摘要:

The newborn has a limited ability to regulate H+/HCO-3homeostasis, due in part to immaturity of the intercalated cells in the distal nephron. We traced the postnatal differentiation of the intercalated cells of the rabbit cortical collecting duct (CCD) and outer medullary collecting duct(OMCD) using MAb to the 31-kD subunit of the vacuolar H+-ATPase, membrane portion of erythrocyte band 3, and apical surface of B-intercalated cells (peanut agglutinin [PNA], MAb B63). In the most superficial CCD of the newborn there was no binding to these probes, although deeper in the cortex there was faint apical staining with PNA and MAb B63 and a few patterns of H+-ATPase and band 3 labeling of neonatal intercalated cells. The OMCD showed mostly apical H+-ATPase and both cytoplasmic and basolateral band 3 labeling but B-intercalated cell markers were not seen. By 3 wk of age the staining of the CCD and OMCD was more polarized, resembling those in the adult. Band 3 positive cells (as a percentage of total cells) in the CCD increased from 13 to 17% during maturation, and in the OMCD they increased from 22 to 37%. Some basolateral band 3 and apical H+-ATPase staining was also seen in the inner medullary collecting duct of 3-wk-old rabbits to a greater extent than in newborn or adult rabbits. Labeling of intercalated cells in the CCD and OMCD was weakest and least numerous in the newborn, greater in the 3 wk old, and greatest in the adult. Most maturing cortical intercalated cells bound both PNA and H+-ATPase MAb, comparable to what has been observed in the adult CCD. PNA-negative cells showing apical H+-ATPase labeling, consistent with the classic A-intercalated cell phenotype, comprised only 5% of identified intercalated cells in the newborn CCD compared with 12% in older animals. In or near the developing renal vesicles and ampullary structures were occasional cytoplasmically staining PNA- and B63-positive cells. Whether these cells are precursors of specific renal tubular cells cannot yet be established. Staining for principal cells(ST.9) was less intense in the neonatal cortex than in more mature cortex, but the deep cortex and outer medulla were heavily labeled at all ages. These data indicate that immature intercalated cells, in the CCD and OMCD, may undergo significant postnatal proliferation and differentiation, acquiring mature phenotypes during the first month of life. The A-intercalated cell appears more differentiated than the B cell during the 1st wk of life, suggesting that A-intercalated cells contribute more than B cells to the maintenance of acid-base homeostasis in the newborn.Abbreviations: CCD,cortical collecting duct;OMCD,outer medullary collecting duct;IMCD,inner medullary collecting duct;PNA,peanut agglutinin

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside (PAN) nephropathy, an experimental model of glomerular disease. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of growth failure in rats with chronic PAN nephropathy. The glomerulopathy was induced by seven serial injections of PAN over 12 wk. Experimental animals(n= 6) received rhIGF-I, 400 μg/d, whereas control rats(n= 6) received the vehicle. rhIGF-I improved weight gain by 14%(p< 0.05), without altering hematocrit or blood pressure in rats with renal disease. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic PAN nephropathy. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 ± 0.08versus0.24 ± 0.06 mL/min/100 g of body weight in untreated PAN nephropathy animals,p< 0.05. The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental glomerulosclerosis, tubulointerstitial injury, or renal cortical malondialdehyde content. In rats with PAN nephropathy, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n= 4) did not alter weight gain, blood pressure, proteinuria, GFR, glomerular planar area, renal cortical malondialdehyde content, or glomerular or tubulointerstitial damage, compared with untreated animals (n= 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that:1) administration of rhIGF-I improves growth and GFR in rats with chronic PAN nephropathy and2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model.Abbreviations: BW,body weight;CRF,chronic renal failure;FSGS,focal segmental glomerulosclerosis;PAN,puromycin aminonucleoside;rh,recombinant human

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

To verify some animal experimental results in humans, we have studied urinary epidermal growth factor (EGF) excretion in normal children as well as children with acute renal failure (ARF). Urinary EGF excretion was expressed as a ratio of urinary EGF to urinary creatinine concentration (EGF/Cr) for random and 24-h urine, and a daily total urinary EGF for 24-h urine. The highest urinary EGF/Cr in children was found at 1 mo to 3 y of age. There was a highly significant correlation between random urine EGF/Cr and 24-h urine EGF/Cr (r= 0.92,p< 0.001), whereas no correlation of urinary EGF/Cr with daily total urine EGF was found. During the course of ARF, a decline in urinary EGF/Cr from the period before peak serum creatinine to the period after the declination of serum creatinine was noted (p= 0.013,n= 13, by repeated measure analysis), with a constant low daily total urine EGF (pvalue not significant). However, a rise in both urinary EGF/Cr and daily total urine EGF was found between the period of serum creatinine decline and the period of completely normal serum creatinine(p< 0.001). Serum EGF remained unchanged throughout the course of ARF. These results suggest1) the possible role of EGF in renal growth or maturation during the first 2 or 3 y of life,2) the possible renal origin of human urinary EGF, and3) decreased urinary EGF excretion in children with ARF. In particular, EGF/Cr is not a reliable indicator for the expression of actual urinary EGF excretion in ARF. Instead of urinary EGF/Cr, urinary EGF concentration may be used to predict the daily total urinary EGF excretion during ARF. These results provide the pattern of urinary EGF excretion during ARF in children and may be of help for further clinical studies.Abbreviations: ARF,acute renal failure;EGF,epidermal growth factor;EGF/Cr,ratio of EGF to creatinine

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Previous studies suggest that elevated basal levels of cGMP in newborn arteries may help explain why vascular resistance is lower in newborns than adults. To explore the reasons why basal cGMP is higher in neonatal arteries, the present studies examined rates of cGMP synthesis and degradation in newborn and adult ovine common carotid arteries. The measurements were performed in both intact and homogenized arteries, and results were normalized relative to cell water to estimate intracellular concentrations and minimize errors due to compositional differences between newborn and adult arteries. Steady state levels of cGMP measured under baseline conditions averaged 0.11± 0.02 μM in adult arteries and 0.59 ± 0.11 μM in newborn arteries. These resting cGMP levels were unaffected by endothelium removal. Under baseline conditions, steady state rates of cGMP synthesis (μmol of cGMP/L of cell water/min) were higher in newborn (0.31 ± 0.06) than in adult (0.15 ± 0.04) arteries. Maximal rates of cGMP degradation(μmol of cGMP/L of cell water/min) measured in artery homogenates were also much higher in preparations of newborn (106 ± 6) than of adult (78± 6) arteries. Together, these data suggest that the reason resting cGMP concentrations were higher in newborn than in adult arteries was due at least in part to a higher basal rate of cGMP synthesis in the newborn. Estimates of apparent Km values for PDE were also greater in newborn (2.9μM) than in adult (1.5 μM) preparations, suggesting that age-related differences in the Km for PDE may also contribute to the elevated basal concentration of cGMP observed in the newborn.Abbreviations: cGMP,guanosine 3′,5′-cyclic monophosphate;PDE,cGMP-specific phosphodiesterases;SNAP,S-nitroso-N-acetyl-penicillamine;IBMX,3-isobutyl-1-methylxanthine;TCA,trichloroacetic acid;EDRF,endothelium-derived relaxing factor

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We have used second differential near infrared spectroscopy of water to determine the mean optical path length of the neonatal brain. By obtaining the ratio of the second differential features of deoxyhemoglobin to those of water, theabsolutecerebral concentration of deoxyhemoglobin can be monitored continuously and noninvasively. Nineteen neonates were studied; the gestational age at birth varied from 23 to 38 wk, and the postconceptual age, when the spectra were recorded, ranged from 35 to 48 wk. The calculated mean deoxyhemoglobin concentration was 14.6 ± 4.0 μM; the differential path length factor (mean optical path length/optode separation) calculated from the water peak at 730 nm was 4.66 ± 1.01, and that calculated at the 830-nm peak was 3.91 ± 0.75. These values are consistent with path length measurements using laser time-of-flight spectroscopy on postmorten neonates and phase-resolved spectroscopy on live neonates. Induced arterial oxygen saturation decreases from 98 to 93% showed no significant change in the mean optical path length, despite significant cerebral desaturation. Changes in the deoxyhemoglobin concentration after this procedure were identical, whether measured by second differential analysis at 760 nm or by multilinear regression over the wavelength range 740-900 nm. When combined with existing methods of measuring total cerebral hemoglobin concentration, second differential near infrared spectroscopy can be used to derive the mean cerebral oxygen saturation. A preliminary experiment outlined the feasibility of this approach and yielded a saturation value of 63%, consistent with near infrared sampling of a predominantly venous pool in the brain.Abbreviations: NIRS,near infrared spectroscopy;NIR,near infrared;CBF,cerebral blood flow;CBV,cerebral blood volume;CHC,cerebral hemoglobin concentration (μmol/L of brain tissue);Hb,deoxyhemoglobin;Hbo2, oxyhemoglobin;Δ[Hbo2],change in [oxyhemoglobin];Sao2,arterial oxygen saturation;Paco2,arterial carbon dioxide tension;Fio2,inspired oxygen fraction;CSvo2,cerebral mixed venous oxygen saturation;Smco2,mean cerebral oxygen saturation;CCD,charge-coupled device;DPF,differential path length factor

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Activated microglia may contribute to the progression of neuronal injury after a wide range of CNS insults. In this study, we used two complementary methods to evaluate acute changes in the morphology and regional distribution of microglia induced by a focal hypoxic-ischemic insult in 7-d-old (P7) rats. To elicit injury, P7 rats underwent right carotid ligation followed by 3 h of 8% O2exposure; rats were killed 10 min to 5 d later (n≥ 3/group). A histochemical assay usingGriffonia simplicifoliaB4-isolectin enabled detection of both resting and activated microglia in tissue sections; vascular cells were also reactive. Activated microglia were also identified immunocytochemically using a macrophage-specific MAb, ED-1. In normal P7-12 brain, lectin, and ED-1 immunoreactive-activated microglia were concentrated in white matter; lectin-positive resting, ramified microglia were also detected throughout the gray and white matter. Subtle morphologic evidence of microglial activation was noted 10 min posthypoxia-ischemia in the lesioned right cerebral hemisphere; activated microglia began to accumulate within the next 4 h. Accumulation of lectin-positive activated microglia peaked at 2-4 d posthypoxia-ischemia. ED-1 immunoreactive-microglia were first noted 4 h after hypoxic-ischemic injury in the lesioned right hemisphere, and there was a corresponding increase in accumulation over the first 48 h posthypoxia-ischemia. In the left hemisphere, contralateral to the ligation, no increase in activated microglia were detected with either method. In brain sections where no neuronal injury was evident, activated microglia did not accumulate. These data demonstrate that perinatal hypoxicischemic brain injury induced rapid accumulation of activated microglia in hypoxic-ischemic forebrain.Abbreviations: P,postnatal day;PLP,periodate-lysine-paraformaldehyde;RT,room temperature;CA,cornu ammonisThere is increasing evidence that phagocytic cells, including microglia and macrophages, respond acutely to diverse forms of CNS injury. In the adult CNS, ischemic and excitotoxic injury stimulate a well characterized microglial response that includes both changes in morphology and increased accumulation in regions of injury(1-9). Considerable data indicate that, in addition to phagocytosis of degenerating elements, these cells secrete a wide range of soluble factors, such as cytokines(10-13), substances with excitatory amino acid agonist properties(14), and glial promoting factors(10, 11), that may influence the extent of neuronal injury, axonal growth, synaptic plasticity, and astroglial hyperplasia. Microglia also play important roles in normal CNS development(15), and activated microglia are detectable in normal immature rodent brain; yet, little is known about the response of these cells after injury in the developing brain. In the only study that has attempted to compare the microglial response in the developing and adult brain(1), lesions in the adult visual cortex induced slower cell death and a much more protracted phagocytic response than in younger animals.

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The study investigated the hypothesis that delayed cerebral injury after transient cerebral ischemia is associated with vasoconstriction and decreased cerebral oxygenation. Eight chronically instrumented, late gestation fetal sheep were subjected to 30 min of cerebral ischemiain utero. Cortical impedance (CI) and electrocorticogram (ECoG) were recorded to determine the time course of cellular dysfunction. Histologic outcome was assessed 4 d postischemia. Changes in cerebral vascular tone and oxygenation were observed during and for 4 d after the insult using near infrared spectroscopy to measure changes in total cerebral Hb ([tHb]), oxyhemoglobin([Hbo2]), and oxidized cytochromeaa3([Cyto2]). Results are expressed as mean ± SEM. CI increased transiently during ischemia; then a delayed increase commenced 17.5 ± 2.3 h postischemia and peaked at 42.3 ± 2.4 h. ECoG was depressed during and after the insult. Seizures started 13.6 ± 3.0 h postinsult and persisted for 25.4 ± 3.2 h. Increases in [tHb] indicated two periods of cerebral vasodilation: immediately after early reperfusion, lasting 2.3 ± 0.4 h and peaking to 20 ± 2.0 μmol·L-1; and a later phase, commencing 12.8 ± 2.0 h postischemia, peaking to 43± 4.0 μmol·L-1and lasting 43.1 ± 5.2 h.[Hbo2] was relatively elevated (18 ± 3.0μmol·L-1) during d 4 postischemia, demonstrating a delayed increase in mean cerebral oxygen saturation. [Cyto2] fell during the insult (-0.7 ± 0.2 μmol·L-1); and, commencing at 28-30 h postischemia, fell progressively to reach a minimum of -5.0 ± 2.8μmol·L-1at 78-80 h postischemia. A greater fall in[Cyto2] was related to worse cerebral injury (p< 0.05). Delayed cerebral injury is accompanied by vasodilation and increased mean cerebral oxygen saturation, although a progressive fall in [Cyto2] might indicate a fall in mitochondrial oxygenation, cell loss, or changes in tissue optical characteristics.Abbreviations: ECoG,electrocorticogram;CI,cortical impedance;NIRS,near infrared spectroscopy;[tHb],concentration of total cerebral Hb;[Hbo2],concentration of oxyhemoglobin;[Cyto2],concentration of oxidized cytochromeaa3;CBF,cerebral blood flow;MAP,mean arterial pressure;Paco2,partial pressure of arterial CO2;Pao2,parital pressure of arterial O2;Sao2,arterial oxygen saturation

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We investigated whether group B streptococcal (STREP) infusion impairs the cerebral blood flow (CBF) response to acute hypercarbia in piglets, and whether STREP-induced prostanoids or hemodynamic alterations could account for this impairment. Piglets, 2-3 wk old, were anesthetized, paralyzed, and mechanically ventilated (50% O2; partial pressure of arterial CO2(Paco2) ≈ 40 torr). CBF was assessed by internal carotid artery blood flow (ICBF). Group 1 (n= 5) received a continuous infusion of STREP for 4 h (2.0-8.0 × 107org/kg-min). Group 2(n= 5) was pretreated with indomethacin (5 mg/kg), then received the identical STREP infusion. Group 3 (n= 6) did not receive STREP, but cardiac output (CO) and systemic blood pressure (BP) were reduced to levels equal to that of group 1 by incremental inflation of a left atrial balloon (LAB) catheter. Cerebral vascular reactivity to acute hypercarbia(Paco2≈ 70 torr for 7.5 min) was assessed at baseline and after each hour of STREP infusion or LAB inflation. We found that 4 h of STREP infusion caused CO to fall significantly (634 ± 121 to 324 ± 172 mL/min, group 1; 600 ± 68 to 291 ± 80 mL/min, group 2) and BP to fall significantly (104 ± 20 to 57 ± 4 mm Hg, group 1; 91± 11 to 53 ± 16 mm Hg, group 2) By design, in group 3 LAB inflation caused CO (573 ± 181 to 375 ± 159 mL/min) and BP (104± 14 to 60 ± 9 mm Hg) to fall to values not significantly different from septic groups 1 and 2. At 4 h, unilateral ICBF decreased significantly during STREP infusion in group 1 (32.0 ± 10.8 to 21.0± 7.3 mL/min) and group 2 (22.9 ± 9.9 to 13.1 ± 4.3 mL/min), but not in nonseptic group 3 (23.1 ± 7.4 to 19.6 ± 6.3 mL/min). At baseline, hypercarbia induced an increase in ICBF (%ΔICBF = 68.7 ± 13.0% in group 1, 62.2 ± 15.6% in group 2, and 87.7± 34.0% in group 3). After 4 h of STREP, this response was completely ablated as ICBF fell during hypercarbia by -7.8 ± 23.2% (group 1). Indomethacin did not protect cerebral vascular reactivity after 4 h of STREP infusion, as%ΔICBF fell during hypercarbia by -10.9 ± 17.7%(group 2). In contrast, despite equivalent reductions in CO and BP after 4 h of LAB inflation in nonseptic group 3, ICBF rose during hypercarbia by 61.8± 23.2%, not significantly different from baseline, but significantly different from the decrease in%ΔICBF in groups 1 and 2. We conclude that STREP infusion reduces ICBF and cerebral vascular reactivity to acute hypercarbia in piglets. This phenomenon is not accounted for by STREP-induced reduction in CO or BP, and is not mediated by prostanoids.Abbreviations: STREP,group B Streptococcus;CBF,cerebral blood flow;LAB,left atrial ballon;ICBF,internal carotid artery blood flow;CO,cardiac output;PA,pulmonary artery;PAP,pulmonary artery pressure;BP,systemic blood pressure;EDRF,endothelium-derived relaxation factor;CVP,central venous pressure;SSP,sagittal sinus pressure;RMANOVA,repeated measures analysis of variance;Pao2,partial pressure of arterial O2;Paco2,partial pressure of arterial CO2

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Kernicterus is characterized by the accumulation of bilirubin mainly into subcortical brainstem nuclei. Inasmuch as premature infants are more susceptible to kernicterus, we hypothesized that the cerebral permeability to bilirubin could vary by cerebral region and with age. Therefore, in the present study, we measured the blood-to-brain transfer constant(Ki) of [3H]bilirubin in 6-8 rats at postnatal age 10(P10) or 21 d (P21) in basal conditions and after a bilirubin perfusion to explore age-related and bilirubin-induced changes in the cerebral permeability to the dye. Blood-to-brain transfer of [3H]bilirubin was measured in 39 brain regions by quantitative autoradiography in 15-min experiments. Rats exposed to unlabeled bilirubin received a loading dose of 160 mg/kg over 15 min followed by a 90-min bilirubin perfusion at a speed of 64 mg/kg/h. At P10, cerebral permeability to bilirubin ranged from 0.07 to 0.12 μL/g/min, except in the auditory nerve, dentate nucleus, hypothalamus, and thalamus where it reached 0.41-0.47 μL/g/min. At P21,Kiof bilirubin was significantly lower than at P10 and ranged from 0.03-0.06μL/g/min in most brain areas. In P10 bilirubin-exposed rats, permeability to bilirubin significantly increased over control levels in all brain regions but three. The largest increases (>350%) were recorded in the sensory regions, most limbic areas, hypothalamus, and thalamus. At P21, hyperbilirubinemia induced increases in blood-to-brain transfer of bilirubin of 50-200% in 16 brain areas, except in the hippocampus, sensory-motor cortex, and thalamic nuclei where they reached 200-433%. Thus, it appears that the immature rat brain (P10) is very permeable to bilirubin. The increased permeability with preexposure to the dye, especially in brain regions which are affected in infants with kernicterus, could be related either to the large decrease in the value of the albumin:bilirubin ratio between control (15-16) and hyperbilirubinemic conditions (1.7-1.8) and/or to an increased permeability to bilirubin.Abbreviations:Ki,blood-to-brain transfer constant;P,postnatal day

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Brain bilirubin concentrations are increased by hyperosmolality and hypercarbia, but the mechanism is not known. The same applies to the mechanism for preferential localization of bilirubin to basal ganglia. Young Sprague-Dawley rats were used. Groups were: control (n= 15), hypercarbia (n= 16, pH ≅ 6.95), and hyperosmolality(n= 13, serum osmolality ≅390 mosm/L). Hyperbilirubinemia was induced by a 5-min infusion of 50 mg/kg bilirubin, containing ≅20 μCi[3H]bilirubin. Rats were killed at 15-min intervals up to 60 min, and the brains were flushedin situ,dissected into seven regions, weighed, and dissolved. Brain bilirubin was determined by scintillation counting. The half-life of bilirubin in brain was calculated by exponential fitting, which also allowed an estimation of brain bilirubin at the end of the bilirubin bolus. The kinetics of bilirubin clearance from brain were first order. The half-life of bilirubin in brain was significantly prolonged in hyperosmolality (38.2 ± 28.8 min [mean ± SD]) compared with control (16.1 ± 7.7 min) and hypercarbia (12.6 ± 8.6 min)(F= 12.6,p< 0.0001 after log transformation) results. The estimated acute entry of bilirubin into brain was significantly increased in hypercarbia (13.9 ± 7.4 nmol/g) compared with control (5.6± 2.1 nmol/g) and hyperosmolality (6.5 ± 2.1 nmol/g)(F= 19.2,p< 0.0001 after log transformation) results. There were no significant differences between brain regions in acute entry or clearance of bilirubin. The kinetics of increased brain bilirubin differ between hypercarbia (increased acute entry) and hyperosmolality(delayed clearance). Preferential localization of bilirubin to basal ganglia is not produced under, and may not be explained by, the conditions investigated.

ISSN:0031-3998    

出版商:OVID    

年代:1996

数据来源: OVID