Visceral reflex activity: development in postnatal rabbit.

In postnatal rabbits there is progressive development of central regulation of the micturition reflex. During the first 1 to 2 days of postnatal life a coordinated sustained reflex may be obtained from the bladder which has been isolated from the central nervous system. Changes in reflex integration occur over the following 7 to 12 days, which result in a coordinated reflex dependent upon supraspinal influiences.

Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cyanide.

Microperfusion experiments have shown that increases in flow rate of tubule fluid through the loop of Henle are followed by reductions in single nephron glomerular filtration rate (SNGFR) and stop-flow pressure (SFP) measured in the proximal tubule of the same nephron. Because changes in luminal sodium concentration are not consistently related to changes in SNGFR and SFP, we explored the possibility that a transport step at a flow-dependent distal-sensing site might be involved in feedback control of SNGFR. Because the macula densa cells of the distal tubule are adjacent to the glomerular vessels of the same nephrons, they could be the distal-sensing mechanism. We perfused superficial loops of Henle from late proximal to early distal segments in three groups of rats while measuring SFP in the proximal tubule of the same nephron, SNGFR in the proximal tubule of the same nephron, or flow rates of fluid, Na, K, and Cl emerging from the perfused loops. Perfusion solutions used were 0.15 NaCl, Ringer or Ringer with one of several inhibitors of electrolyte transport. Perfusion rates were 10 or 40 nl/min (also, zero during measurements of SFP and SNGFR). With Ringer alone the loop-flow rate increased from 10 to 40 nl/min, caused a decrease in SFP from 37.6 to 32.1 mm Hg, and a decrease in SNGFR from 29.9 to 18.7 nl/min. Concentrations of Na, K, and Cl in early distal fluid and absorption of Na and Cl along the loop segment were also increased when loop perfusion rate was increased. Decreasing the perfusion rate to zero had little effect on SFP or SNGFR. The SFP response to increased flow rate did not occur when the perfusion solution contained furosemide (10(-4) M). No reduction of the SFP response was seen with other diuretics tested (amiloride, acetazolamide, ethacrynic acid, mercaptomerin) or with 0.15 M NaCl alone. The SNGFR response to increased perfusion rate was reduced by furosemide, triflocin, and cyanide but not by amiloride. Na and Cl absorption by the perfused segment were inhibited by furosemide, triflocin, cyanide, and amiloride. Amiloride and acetazolamide, probably do not act in the ascending limb. Ethacrynic acid and mercaptomerin are known to be ineffective in rat nephrons. Thus, agents that could have inhibited NaCl absorption by macula densa cells interfered with the feedback mechanism.

Dietary protein suppresses feedback control of glomerular filtration in rats.

We have examined the possibility that changes in glomerular filtration rate (GFR) after changes in dietary protein intake may depend on altered function of the tubuloglomerular (TG) feedback system. We studied male Sprague-Dawley rats after dietary pretreatment for 9.6 +/- 3.6 (SD) d with isocaloric diets containing either 6% or 40% casein. We found that GFR in rats fed the high protein diet was 24-29% higher than in rats fed the low protein diet. Simultaneous measurements of single nephron GFR (SNGFR) in the distal tubule were 6.3 nl/min or 21% higher in the rats fed the high protein diet whereas proximally measured SNGFR was not statistically different in the two groups. The higher distally measured SNGFR of rats receiving the high protein diet was associated with a 4.2 nl/min or 50% smaller suppression of SNGFR by TG feedback (-4.3 vs. -8.5 nl/min, P less than 0.001). Loop perfusion experiments demonstrated that in rats fed the high protein diet the TG feedback mechanism was less sensitive than in rats fed the low protein diet. The TG feedback response in rats fed the low protein diet, as assessed by reductions in stop-flow pressure and SNGFR, was half-maximal at flows of 14-15 nl/min. In contrast, the TG feedback response in rats fed the high protein diet was half-maximal at 22-24 nl/min. Maximal suppression of stop-flow pressure and SNGFR and the slope of the TG feedback response to increasing loop flow rates were not different in the two groups. We conclude that the sensing mechanism of the TG feedback system is rendered less responsive by a high protein intake, and that this change permits GFR to increase.

Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion.

We studied the effects of dietary NaCl intake on the renal distal tubule by feeding rats high or low NaCl chow or by chronically infusing furosemide. Furosemide-treated animals were offered saline as drinking fluid to replace urinary losses. Effects of naCl intake were evaluated using free-flow micropuncture, in vivo microperfusion, and morphometric techniques. Dietary NaCl restriction did not affect NaCl delivery to the early distal tubule but markedly increased the capacity of the distal convoluted tubule to transport Na and Cl. Chronic furosemide infusion increased NaCl delivery to the early distal tubule and also increased the rates of Na and Cl transport above the rates observed in low NaCl diet rats. When compared with high NaCl intake alone, chronic furosemide infusion with saline ingestion increased the fractional volume of distal convoluted tubule cells by nearly 100%, whereas dietary NaCl restriction had no effect. The results are consistent with the hypotheses that (a) chronic NaCl restriction increases the transport ability of the distal convoluted tubule independent of changes in tubule structure, (b) high rates of ion delivery to the distal nephron cause tubule hypertrophy, and (c) tubule hypertrophy is associated with increases in ion transport capacity. They indicate that the distal tubule adapts functionally and structurally to perturbations in dietary Na and Cl intake.

An inhibitory effect of furosemide on sodium reabsorption by the proximal tubule of the rat nephron.

The evidence from previous micropuncture studies for an inhibitory effect of furosemide on proximal sodium reabsorption in the rat has been conflicting. Intrinsic reabsorptive capacity, estimated in free flow and shrinking drop experiments, has been reported to be depressed, whereas fractional reabsorption usually remains unchanged. We have recently reported that, during conditions of elevated intraluminal hydrostatic pressure, unless care is taken to prevent retrograde flow of tubule fluid from more distal sites, the concentration of inulin in late proximal fluid is often factitiously elevated. Since furosemide raises intraluminal pressures, often markedly, the failure to detect a depression of fractional reabsorption might be the consequence of retrograde contamination during fluid collection. Experiments were designed to compare the effect of furosemide on fractional sodium reabsorption by the proximal tubule when collections were obtained with distal oil blocks of conventional length as well as with unusually long blocks of oil of low and high viscosities. When reflux is prevented, fractional sodium reabsorption is usually depressed by furosemide, whereas when conventional distal blocks are used, the calculated values for fractional reabsorption either remain unchanged or increase. Simultaneous measurements of nephron glomerular filtration rate indicate that the latter is the consequence of retrograde contamination.

Depression of fractional sodium reabsorption by the proximal tubule of the dog without sodium diuresis.

The effect of infusions of hyperoncotic solutions on fractional sodium reabsorption by the proximal tubule of the dog was studied by the recollection micropuncture method. Tubule fluid to plasma inulin concentration ratios were measured for identified proximal tubule segments before and after infusion of 25% albumin or dextran solutions. Results were compared with changes in fractional reabsorption during saline diuresis. Plasma volume increased 66% +/- SE 5.8 after infusion of albumin solution and 94% +/- SE 8.2 after infusion of dextran solution. Fractional sodium reabosorption by the proximal tubule was depressed after infusion of both of these hyperoncotic solutions. Nevertheless, changes in sodium excretion after infusion of albumin and dextran were small. In contrast, after infusions of isotonic sodium chloride solution, which increased plasma volume 61% +/- SE 5.8, a decrease in fractional reabsorption of 50.7% +/- SE 7.2 was associated with large changes in sodium excretion.

Failure to demonstrate a hormonal inhibitor of proximal sodium reabsorption.

Recently, it has been reported that a humoral inhibitor of proximal sodium reabsorption could be detected in plasma, and dialysates of plasma, of rats and dogs undergoing saline diuresis. We have repeated these studies using similar techniques and protocols. Fractional sodium reabsorption by the proximal tubule (as estimated in free-flow micropuncture studies from tubule fluid-to-plasma inulin ratios) was found not to be lower during infusion of "natriuretic" plasma than during subsequent infusion of "hydropenic" plasma. Similarly, infusion of natriuretic plasma failed to prolong reabsorptive half-time of the shrinking drop beyond that seen during hydropenic plasma infusion. No increase in urine volume or rate of sodium excretion was observed during the period of natriuretic plasma infusion, nor did natriuretic plasma result in an increase in these measures in rats undergoing water diuresis. It also has been reported that dialysates of natriuretic plasma, but not of hydropenic plasma, when placed directly into the tubule lumen, inhibit proximal sodium reabsorption. In double blind studies carried out independently in Bethesda, London, and Cologne, we failed to detect the presence of a dialyzable inhibitor in natriuretic plasma. Finally, in contrast to other recent reports, we were unable to detect inhibitory activity in plasma obtained from dogs during the "escape" phase of chronic deoxycorticosterone acetate administration.

Carbamazepine plasma concentration. Relationship to cognitive impairment.

Neuropsychological function was assessed before and after carbamazepine monotherapy in children with newly diagnosed complex partial epilepsy. Simultaneous video-electroencephalographic monitoring examined the influence of subclinical abnormal electrical discharges on performance. Total and unbound plasma carbamazepine concentrations were examined in relation to changes in performance at low (carbamazepine level, less than or equal to 32 mumol/L [less than or equal to 7.5 mg/L]) and moderate (carbamazepine level, greater than 34 mumol/L [greater than 8.0 mg/L]) drug levels. The data suggest a mild beneficial effect of carbamazepine on speeded eye-hand coordination and, at low drug levels, more rapid processing of items in memory. Efficiency of learning new information and memory-scanning rate displayed a concentration-dependent relationship with carbamazepine level, with poor performance significantly associated with higher carbamazepine plasma concentrations. Carbamazepine free levels were equivalent to total levels in predicting cognitive side effects.

Intraventricular hemorrhage in the full-term neonate.

Intraventricular hemorrhage (IVH) can occur in full-term newborns with a variety of clinical pictures. We studied five full-term infants who suffered IVH in the neonatal period and survived. No apparent cause for hemorrhage could be found in four. All had normal results of neurologic examinations at birth, and four had no major antecedent perinatal or postnatal difficulties. In 19 previously described full-term infants with IVH, no perinatal problems were noted in 45% of those who survived. Although more common in premature infants, IVH can occur in full-term infants and should be suspected when there is a sudden change in the neurologic status. In subsequent examinations, three of our five infants had mild spasticity and two appeared to be normal. The grading system developed for IVH in premature infants, while indicating severity of the hemorrhage, does not predict clinical outcome in full-term infants. A more definitive statement of outcome will require a longer period of observation.

Episodic symptoms mistaken for seizures in the neurologically impaired child.

We found neurologically impaired children studied by time-locked video-EEG to have episodes of abnormal behaviors which had been mistaken for epileptic seizures. Recognition that other neurologically abnormal phenomena can closely mimic epilepsy is important for prevention of erroneous diagnoses of epilepsy, and thus overtreatment, in this patient population.

Epilepsy evoked by eating: the role of peripheral input.

A 13-year-old boy with documented epilepsy evoked by eating, a rare form of reflex epilepsy, experienced only partial control with anticonvulsant medication. Repetitive peripheral sensory input was necessary to evoke seizures in this patient. The seizures remitted completely after he lost several fingers in an accident. Decreased sensory input presumably altered the seizure threshold so that the seizures were eliminated.

Cerebral dysfunction after chronic hypoxia in children.

Although the long-term effects of acute anoxia have been studied, the effects of chronic hypoxia on the developing human brain have received little attention. We studied children with a cyanotic congenital heart defect to assess the impact of chronic hypoxia by eight measures: neurologic examination, visual evoked response, EEG, behavioral adjustment, cognitive, perceptual-motor, and attentional functioning, and school performance. On outcome evaluation, these children evidenced diverse neurophysiologic dysfunction. Chronic hypoxia was associated with impaired motor function, inability to sustain attention, and low academic achievement.

Dietary essential fatty acids, vitamin E, and Charcot-Marie-Tooth disease.

Twenty patients with type I Charcot-Marie-Tooth disease received dietary supplementation with the essential fatty acids (EFA), linoleic and gamma-linolenic acids, and vitamin E. A 3-month blinded trial of placebo (paraffin oil and vitamin E, 81.6 IU/d) was followed by 1 year of 3 grams daily of EFA and vitamin E. Serum fatty acid values doubled, but total esterified fatty acid proportions did not change. Arachidonic acid proportions correlated with the amount of prostaglandin-mediated lymphocyte suppression measured at the same times. Improvement demonstrated at the end of the placebo period by neuropsychological tests and neurologic examination was maintained during the 1 year of EFA supplementation. This effect may reflect a membrane stabilization benefit of vitamin E.

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Activated T cells in type I Charcot-Marie-Tooth disease: evidence for immunologic heterogeneity.

Common recognized variability in the familial peripheral neuropathy, type I Charcot-Marie-Tooth disease (CMT I), led to an examination of cell-mediated immune responses in 23 CMT I patients. Increased numbers of activated T cells were found in the peripheral blood of 14 (61%) patients using fluorescent monoclonal Ta1 antibody as quantitated by flow cytometry. Altered immunoregulation was also suggested by increased levels of prostaglandin-mediated lymphocyte suppression. In the other nine CMT I patients, immune responses were normal. Lack of a relationship between Ta1 expression and CMT clinical symptoms, but with consistency within six CMT families, support the concept of immunologic heterogeneity in type I CMT with a possible genetic component.

Expression of Schwann cell and peripheral T-cell activation epitopes in hereditary motor and sensory neuropathy.

To evaluate possible immune-mediated mechanisms in hereditary motor and sensory neuropathy (HMSN-I, Charcot-Marie-Tooth syndrome), we examined class II major histocompatibility complex antigen expression (MHC-II, HLA-DR) in Schwann cells and peripheral lymphocyte T-cell (Ta1, CD26) activation in five unrelated adults with HMSN-I. Evidence of increased activation expression was found in both compartments but the pattern did not suggest a general state of hyperimmunity or appear related to clinical characteristics of HMSN. Significantly increased CD26+ T-cell activation and greater than normal fluctuation of values occurred intermittently in sequential tests of eight HMSN patients and at single time points in 24 others. The combined data, consistent with repeated stimulations of an immune reaction under normal feedback control, suggest that HMSN-I expresses some characteristics also found in autoimmune polyneuropathies.

Studies of the sensing mechanism in the tubuloglomerular feedback pathway.

Two aspects of the single nephron feedback response previously observed by us have been reexamined. The first, the effect of modifying the composition of fluid used to perfuse the loop of Henle of a single nephron, was studied in rats by comparing flow-induced changes in stop-flow pressure (PSF) with three different perfusion solutions: artificial tubule fluid (ATF); 0.3 M mannitol (M); and mannitol plus 25 to 30 mM sodium chloride (M + E). The second, triggering of the feedback response by injection of ionic current into the distal tubule, was studied in similarly prepared rats by monitoring PSF while passing current. Increasing the rate of loop of Henle perfusion with either ATF or M + E resulted in similar decreases in PSF. In contrast, with M, changes in PSF were usually transient and if persistent were smaller than the changes observed with the other two solutions. When loops of Henle were perfused with ATF at a constant rate, injection of current into the early distal tubule making the lumen more negative resulted in decreases in PSF. Currents of opposite polarity caused no change in PSF if loop flow rate was low; these currents increased PSF if the loop flow rates had previously been high. Current-induced feedback responses were obtained with micropipette electrodes filled with either potassium chloride or lithium acetate. Addition of 10(-4) M furosemide blocked the current-induced feedback responses.

Association of 17p loss with late-stage or refractory disease in hematologic malignancy.

Twenty-five patients with loss of part or all of 17p were selected from 701 patients with hematologic malignancies karyotyped either at diagnosis and/or at relapse and/or in refractory disease. Loss of 17p resulted from partial arm deletion (eight cases), unbalanced translocation (12 cases), i(17)(q10)(five cases) or monosomy 17 (four cases). In three cases, both 17ps were missing; in one case, two sublines independently acquired loss of 17p. In eight cases, loss of 17p was confirmed as a secondary change. The karyotypes generally were complex, with an average of 4.0 structurally abnormal chromosomes in the simplest lines showing 17p loss. The incidence at diagnosis was acute lymphoblastic leukemia (ALL) 2.2%, acute myeloid leukemia (AML) 2.4%, and myelodysplastic syndrome (MDS) 3.4%. The incidence in relapse and refractory disease was ALL 8.9%, AML 3.3%, and MDS 6.3%. The increased incidence of 17p loss in relapse and refractory disease was statistically significant (p < 0.05). Loss of 17p appears to be a feature of late-stage or resistant disease in hematologic malignancy.

Arachidonic fatty acid in red blood cell membranes, lymphocytes, and cultured skin fibroblasts of dominant Charcot-Marie-Tooth syndrome.

Altered proportions of long-chain unsaturated n - 6 fatty acids (FA) in plasma and myelin of the heredodegenerative peripheral neuropathy, Charcot-Marie-Tooth syndrome (CMT), may implicate FA metabolism in the pathogenesis of CMT demyelination. A significant relationship between low plasma values of the polyunsaturated n - 6 FA, arachidonic acid, and an increased amount of prostaglandin-mediated immune responses had suggested the possibility of immune system metabolic usage of these n - 6 FA rather than an inherited FA enzyme defect. This relationship between peripheral immunostimulation and altered FA was documented repeatedly in CMT patients. Increased and cyclic lymphocyte activation expressions were measured at the same time as low amounts of plasma arachidonic acid, which is the FA precursor of prostaglandin immunoregulatory agents. An autoimmune process with possible enhanced formation of the n - 6 immune prostenoid agents in CMT had also been suggested by increased class II antigen expression on CMT sural nerves. Here, normal proportions of total FA in cultured CMT skin fibroblasts diminishes a notion of hereditary defects in CMT fatty acid metabolism. In addition, a significant depletion of the key arachidonic acid in lipid stores of CMT red blood cell membranes with elevated values of this FA in functional CMT lymphocytes, compared to controls, support the concept in CMT patients of a metabolic diversion of n - 6 FA, particularly arachidonic acid, from tissue stores for immunoregulatory prostenoid agent formation.

Sleep, epilepsy, and the EEG in infancy and childhood.

Each of the major epileptic syndromes that occur in infants and children demonstrates relationships to sleep and wakefulness that are particular to that syndrome. These relationships include activation or suppression of clinical seizures during certain portions of the sleep-wake cycle, differences in symptomatology of the seizures or in seizure type, alterations in distribution or morphology of epileptiform waveforms, and changes in duration and composition of sleep stages. Knowledge of the interactions between sleep and seizures helps to increase understanding of the physiological mechanisms underlying epilepsy, as well as to improve clinical diagnosis.