human skull was present. A significant increase in localization error therefore occurs if an algorithm based on a homogeneous sphere is used on data acquired from a head-shaped tank. The increased error is due to the presence of the skull, as no significant increase in error occurred if a head-shaped tank was used without the skull present, compared to the localization error within the hemispherical tank. The error due to the skull significantly shifted the impedance change within the skull towards the centre of the image. Although the increased localization error due to the skull is not sufficient to explain the localization errors of up to 50% of the image diameter present in the images of some human subjects, the future use of a realistic head model in the reconstruction algorithm is likely to reduce the localization error in the human images due to the presence of the skull.

Algorithms↗
PubMed2001

Effects of limb-length discrepancy on gait economy and lower-extremity muscle activity in older adults.

BACKGROUND: The amount of limb-length discrepancy necessary to adversely affect gait parameters in older adults is unknown, with information being largely anecdotal. This investigation was conducted to determine the effects of limb-length discrepancy on gait economy and lower-extremity muscle activity in older adults. METHODS: Forty-four men and women ranging in age from fifty-five to eighty-six years with no evidence of limb-length discrepancy of >1 cm participated in the study. Subjects walked on a treadmill at a self-selected normal walking pace with artificial limb-length discrepancies of 0, 2, 3, and 4 cm applied in a randomly selected order. Indirect calorimetry was used to measure oxygen consumption and minute ventilation. Electromyography was used to measure muscle activity of the right and left quadriceps femoris, plantar flexors, gluteus maximus, and gluteus medius. Heart rate, the rating of perceived exertion, and frequency of gait compensation patterns were also measured. RESULTS: There was a significant increase in oxygen consumption and the rating of perceived exertion with 2, 3, and 4-cm artificial limb-length discrepancies; a significant increase in heart rate, minute ventilation, and quadriceps activity in the longer limb with 3 and 4-cm artificial limb-length discrepancies; and a significant increase in plantar flexor activity in the shorter limb with a 4-cm artificial limb-length discrepancy compared with the same parameters with no artificial limb-length discrepancy. CONCLUSIONS: Both oxygen consumption and the rating of perceived exertion were greater with a 2-cm artificial limb-length discrepancy than they were with no artificial limb-length discrepancy. There appears to be a breakpoint between 2 and 3 cm of artificial limb-length discrepancy in older adults with regard to the effects on most other physiological parameters. A 3-cm artificial limb-length discrepancy is likely to induce significant quadriceps fatigue in the longer limb. Elderly patients with substantial pulmonary, cardiac, or neuromuscular disease may have difficulty walking with a limb-length discrepancy as small as 2 cm.

Aged↗
PubMed2000

Sildenafil citrate on nitrergic transmission in anococcygeus muscles from the urogenital system of male and female mice.

The effects of sildenafil on nitrergic relaxations were compared in anococcygeus muscles from male and female mice. In muscles from both sexes, sildenafil (10-300 nM) produced a weak, direct relaxation of carbachol-induced tone, and increased both the amplitude and duration of nitrergic relaxations. The most marked effect was on nitrergic duration (300-400% increase with 300 nM sildenafil); no differences in potency were observed between male (EC(50), 30 nM) and female (EC(50), 25 nM). The rate of onset for potentiation of nitrergic duration was similar in both sexes; but, on washout, the effects of sildenafil declined more slowly in the male muscle. Relaxations to both nitric oxide (NO) and sodium nitroprusside were also increased in amplitude and duration by 50 nM sildenafil, while those to forskolin and papaverine were unaffected. The results demonstrate that sildenafil causes a similar, potent and selective potentiation of nitrergic transmission in urogenital smooth muscle from both male and female mice.

Animals↗