Suppression of black-hole growth by strong outflows at redshifts 5.8-6.6.

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old1. How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass2,3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver4. Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲ z ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z ≳ 5.8 is ≈2.4 times higher than at z ≈ 2-4. We infer that outflows at z ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion5.

Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies.

We examined the roles of the extracellular domains of a gap junction protein and a cell adhesion molecule in gap junction and adherens junction formation by altering cell interactions with antibody Fab fragments. Using immunoblotting and immunocytochemistry we demonstrated that Novikoff cells contained the gap junction protein, connexin43 (Cx43), and the cell adhesion molecule, A-CAM (N-cadherin). Cells were dissociated in EDTA, allowed to recover, and reaggregated for 60 min in media containing Fab fragments prepared from a number of antibodies. We observed no cell-cell dye transfer 4 min after microinjection in 90% of the cell pairs treated with Fab fragments of antibodies for the first or second extracellular domain of Cx43, the second extracellular domain of connexin32 (Cx32) or A-CAM. Cell-cell dye transfer was detected within 30 s in cell pairs treated with control Fab fragments (pre-immune serum, antibodies to the rat major histocompatibility complex or the amino or carboxyl termii of Cx43). We observed no gap junctions by freeze-fracture EM and no adherens junctions by thin section EM between cells treated with the Fab fragments that blocked cell-cell dye transfer. Gap junctions were found on approximately 50% of the cells in control samples using freeze-fracture EM. We demonstrated with reaggregated Novikoff cells that: (a) functional interactions of the extracellular domains of the connexins were necessary for the formation of gap junction channels; (b) cell interactions mediated by A-CAM were required for gap junction assembly; and (c) Fab fragments of antibodies for A-CAM or connexin extracellular domains blocked adherens junction formation.

Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand.

Monkeys and human subjects were exposed to a series of thermal stimuli before and after a 53 degrees C, 30-second burn to the glabrous skin of the hand. The responses of C- and A-fiber nociceptive afferents in the monkeys and subjective responses by the humans were compared. The burn resulted in increased sensitivity of the A fibers, decreased sensitivity of the C fibers, and increased pain sensibility (hyperalgesia) in the human subjects.

Coupling of action potential activity between unmyelinated fibers in the peripheral nerve of monkey.

Bidirectional coupling of action potential activity occurs between unmyelinated fibers in the normal peripheral nerve of monkey. The site of coupling is near the cutaneous nociceptive receptor associated with one of the fibers. This coupling could be due to an electrical synapse and could provide the basis for the flare associated with the axon reflex.

The Vascular Access Questionnaire: assessing patient-reported views of vascular access.

BACKGROUND: The use of central venous catheters for vascular access in hemodialysis (HD) patients is associated with an increased risk of complications compared to arteriovenous fistulas (AVF). Despite this, catheter use remains high and patient satisfaction may be an important driver of catheter use. METHODS: We developed the Vascular Access Questionnaire (VAQ) to measure patient-reported views of their vascular access. Chronic HD patients at two centers were asked to rate how bothered they were by 17 access-related problems. VAQ symptom scores were compared between patients using catheters and those using fistulas for vascular access. RESULTS: Two hundred and twenty-two patients were eligible for the study. Symptom score was not different between patients using catheters and those using fistulas (p=0.36). However, patients using fistulas were more likely to be at least moderately bothered by pain, bleeding, bruising, swelling, and the appearance of their access than patients using catheters. Elderly patients reported lower symptom scores with catheters than fistulas. CONCLUSIONS: Patients appear to be primarily concerned with the appearance of their access and cannulation-related complications, particularly the elderly. Better education about the risk of adverse events with catheters and the implementation of measures aimed at reducing cannulation-related complications may help to increase fistula rates and improve patient satisfaction with their vascular access.

Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma.

Biomimetic materials that target the immune system and generate an anti-tumor responses hold promise in augmenting cancer immunotherapy. These synthetic materials can be engineered and optimized for their biodegradability, physical parameters such as shape and size, and controlled release of immune-modulators. As these new platforms enter the playing field, it is imperative to understand their interaction with existing immunotherapies since single-targeted approaches have limited efficacy. Here, we investigate the synergy between a PLGA-based artificial antigen presenting cell (aAPC) and a checkpoint blockade molecule, anti-PD1 monoclonal antibody (mAb). The combination of antigen-specific aAPC-based activation and anti-PD-1 mAb checkpoint blockade induced the greatest IFN-γ secretion by CD8+ T cells in vitro. Combination treatment also acted synergistically in an in vivo murine melanoma model to result in delayed tumor growth and extended survival, while either treatment alone had no effect. This was shown mechanistically to be due to decreased PD-1 expression and increased antigen-specific proliferation of CD8+ T cells within the tumor microenvironment and spleen. Thus, biomaterial-based therapy can synergize with other immunotherapies and motivates the translation of biomimetic combinatorial treatments.

Peripheral and central mechanisms of cutaneous hyperalgesia.

Hyperalgesia after cutaneous injury can be divided into two phenomena: Primary hyperalgesia occurs at the site of injury and is characterized by hyperalgesia to mechanical and heat stimuli. Secondary hyperalgesia occurs outside the injury site and is characterized by mechanical hyperalgesia only. Hyperalgesia in inflammatory processes corresponds to primary hyperalgesia. Hyperalgesia in referred pain and neuropathic pain resembles secondary hyperalgesia (Table 3). Evidence for the latter would be strengthened if hyperalgesia to cooling stimuli, which is observed in neuropathic pain, was also demonstrated in referred pain and in secondary hyperalgesia. Some of the more likely neural mechanisms to explain primary and secondary hyperalgesia are illustrated in Fig. 8. Primary hyperalgesia to heat stimuli has a counterpart in the sensitization of peripheral nociceptors to heat stimuli (Fig. 8A), leading to similar changes in central neurons. In addition, the enlargement of the mechanical receptive field of primary afferent nociceptors to include the site of injury may account for the primary hyperalgesia to mechanical stimuli (Fig. 8B). In the literature, there are some contradictions with respect to the stimulus modalities to which hyperalgesia and sensitization occur. In spite of the well-documented sensitization of primary afferent nociceptors to heat stimuli, there are few studies on its molecular mechanisms. On the other hand, there is pharmacological evidence for a peripheral mechanism of primary mechanical hyperalgesia, but little direct evidence that nociceptors can be sensitized to mechanical stimuli by injury. This contradiction should spawn further investigations into the mechanical response properties of nociceptors and into the molecular mechanisms of heat sensitization. Secondary hyperalgesia to mechanical stimuli is likely due to the sensitization of central pain signalling neurons (CPSNs). This sensitization could involve only input from nociceptors (Fig. 8C), since mechanical pain thresholds after a cutaneous injury are of the same order as those of nociceptors. Central sensitization could also be the result of enhanced connectivity between low-threshold mechanoreceptors and CPSNs (Fig. 8D). This form of sensitization may account for the pain to light touch associated with neuropathic pain. Receptive field plasticity is a prevalent property of dorsal horn neurons and probably plays a vital role with regard to hyperalgesia. The molecular mechanisms of synaptic plasticity are currently subject to intense experimental investigation and may provide new insights on the mechanisms of pain and hyperalgesia.

An ex vivo model for the study of tumor metabolism by nuclear magnetic resonance: characterization of the phosphorus-31 spectrum of the isolated perfused Morris hepatoma 7777.

We have developed an isolated perfused tumor model to study the metabolism of solid tumors by nuclear magnetic resonance spectroscopy. Morris hepatomas (7777) were implanted in the inguinal region of Buffalo rats, such that they developed an isolated blood supply. These tumors were perfused with a RBC perfusate, removed from the animal, and studied by 31P nuclear magnetic resonance spectroscopy. ATP levels, as determined from the spectra, were stable for as long as the tumors were maintained in the magnet (7 h) only if the perfusate contained inosine, adenosine, and insulin. The adenosine and inosine were also required for recovery from ischemia. Under these conditions, ischemia did not result in a change in tumor pH. The gamma nucleoside triphosphate resonance was significantly larger than the beta nucleoside triphosphate resonance in spectra of some of the perfused tumors, suggesting that ADP above about 300 nmol/g wet weight was not complexed in these tumors. The adenylate levels determined from extracts, O2 consumption, histology, and 31P nuclear magnetic resonance spectra of extracts of perfused tumors and tumors in situ were all similar, indicating the perfused tumor is a reasonable model of the tumor in vivo.

Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors.

The recently cloned vanilloid receptor (VR1) is postulated to account for heat and capsaicin sensitivity in unmyelinated afferents. We sought to determine whether heat and capsaicin sensitivity also coexist in myelinated nociceptive afferents. Action potential (AP) activity was recorded from single A-fiber nociceptors that innervated the hairy skin in monkey. Before intradermal injection of capsaicin (10 microg/10 microl) into the receptive field, nociceptors were classified as heat-sensitive (threshold,

Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers.

Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.

Comparison of structural glycoproteins from mucus of different sources.

The main structural glycoprotein derived from three mammalian mucociliary epithelial secretions (bovine cervical, human lung and human middle ear mucus) were compared. The glycoprotein was purified on a cesium chloride density gradient after prior cleavage of disulphide bonds. Marked similarities were seen for the glycoproteins in their sugar and amino acid composition, in electrophoretic mobility, in sedimentation rate and in their banding densities in a cesium chloride density gradient. The molecular weight of these materials was approximately 0.6-10(6). The similarity noted for these materials occurred despite two of them (lung and middle ear) being derived from pathological sources. The glycoprotein derived from an amphibian mucociliary epithelial secretion (frog palatal mucus) was different; it banded at a lower buoyant density and had a lower sugar content. These findings are discussed in terms of the rheological properties and physiological transport role of mucus on ciliated epithelia. It is suggested that reported differences in the properties of mammalian secretions from different sources is due to differences in the extent of crosslinking between glycoprotein units rather than to chemical or structural differences. In the case of the frog its very different composition may be in keeping with its rather different rheological properties.

Echocardiographically determined left ventricular mass index in normal children, adolescents and young adults.

Left ventricular hypertrophy is an important diagnostic and prognostic finding in children with cardiovascular disease, but there are currently no well established criteria for its determination by M-mode echocardiography. Three hundred thirty-four subjects, aged 6 to 23 years, who were free of cardiovascular disease were studied. Left ventricular mass was calculated using echocardiographic measurements in a regression equation for left ventricular mass. Intraobserver (r = 0.96, p less than 0.01) and interobserver (r = 0.89, p less than 0.01) variability were low. To anatomically validate the echographic formula for left ventricular mass, left ventricular measurements made at autopsy were inserted into the formula. Mass was then calculated and compared with the actual mass. There was a strong correlation between the calculated and the measured left ventricular mass (r = 0.89, p less than 0.01). Left ventricular mass was not statistically related to race, but it was strongly associated with gender (p less than 0.001). It was strongly correlated with height (r = 0.82 for males, r = 0.71 for females) and body surface area (r = 0.83 for males, r = 0.74 for females). Echocardiographic criteria for left ventricular hypertrophy in children and adolescents, based on the 95th percentile, for left ventricular mass, left ventricular mass corrected for body surface area and left ventricular mass corrected for height are, respectively: 184.9 g, 103.0 g/m2 and 99.8 g/m for males and 130.2 g, 84.2 g/m2 and 81.0 g/m for females.(ABSTRACT TRUNCATED AT 250 WORDS)

Differentiation of constrictive pericarditis and restrictive cardiomyopathy using digitized echocardiography.

Constrictive pericarditis and restrictive cardiomyopathy are difficult to distinguish at the bedside and occasionally at routine cardiac catheterization. Left ventricular diastolic function was studied by computer analysis of digitized M-mode echocardiograms in four patients with constrictive disease and three with restrictive disease, and the data were compared with those of normal subjects. The respective distinguishing echographic features of constrictive pericarditis and restrictive cardiomyopathy were as follows: the major filling period of the left ventricle was 78 +/- 9% of normal versus 128 +/- 4% (p less than 0.01), minimal left ventricular dimension to peak filling interval was 50 +/- 10 versus 110 ms (p less than 0.05) and the maximal rate of left ventricular posterior wall thinning was -4.9 versus -2.3 seconds-1 (p less than 0.05). This preliminary study suggests that it may be possible to accurately diagnose the two disease entities using this technique at the bedside and to avoid cardiac catheterization.

Relation of left ventricular mass, preload, afterload and contractility in pediatric patients with essential hypertension.

OBJECTIVES: The aim of this study was to determine if left ventricular preload, afterload or contractility is a correlate of left ventricular mass index in hypertensive pediatric patients. BACKGROUND: It is believed that decreased contractility and increased preload are associated with left ventricular hypertrophy in adult hypertensive patients. METHODS: Ninety pediatric hypertensive patients underwent echocardiography to assess left ventricular mass, preload (diastolic dimension and volume) and afterload (end-systolic wall stress, vascular resistance and blood pressure). Contractility was assessed by 1) the end-systolic stress/volume ratio, and 2) the difference between measured and predicted velocity of circumferential fiber shortening. Univariate and multivariate analyses were performed. RESULTS: Univariate analysis showed significant correlations between left ventricular mass and 1) body mass (r = 0.33, p < 0.001), 2) black race (r = 0.37, p < 0.0003), 3) diastolic dimension (r = 0.26, p < 0.01), 4) diastolic volume (r = 0.20, p < 0.05), and 5) stress/volume ratio (r = -0.53, p < 0.0001) but not the difference between measured and predicted velocity of circumferential fiber shortening. A multivariate model included body mass, age at diagnosis, diastolic dimension, wall stress and vascular resistance but not the difference between measured and predicted velocity of circumferential fiber shortening. CONCLUSIONS: Contractility is not significantly related to left ventricular mass. The positive correlation between mass and stress/volume may be due to the dependence of the latter variable on loading conditions. We speculate that both elevated preload and systemic vascular resistance may have a role in the development of hypertrophy in hypertensive pediatric patients.

Coronary artery caliber in normal children and patients with Kawasaki disease but without aneurysms: an echocardiographic and angiographic study.

A total of 110 children aged 3 months to 16 years underwent two-dimensional echocardiography of the coronary arteries. Forty-two normal subjects and 68 patients with Kawasaki disease were evaluated. All 68 patients with Kawasaki disease underwent selective coronary arteriography. The objectives of this study were to 1) develop a normal profile of the proximal left and right coronary arteries as to caliber and shape in infants, toddlers and children using echocardiography; 2) compare the dimensions and shape of the coronary arteries of patients with Kawasaki disease but no obvious aneurysms with those of the coronary arteries of normal children; and 3) develop criteria that would permit distinguishing a large but normal coronary artery from a true aneurysm in patients with Kawasaki disease. In the normal subjects and patients with Kawasaki disease, the caliber of the coronary arteries showed little variability from the ostium to 10 mm distally, and ranged in size from 2 mm in infants to 5 mm in teenagers. There was no significant difference between male and female subjects. The feature that distinguished the large but normal coronary artery without aneurysm from that with an aneurysm was its uniformity of caliber. Also, the caliber of the opposite coronary artery was generally at the lower limits of normal. It appears that the proximal coronary arteries of infants and children can be accurately assessed using high resolution two-dimensional echocardiography, and that sequential evaluation of subtle changes over time may be performed.

Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease.

Seventy-seven patients with Kawasaki disease were prospectively evaluated from 1978 to 1983 to determine the sensitivity, specificity and predictive value for detecting coronary artery aneurysms with two-dimensional echocardiography. Seventy (91%) underwent selective coronary arteriography and are included in this report. The study was divided into two periods because of increased experience and the use of a systematic approach with two-dimensional echocardiography in the second period as compared with the first. Aneurysms were demonstrated in nine patients (13%). The coronary artery system was divided into six regions: proximal third of the main right coronary artery, distal right coronary artery, left main coronary artery, left anterior descending coronary artery, circumflex coronary artery and distal left coronary artery. The sensitivity and specificity were high when imaging the proximal regions, and improved from the first period to the second. Both sensitivity and specificity were lower for the more distal regions of the right and left coronary arteries. Overall, the sensitivity of two-dimensional echocardiography was 100% because there were no patients in our study who had isolated distal coronary artery aneurysms. Two-dimensional echocardiography is a sensitive and specific test for detecting aneurysms in the proximal portions of both the right and left coronary arteries, and is useful in selecting patients for invasive investigation with selective coronary arteriography.

Effect of myocardial hypertrophy on systolic and diastolic function in children: insights from the force-frequency and relaxation-frequency relationships.

OBJECTIVE: The objective of this study was to evaluate the effect of myocardial hypertrophy on systolic and diastolic properties of the left ventricle in children. BACKGROUND: In children with myocardial hypertrophy, ejection phase indices are invariably increased. However, indices of force-generation, e.g., end-systolic elastance and invasive indices of diastolic properties, have been studied infrequently in children with myocardial hypertrophy. METHODS: We studied 10 children with congenital aortic stenosis or coarctation of aorta and nine control patients. Systolic properties were assessed from shortening fraction, end-systolic fiber elastance (Ef(es)) measured at resting heart rates, and force-frequency relationship measured at heart rates increasing from 110 to 160 beats per minute. Diastolic properties were assessed from time constant of relaxation (tau) at matched heart rates, chamber stiffness constant, myocardial stiffness constant, and relaxation-frequency relationship measured at gradually increasing heart rates. RESULTS: Ef(es) remained unchanged by myocardial hypertrophy, however, tau was prolonged (tauL: 27.3+/-2.3 vs. 21.8+/-2.2 ms, p < 0.001; and tauD: 43.2+/-3.1 vs. 34.3+/-3.3 ms, p < 0.001). Both chamber and myocardial stiffness constants remained unchanged. Incremental increases in heart rate produced incremental improvement in both contraction and relaxation. Slopes of force-frequency and relaxation-frequency relationships remained unchanged in the experimental group. However, the relaxation-frequency relationship manifested a parallel shift upward. CONCLUSIONS: In conscious, sedated children with myocardial hypertrophy, systolic function assessed by an index of force generation remains unchanged. However, relaxation is prolonged but passive diastolic properties remain unaffected. The combined effect of hypertrophy and heart rate does not alter the force-frequency and relaxation-frequency relationships.

Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk.

OBJECTIVES: We sought to determine whether growth influences the relation between left ventricular mass and body size and whether use of different body size indexes affects the ability of ventricular mass to predict complications of hypertension. BACKGROUND: Allometric (or growth) signals between left ventricular mass and height have recently been reported to improve previous approaches for normalization of ventricular mass for body size. METHODS: Residuals of left ventricular mass-height2.7 relations were analyzed in a learning series of 611 normotensive, normal-weight subjects 4 months to 70 years old and, separately, in 383 children (< 17 years old) and 228 adults. Ten-year cardiovascular morbidity in a test series of 253 hypertensive adults was compared with groups with normal or high baseline left ventricular mass normalized for body weight, height, body surface area and allometric powers of height. RESULTS: The dispersion of residuals of ventricular mass versus height2.7 increased with increasing height or age in children but not in adults, suggesting that the effect of other variables on ventricular growth increases during body growth and stabilizes in adulthood. Therefore, we derived separate allometric signals for adults (predicted ventricular mass = 45.4 x height2.13, r = 0.48) and children (32.3 x height2.3, r = 0.85) (both p < 0.0001). Patients with left ventricular hypertrophy had 3.3 times higher cardiac risk with elevated left ventricular mass/height2.7 (p < 0.001), 2.6 to 2.7 times higher risk with left ventricular mass indexed for height, height2.13 and body surface area (all p < 0.01) and 1.7 times the risk with ventricular mass/weight (p > 0.1). CONCLUSIONS: These results show the following: 1) Variability of left ventricular mass in relation to height increases during human growth; 2) allometric signals of left ventricular mass versus height are lower in adults and children than those obtained across the entire age spectrum; 3) height-based indexes of left ventricular mass at least maintain and may enhance prediction of cardiac risk by hypertensive left ventricular hypertrophy; and 4) the allometric signal derived across the entire spectrum of age appears to be more useful for prediction of cardiovascular risk than that computed in adults.

Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight.

OBJECTIVES: This study was designed to determine the most appropriate method to normalize left ventricular mass for body size. BACKGROUND: Left ventricular mass has been normalized for body weight, surface area or height in experimental and clinical studies, but it is uncertain which of these approaches is most appropriate. METHODS: Three normotensive population samples--in New York City (127 adults), Naples, Italy (114 adults) and Cincinnati, Ohio (444 infants to young adults)--were studied by echocardiography. Relations of left ventricular mass to body size were similar in all normal weight groups, as assessed by linear and nonlinear regression analysis, and results were pooled (n = 611). RESULTS: Left ventricular mass was related to body weight to the first power (r = 0.88), to body surface area to the 1.5 power (r = 0.88) and to height to the 2.7 power (r = 0.84), consistent with expected allometric (growth) relations between variables with linear (height), second-power (body surface area) and volumetric (left ventricular mass and body weight) dimensions. Strong residual relations of left ventricular mass/body surface area to body surface area (r = 0.54) and of ventricular mass/height to height (r = 0.72) were markedly reduced by normalization of ventricular mass for height2.7 and body surface area1.5. The variability among subjects of ventricular mass was also reduced (p < 0.01 to p < 0.002) by normalization for body weight, body surface area, body surface area1.5 or height2.7 but not for height. In 20% of adults who were overweight, ventricular mass was 14% higher (p < 0.001) than ideal mass predicted from observed height and ideal weight; this increase was identified as 14% by left ventricular mass/height2.7 and 9% by ventricular mass/height, whereas indexation for body surface area, body surface area1.5 and body weight erroneously identified left ventricular mass as reduced in overweight adults. CONCLUSIONS: Normalizations of left ventricular mass for height or body surface area introduce artifactual relations of indexed ventricular mass to body size and errors in estimating the impact of overweight. These problems are avoided and variability among normal subjects is reduced by using left ventricular mass/height2.7. Simple nomograms of the normal relation between height and left ventricular mass allow detection of ventricular hypertrophy in children and adults.

Increased intestinal absorption of calcium in young and adult X-linked hypophosphatemic mice after the administration of 1,25-dihydroxyvitamin D3.

We have reported that X-linked hypophosphatemic (Hyp) and normal mice respond equally to the administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] with uptake of 45Ca from an oral test meal as judged by the isotope remaining in the fecal samples. To determine whether this was due to specific stimulation of calcium absorption, as opposed to changes in calcium secretion or transit time, 1,25(OH)2D3 was administered to 4-week-old (young) and 13-week-old (adult) normal and Hyp mice at a dose of 0.12 micrograms/kg per day by continual infusion from an Alzet minipump. After 3 days of infusion, absorption of 45Ca from the isolated duodenum was measured in situ. Malabsorption of calcium was shown in vehicle-treated 4-week-old Hyp mice by significantly more 45Ca remaining in the intestinal segment and by significantly reduced plasma levels and reduced skeletal levels of 45Ca. Treatment of the young mice, both normal and Hyp, with 1,25(OH)2D3 resulted in increased absorption of 45Ca, increased plasma 45Ca, and increased incorporation of 45Ca into the femur. The young Hyp mice treated with 1,25(OH)2D3 showed a significant increase in femoral ash weight. At 13 weeks of age both normal and Hyp vehicle-treated mice showed equivalent absorption of calcium, and both responded to 1,25(OH)2D3 administration with enhanced calcium absorption. At both ages plasma phosphate rose in only the Hyp mice treated with 1,25(OH)2D3, whereas plasma and urine calcium were increased in only the hormone-treated normal mice. In conclusion, 1,25(OH)2D3 stimulates the absorption of calcium in the isolated duodenum of the young Hyp mouse with equal potency to that of young normal mice.