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T M Mayhew

Publications and source records attributed to T M Mayhew.

At least 19 recordsLinked to original sources
PubMed2000

To what extent are the retinal capillaries ensheathed by Müller cells? A stereological study in the tree shrew Tupaia belangeri.

The cellular ensheathment of capillaries in the 3 outer capillary layers of the central retina of the adult tree shrew Tupaia belangeri was studied quantitatively by transmission electron microscopy. Using a stereological approach, the relative surface of capillary basal lamina ensheathed by Müller cells and by nonmacroglial cells (collectively termed non-Müller cells) was estimated in 5 animals. The participation of Müller cells was distinctly different in the 3 capillary layers studied. In the outermost capillary layer 1, the mean (standard deviation) percentage surface coverage by non-Müller cell processes was 46.8 (15.3)%. Much less of the capillary basal lamina was ensheathed by non-Müller cells in capillary layers 2 and 3 (3.0 (2.1)% and 0.3 (0.3)% respectively). The observed total variation of the stereological estimates for the surface fraction of Müller cells (expressed as the between-subject coefficient of variation) was significantly higher in capillary layer 1 (28.8%) compared with capillary layers 2 (2.2%) and 3 (0.3%). In capillary layer 1, the high observed total variation was due to a high biological variation among animals for the fractions of both Müller cell and non-Müller cell ensheathment. The rare occurrence of direct contacts between the capillary basal lamina and the perikarya of either microglial cells (capillary layer 3) or amacrine cells (capillary layer 2) corresponded well to the low stereological values obtained for the relative capillary surface ensheathed by non-Müller cells in these capillary layers. Previously, extensive and frequent contacts between the basal lamina of capillaries belonging to capillary layer 1 and horizontal cells had been observed in single sections. The present study quantitatively demonstrates a marked paucity of macroglial investment of capillaries located in capillary layer 1 of Tupaia. It can be concluded that horizontal cells ensheath most of the capillary surface not invested by Müller cells.

Animals↗
PubMed1999

Ventricular myocardium in control and growth-retarded human fetuses: growth in different tissue compartments and variation with fetal weight, gestational age, and ventricle size.

The aim of this study was to assess the growth of different tissue compartments in ventricular myocardium of control and intrauterine growth-retarded (IUGR) human subjects. Stereological counting and sizing methods were applied to cross-sectional samples of hearts collected post mortem at 16 to 35 (control) and 32 to 42 (IUGR) gestational weeks. Total tissue volumes and total numbers of myocyte, connective tissue, and endothelial cell nuclei were estimated. In control hearts, the volume of each tissue compartment increased linearly over the period of gestation, and this was due to proliferation, because in each case the tissue volume per nucleus remained constant. In IUGR subjects, fetal weight, ventricle volume, myocyte volume, connective tissue volume, and endothelial nuclear number were less than expected for gestational age up to at least 35 weeks. Between this age and 8 postnatal weeks, these variables are predicted to achieve equivalence with values found in control fetuses. Similar deficits were found when variables were related to fetal weight, and it is predicted that equivalence with control values would be reached at weights of between 2.3 and 3.6 kg. No such differences between groups were detected when variables were related to ventricle size. These findings indicate that growth deficits in cardiomyocytes are accompanied, and may be influenced, by developmental delays that involve the intramyocardial interstitium (capillary bed, endothelium, and surrounding connective tissues). The delays and deficits exhibit "catch-up" to control values between 35 weeks and term.

Embryonic and Fetal Development↗
PubMed1999

Effects of neonatal capsaicin administration on the numbers and volumes of neurons in left and right T10 dorsal root ganglia in the rat.

The long-term effects of neonatal capsaicin were studied in left and right dorsal root ganglia (T10) from control and capsaicin-treated groups of Wistar rats. At 12 hours post partum, 5 females per group were injected subcutaneously with capsaicin or vehicle solution and killed at 6 months of age. Tissues were perfusion-fixed, embedded in resin and serially sectioned. A Nissl stain was used to distinguish between A and B neurons and systematic random sampling schemes were employed to obtain stereological estimates of numbers of neurons and mean volumes of their perikarya. Numbers were calculated from ganglion volumes (estimated via the Cavalieri principle) and neuron packing densities (estimated using physical disectors). Mean perikaryal volumes were calculated from packing densities and volume densities (estimated by point counting). Data were analysed to isolate main and interaction effects of neuron subtype, laterality and treatment. There was no evidence of lateral asymmetry or interaction effects. Control ganglia contained 3320 (coefficient of variation, CV, 8%) neurons. Most (73%) were B cells with a mean volume of 13,100 microm(3) (CV 17%) of which the nucleus accounted for 1,800 microm(3) (CV 18%). About 22% were A cells with a mean volume of 79,800 microm(3) (CV 24%) and a nucleus of 6,100 microm(3) (CV 26%). After capsaicin, over half the original population of cells was destroyed and B cell loss was significantly greater than that of A cells (about 80% of all cells lost were B cells). The mean size of A cells was greater after capsaicin due to selective loss of smaller cells and a greater volume of cytoplasm. B cell perikaryal volume was not affected but nuclear volume declined. The findings show that capsaicin destruction of peripheral sensory neurons is bilaterally symmetrical. In general, smaller neurons are selectively destroyed but this operates differently in A and B cells. It is size-dependent in A cells but size-independent (possibly random) in B cells.

Animals↗
PubMed1999

Second-order stereology and ultrastructural examination of the spatial arrangements of tissue compartments within glomeruli of normal and diabetic kidneys.

The present study explores 3D spatial arrangements of compartments within the rat renal glomerulus and tests for differences after chemically-induced diabetes. In particular, the arrangements of capillaries, podocytes, mesangium and urinary space are quantified and compared between (a) kidneys within groups and (b) kidneys from streptozotocin-diabetic rats and age-matched controls. The stereological tool employed is the pair correlation function which is estimated by counting linear dipole probes of different sizes superimposed on ultrathin sections so as to be random in position and orientation. Unbiased estimates of the volume density of each glomerular component were estimated by point counting. Thereafter, estimates of the covariance and pair correlation function were determined from corresponding dipole counts. Plots of covariance and pair correlation functions against dipole length were almost identical in control and diabetic groups, indicating that diabetes did not disturb the normal spatial arrangements within glomeruli. However, differences were detected between compartments within groups. Whilst volume elements within all compartments were clustered at distances below about 8 microm (the approximate size of the basic cellular or other structural unit), the cluster size varied between compartments. The pattern was one of progressively smaller clusters in the sequence capillaries, podocytes, urinary space, mesangium. Beyond a distance of 8 microm, all glomerular components (in both control and diabetic groups) were arranged as expected for a 'random' (meaning neither clustered nor repulsed) volume process. These studies re-emphasize the relative invariance of biological organization and the value and limitations of covariance analysis for quantifying different levels of organization in different tissues and experimental groups.

Animals↗
PubMed1999

Quantitative description of the spatial arrangement of organelles in a polarised secretory epithelial cell: the salivary gland acinar cell.

Previous quantitative descriptions of cellular ultrastructure have focused on spatial content (volume, surface area and number of organelles and membrane domains). It is possible to complement such descriptions by also quantifying spatial arrangements. Hitherto, applications of stereological methods for achieving this (notably, estimation of covariance and pair correlation functions) have been confined to organ and tissue levels. This study explores 3-dimensional subcellular arrangements of key organelles within acinar cells of rabbit parotid salivary glands, highly polarised epithelial cells specialised for exocrine secretion of alpha-amylase. It focuses on spatial arrangements of secretion product stores (zymogen granules), rough endoplasmic reticulum (RER) and mitochondria. Systematic random samples of electron microscopical fields of view from 3 rabbits were analysed using test grids bearing linear dipole probes of different sizes. Unbiased estimates of organelle volume densities were obtained by point counting and estimates of covariance and pair correlation functions by dipole counting. Plots of pair correlation functions against dipole length identified spatial arrangement differences between organelle types. Volumes within RER and mitochondrial compartments were positively correlated with themselves at distances below 4 microm and 2 microm respectively but were essentially randomly arranged at longer distances. In sharp contrast, zymogen granules were not randomly arranged. They were clustered at distances below 6-7 microm and more widely scattered at greater distances. These findings provide quantitative confirmation of the polarised arrangement of zymogen granules within acinar cells and further support for the relative invariance of biological organisation between subjects.

Animals↗
PubMed1999

Epithelial integrity, cell death and cell loss in mammalian small intestine.

In recent years, the different mechanisms of epithelial cell loss which occur in mammalian and avian small intestine have been re-investigated. Information is now available for a variety of mammalian types and mechanisms can be divided into two major classes: [i] those preserving epithelial integrity by maintaining intercellular tight junctions throughout early-to-late stages of cell extrusion; and [ii] those which compromise integrity by introducing breaches in epithelial continuity. Both classes are associated with the activity and/or proximity of non-epithelial cells (mainly lymphocytes and mononuclear phagocytes) located in the epithelium or underlying lamina propria. Intraepithelial lymphocytes may be involved in enterocyte targetting and killing whilst lamina propria (LP) macrophages sequester cell debris. Where epithelial integrity is maintained, two types of loss can be identified. In the first (type 1), complete cells are extruded into the lumen. In the second (type 2), only anucleate apical cell fragments pass into the lumen. There are two variants of type 2 loss distinguishable by the fate of the nucleated basal portions of cells. One variant (type 2a) creates large intercellular spaces extending from the preserved apical cap to the basal lamina and containing enterocyte debris for phagocytosis. The second (type 2b) involves the gradual shrinkage of individual cells (which become more electron-dense) and in situ degeneration of their nucleated subapical portions in increasingly narrower intercellular spaces between adjacent healthy enterocytes. The mechanism of removal of these fragments is unclear but may be via macrophages or surrounding enterocytes. Apoptosis has been implicated in both type 1 and type 2 extrusion. In contrast, type 3 loss involves morphological changes in enterocytes which are reminiscent of those seen in necrosis and is accompanied by breaks in epithelial continuity following cell swelling, a decrease in cell electron density and total or subtotal degradation of organelles and membranes. It ends in loss of either an abnormal cell apex (with subsequent exposure of the degraded cell contents and their spillage into the lumen) or a complete cell remnant (extruded into the lumen before total disintegration of plasma membranes).

Animals↗
PubMed1998

Numbers of nuclei in different tissue compartments of fetal ventricular myocardium from 16 to 35 weeks of gestation.

The aim of this study was to examine mechanisms of growth in different tissue compartments of the ventricular myocardium of prenatal human hearts. To this end, stereological methods were applied in order to estimate tissue volumes and total numbers of myocyte, connective tissue and endothelial nuclei in hearts collected after death at between 16 and 35 weeks of gestation. Volumes of tissue compartments were obtained after multiplying volume densities (estimated by test-point counting) by ventricular volumes (estimated from ventricular mass and tissue density). Absolute numbers of nuclei were calculated in similar fashion from corresponding nuclear packing densities (estimated using physical disectors). The volumes of all three tissue compartments increased linearly over the period of gestation examined, and in each case, the increase in tissue volume appeared to be due entirely to proliferation. Numbers of all three types of nuclei increased linearly whilst tissue volumes per nucleus remained constant. The net rate of production of myocyte nuclei was 35 x 10(7) per week (2.1 million nuclei per hour). The net rate of production of connective tissue nuclei was 12 x 10(7) per week (0.7 million nuclei per hour) and that for endothelial cell nuclei was 5.1 x 10(7) per week (0.3 million nuclei per hour). Predictions are made about the postnatal ages at which adult ratios of different nuclear types might be attained.

Body Weight↗
PubMed1998

Further evidence of species variation in mechanisms of epithelial cell loss in mammalian small intestine: ultrastructural studies on the reindeer (Rangifer tarandus) and seal (Phoca groenlandica).

Ultrastructural studies were conducted on mechanisms of epithelial cell loss in the small intestine of seal and reindeer. Mechanisms maintaining epithelial integrity were distinguished from those that did not and the non-epithelial cell types involved were identified. Three types of cell extrusion were noted. In two, tight junctional integrity was preserved and anucleate apical cell fragments (rather than complete cells) were lost into the lumen. In reindeer (type 1), this involved creating large intercellular spaces extending from the preserved apical cap to the lamina propria and containing enterocyte debris probably phagocytosed by subepithelial macrophages. A variant of this process (type 2) involved the gradual shrinkage of individual cells, which became more electron-dense, and the in situ degeneration of their nucleated subapical portions. Degenerated cell fragments and membrane whorls were confined to narrow intercellular spaces between approximating adjacent healthy enterocytes. The mechanism of removal of these fragments was unclear. In both cases, the proximity of intraepithelial lymphocytes suggested that they were involved in cell targetting and killing. Evidence of apoptotic nuclei was not found but nucleated cell fragments could have been washed out of the lumen during tissue preparation. Type 2 cell loss was seen in both species, as was another mechanism (type 3) reminiscent of necrosis. In contrast to other mechanisms, this was accompanied by breaks in epithelial continuity following gradual loss of cell electron density and total or subtotal degradation of organelles and membranes. In seal, this terminated in the loss of an abnormal cell apex and exposure of the contents of the cell remnant to the lumen. In reindeer, all the cell remnants may have been extruded before total membrane degeneration but, in both species, the otherwise tight epithelial barrier was clearly breached. Again, intraepithelial lymphocytes were associated with sites of necrosis. These findings provide evidence for further species differences in mechanisms of epithelial cell extrusion and suggest that necrotic cell loss may be more common than previously admitted.

Animals↗
PubMed1998

Thinning of the intervascular tissue layers of the human placenta is an adaptive response to passive diffusion in vivo and may help to predict the origins of fetal hypoxia.

OBJECTIVES: To test the hypothesis that thinning of the placental intervascular layers, and greater variability in thickness, are positive adaptations to facilitate passive diffusion and may help to resolve different categories of fetal hypoxia. STUDY DESIGN: Placentas from 12-41 weeks of normal gestation and from pregnancies associated with fetal hypoxic stress (high altitude, diabetes mellitus) were sampled systematically, fixed in formalin, wax-embedded and quantified using stereological methods. Arithmetic and harmonic mean distances across villous trophoblast, stroma and fetal plasma were estimated by measuring randomly sampled intercept lengths. In each case, an index of variability of layer thickness was calculated by dividing the arithmetic by harmonic mean distance. This index has the value I when a tissue layer is uniformly thick but increases in value as local layer thickness becomes more variable. Comparisons between groups were drawn using variance and regression analysis. RESULTS: During pregnancy, there were significant negative correlations between layer thickness (trophoblast, stroma) and gestational age and fetal weight, and significant positive correlations between thickness irregularity and age and weight. Compared with lowland controls, high-altitude placentas possessed thinner layers but only the trophoblast and stroma (and not fetal plasma) were more variably thick. In maternal diabetes, only fetal plasma distance was reduced but fetal and stromal layers appeared to be more irregular in thickness. CONCLUSIONS: Alterations in placental intervascular layer thicknesses occur in normal and abnormal pregnancies and represent real adaptations leading to improved diffusive conductances. Differences in the tissue location of the adaptive response may depend on the nature and origins of the fetal hypoxia.

Adaptation, Physiological↗
PubMed1997

Photoreceptor number and outer segment disk membrane surface area in the retina of the rat: stereological data for whole organ and average photoreceptor cell.

A random sampling scheme is employed to obtain stereological estimates of disk membrane surface area in the entire retina and in the average photoreceptor cell. The scheme involves the use of vertical sections with combined light and electron microscopy at several magnification levels. Left and right retinas from six albino animals were analysed. There were no significant lateral differences. On average, the retina had a volume of 16 mm3, thickness of 200 microns and surface area of 80 mm2 (representing about 56% of the external surface of the eyeball). Photoreceptor disk membranes within outer segments amplified total retinal surface by almost 1000-fold (final surface 770 cm2 per retina). The retina contained 3 x 10(7) photoreceptors (packing density 374,000 mm-2) with an average disk membrane surface area of 2600 microns2. Mean nuclear volume in photoreceptor cells was 59 microns3 and the coefficient of variation for the distribution of nuclear volumes was 57%. The data are consistent with an average of 700 disks per photoreceptor cell, a membrane area of 4 microns2 per disk and a convergence ratio of approximately 260 photoreceptors per optic nerve fibre. The basic scheme could be modified for other species and for direct cell counts conducted on rods and cones separately.

Animals↗
PubMed1997

Recent applications of the new stereology have thrown fresh light on how the human placenta grows and develops its form.

The availability of design-based stereological methods has made it possible to readdress certain key and contentious issues in placental growth and morphogenesis. Three particular questions are: (i) does the population of cytotrophoblast cells decline during gestation?, (ii) is placental growth biphasic or monophasic? and (iii) what are the consequences for intervillous porosity of the elaboration of terminal villi? These questions cannot be answered definitively without recourse to the new stereology. Applying the disector to estimate nuclear number and star volume to assess pore size, recent studies have helped to resolve these issues. Their findings are reviewed. Nuclei were counted in the trophoblastic epithelium, stroma and vascular endothelium of placental villi. It was found that growth is monophasic and proliferative. All types of nuclei increased in number throughout gestation and this included cytotrophoblast. Trophoblast grows by the continuous recruitment of new proliferative units of uniform mean volume. The so-called 'loss' of cytotrophoblast cells is a misinterpretation of what is seen on microscopical sections and is attributable to disproportionate growth in villous surface area. Cells simply become more widely dispersed. Elaboration of finer terminal branches on villous trees leads to a decline in the star volumes of villi and intervillous pores. Some of the functional implications of these findings are discussed.

Chorionic Villi↗
PubMed1997

Response of substance P-immunoreactive nerve fibres in the anterior pituitary to plasma oestrogen levels in the rat.

The mammalian anterior pituitary has recently been shown to be innervated by substantial amounts of peptidergic nerve fibres. It has also been found that adrenalectomy increases the amount of calcitonin gene-related peptide-like immunoreactive nerve fibres in the anterior pituitary of the rat, and that stimulation of the nerve fibres in vitro can enhance release of ACTH. In the present study, the density of substance P-like immunoreactive nerve fibres in the anterior pituitary of the rat were examined in relation to variations in plasma oestrogen status. The amount of substance P-like immunoreactive nerve fibres increased significantly (P < 0.001) after ovariectomy, and decreased significantly (P < 0.01) under oestrogen replacement, in a dose-dependent manner. The results suggest the possibility of the direct neural involvement of oestrogen secretion in anterior pituitary regulation, which further substantiates the hypothesis of neural-humoral dual regulation of the mammalian anterior pituitary.

Animals↗
PubMed1997

Stereological estimates of nuclear number in human ventricular cardiomyocytes before and after birth obtained using physical disectors.

Design-based stereology is employed to estimate total numbers of myocyte nuclei and mean myocyte volume per nucleus in ventricles of fetal and early postnatal human hearts. Organs were collected postmortem from subjects varying in age from 16 gestational wk to 40 postnatal wk. Numbers of myocyte nuclei per unit volume of ventricle were estimated using physical disectors (parallel pairs of sections). Absolute numbers were calculated by multiplying nuclear packing densities by ventricular volumes estimated from ventricular mass and tissue density. Volumes per nucleus were obtained via estimates of the combined volumes of all myocytes (or of the myocardium as a whole) and the numbers of myocyte nuclei. The findings showed that numbers of myocyte nuclei increase linearly from 16 wk towards term. They were also consistent with the notion that hyperplasia ceases abruptly at birth or soon afterwards. The net rate of production of myocyte nuclei was about 38 x 10(7)/wk (2.3 million nuclei/h). The total volume of myocytes continued to expand in the same way from 16 wk to at least 35 wk of gestation. Published studies on the incidence of binucleate myocytes during early postnatal growth of the ventricles of rats suggest that the volume of a myocyte doubles prior to nuclear division. Prenatal growth in the human heart is consistent with this mechanism. Myocardial hypertrophy after birth must occur by cellular hypertrophy without karyokinesis.

Cell Nucleus↗
PubMed1997

A stereological comparison of villous and microvillous surfaces in small intestines of frugivorous and entomophagous bats: species, inter-individual and craniocaudal differences.

The extents of functional surfaces (villi, microvilli) have been estimated at different longitudinal sites, and in the entire small intestine, for three species of bats belonging to two feeding groups: insect- and fruit-eaters. In all species, surface areas and other structural quantities tended to be greatest at more cranial sites and to decline caudally. The entomophagous bat (Miniopterus inflatus) had a mean body mass (coefficient of variation) of 8.9 g (5%) and a mean intestinal length of 20 cm (6%). The surface area of the basic intestinal tube (primary mucosa) was 9.1 cm2 (10%) but this was amplified to 48 cm2 (13%) by villi and to 0.13 m2 (20%) by microvilli. The total number of microvilli per intestine was 4 x 10(11) (20%). The average microvillus had a diameter of 8 nm (10%), a length of 1.1 microns (22%) and a membrane surface area of 0.32 micron 2 (31%). In two species of fruit bats (Epomophorus wahlbergi and Lisonycteris angolensis), body masses were greater and intestines longer, the values being 76.0 g (18%) and 76.9 g (4%), and 73 cm (16%) and 72 cm (7%), respectively. Surface areas were also greater, amounting to 76 cm2 (26%) and 45 cm2 (8%) for the primary mucosa, 547 cm2 (29%) and 314 cm2 (16%) for villi and 2.7 m2 (23%) and 1.5 m2 (18%) for microvilli. An increase in the number of microvilli, 33 x 10(11) (19%) and 15 x 10(11) (24%) per intestine, contributed to the more extensive surface area but there were concomitant changes in the dimensions of microvilli. Mean diameters were 94 nm (8%) and 111 nm (4%), and mean lengths were 2.8 microns (12%) and 2.9 microns (10%), respectively. Thus, an increase in the surface area of the average microvillus to 0.83 micron 2 (12%) and 1.02 microns 2 (11%) also contributed to the greater total surface area of microvilli. The lifestyle-related differences in total microvillous surface areas persisted when structural quantities were normalised for the differences in body masses. The values for total microvillous surface area were 148 cm2g-1 (20%) in the entomophagous bat, 355 cm2g-1 (20%) in E. wahlbergi and 192 cm2g-1 (17%) in L. angolensis. This was true despite the fact that the insecteater possessed a greater length of intestine per unit of body mass: 22 mm g-1 (8%) versus 9-10 mm g-1 (9-10%) for the fruit-eaters.

Animals↗
PubMed1996

How to count synapses unbiasedly and efficiently at the ultrastructural level: proposal for a standard sampling and counting protocol.

After almost 40 years, there is still no consensus on criteria for identifying different types of synapse seen in electron microscopical thin sections or on methods for counting them unbiasedly in 3D. This review proposes a procedure which meets these aims and could be adopted as a standard best-practice sampling and counting convention. It deals exclusively with unbiased stereological methods for counting particles in 3D space because these are efficient and applicable to arbitrary particles regardless of their size, shape and orientation. Methods based on individual sections are excluded because arbitrary particles cannot be counted unbiasedly with such sections. Model-based methods (e.g. treating synaptic membrane densities as circular disks) are excluded because they are not unbiased in general and now have limited (mainly historical) interest only. For unbiased counting, the absolute minimum requirement is a pair of parallel sections (dissector). The following protocol is recommended for future studies on synapse number: (1) use para(membrane) densities as synaptic counting units, (2) do not qualify definition of the counting unit by reference to a minimum number of synaptic vesicle profiles, (3) sample and count synapses unbiasedly using the dissector, and (4) in preference convert number per volume into absolute number or, in this is not possible, estimate a synapse-to-neuron ratio.

Animals↗
PubMed1996

Patterns of villous and intervillous space growth in human placentas from normal and abnormal pregnancies.

OBJECTIVES: To apply a new stereological approach (relating an exponent of villous surface to volume) to test for patterns of change in placental villi and intervillous space from normal and abnormal pregnancies. STUDY DESIGN: Placentas from normal gestation and pregnancies associated with hypoxic stress (high altitude, diabetes, cigarette smoking) were sampled randomly, fixed in formalin and embedded in paraffin wax for stereological analysis. Volumes (villi, intervillous space) were estimated by point counting and surface areas (villi) by intersection counting. A dimensionless coefficient (S3/2/V) was then calculated to test for isomorphic changes. Comparisons within groups were drawn using analysis of variance. RESULTS: Changes in villi were isomorphic at high altitude and in placentas from women who smoked during pregnancy. The same pattern is seen in placentas associated with preeclampsia. Changes during gestation and diabetes are anisomorphic, i.e. villous surface area alters disproportionately to volume. A similar pattern is seen in maternal anaemia. Alterations in the intervillous space were isomorphic in diabetes and smoking but anisomorphic during gestation, at high altitude and in maternal anaemia and pre-eclampsia. CONCLUSIONS: The approach has advantages over alternatives (star volume and topological analysis). Structural changes influence placental transport and haemodynamics but there are subtle differences between groups which may depend on the nature of the hypoxic stress and the adaptations made by individual tissue compartments.

Altitude↗