Left ventricular hypertrophy in daily dialysis.

Cardiac hypertrophy, a well-known independent risk factor for cardiovascular death, is a very frequent complication in ESRD patients. Its frequency tends to be even higher in dialyzed patients due to the fact that the current dialytic treatments are unable to keep under a satisfactory control the various responsible factors and particularly the blood pressure, which is largely the most important. Daily hemodialysis, a more frequent schedule consisting of 6-7 sessions/week lasting 2 or more hours, has definitely proved its superiority in controlling blood pressure and in improving anemia, and thus has the requisites for positively influencing cardiac hypertrophy. In fact, a series of studies, both retrospective and prospective, performed during the last years by our group, have confirmed that this new, more frequent and thus more physiological schedule, is able not only to stop the progression of the cardiac hypertrophy in uremic patients but also to revert toward the normality, in a relatively short time. This appears to be essentially a consequence of the excellent blood pressure control, which in turn derives from the easier control of the true dry weight, achievable with this type of dialytic treatment.

Clinical experience with a 39 mmol/L bicarbonate-buffered peritoneal dialysis solution.

OBJECTIVE: To investigate the effect on the patient's acid-base status of a 39 mmol/L bicarbonate-buffered continuous ambulatory peritoneal dialysis (CAPD) solution. DESIGN: This was an open, controlled, cross-over, two-center study in 9 patients. After three months of treatment with a 34 mmol/L bicarbonate-buffered solution (t0) patients were switched to a 39 mmol/L bicarbonate-containing solution for four weeks. At the end of the study period (t4) patients were again treated with a 34 mmol/L bicarbonate-buffered CAPD solution for one month (t8). RESULTS: Mean venous plasma bicarbonate level significantly increased during the study and decreased at the baseline level during the control period (t0 = 22.94 +/- 2.54, t1 = 26.74 +/- 3.07, t2 = 28.47 +/- 2.68, t3 = 28.11 +/- 3.56, t4 = 28.71 +/- 3.27, t8 = 24.94 +/- 2.56). Arterial blood pH and plasma bicarbonate significantly increased during the study and significantly decreased at the end of the control period (pH: t0 = 7.37 +/- 0.04, t4 = 7.42 +/- 0.04, t8 = 7.37 +/- 0.06. Bicarbonate: t0 = 21.97 +/- 2.57, t4 = 25.85 +/- 2.02, t8 = 21.87 +/- 2.89). The changes in plasma bicarbonate during the study period were inversely correlated with the metabolic acid production calculated from the protein catabolic rate and with the apparent distribution space for bicarbonate (ABS) of patients. CONCLUSIONS: The 39 mmol/L bicarbonate-buffered CAPD solution improved the patient's acid-base status. Potential undesirable metabolic alkalosis could be prevented by analyzing the ABS and the metabolic acid production of patients.

Bicarbonate versus lactate buffer in peritoneal dialysis solutions: the beneficial effect on RBC metabolism.

OBJECTIVE: Using the erythrocyte as a model for other kinds of cells not directly exposed to peritoneal dialysis (PD) solutions, we investigated the tolerance of the cell metabolism to lactate and bicarbonate buffers. DESIGN: We studied, in vivo (in two groups of 5 PD patients each) and in vitro, the Embden-Meyerhof pathway (EMP) because it represents a potential target for the unphysiological effects of lactate or bicarbonate buffers. The EMP is the main glucose-utilizing route in the red blood cell (RBC), producing energy and reducing power. METHODS: The enzymatic activities of the key steps in the glycolytic pathway and the energy charge (EC), determined by the levels of phosphorylated adenine nucleotides, were investigated spectrophotometrically and by high performance liquid chromatography (HPLC) in two groups of patients undergoing lactate (L-group) and bicarbonate (B-group) PD, respectively. The in vitro effects of both bicarbonate and lactate buffers on some EMP enzyme activities and energy production were determined. Cellular pH (pHi) was also investigated. RESULTS: The B-group showed an EC value near the control levels, while in the L-group a significantly lower EC value was observed (t-test: p < 0.05 vs both B-group and controls). The key enzymes in the EMP, and in particular hexokinase, were higher in the L-versus B-group (p < 0.03 for the comparison of the Hk mean values). As demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, the bound form of glyceraldehyde-3-phosphate dehydrogenase (G-3-PD), an inactive form of this EMP enzyme, was significantly higher in the L-group with respect to the B-group (p < 0.004). In the in vitro experiments, high lactate concentrations acutely inhibited the key enzymatic steps of glycolysis, producing a significant decrease in glucose consumption and adenosine triphosphate production. These effects were not observed when bicarbonate was used in the incubations. Both in vivo and in vitro lactate, but not bicarbonate, induce a significant drop in pHi (p < 0.05). Decreased levels of pHi like those observed in the lactate-incubated RBC were demonstrated to be able to inhibit G-3-PD activity (25 +/- 2%) here used as an indicator of the actual decrease in pH. CONCLUSION: This study provides evidence for a damaging action of lactate with respect to bicarbonate buffer on the RBC metabolism. This condition was demonstrated observing a cell energy depletion, which coincides in vitro with an acute EMP impairment; the lactate accumulation together with the consequent lowering of pHi seem to be responsible for this effect, which was not observed when bicarbonate was used instead of lactate.

A quantitative investigation of the effects of neonatal capsaicin treatment on vagal afferent neurons in the rat.

The sensory cells of the nodose and jugular ganglia of the rat have been quantitatively evaluated in longitudinal paraffin sections. The right vagal ganglia contain significantly more neurons than the left, particularly neurons with somata having sectioned areas 200-400 microm2 and longest diameters 15-25 microm. Such neurons appear to be homogenously distributed because sections of the right vagal ganglia did not show specific areas of neuronal density compared with those of the left. Neonatal capsaicin treatment reduced the number of neurons in both the left and right ganglia to about 30% of controls. Capsaicin destroyed neurons with sectioned areas of 100-600 microm2 and longest diameters of 15-35 microm, but had no statistically significant effects on larger neurons.

Effect of capsaicin on learning, retention and extinction of spatial and active avoidance tasks in adult rats neonatally treated.

The relationship between learning capability and neurological damage following neonatal treatment with capsaicin (50 mg/kg) was studied in adult Wistar rats of either sex using different experimental procedures. First of all, the reaction to a stress-inducing situation was evaluated by analysing the behavior of capsaicin and vehicle-treated rats in an open field situation. No differences were observed between these two groups. Moreover, the parameters considered were similar to those of untreated, age-matched animals. Rats treated with capsaicin showed a marked learning impairment of an appetitive task in a complex maze. On the contrary, no alterations were observed in both retention and extinction of this conditioned behavior. In spatial discrimination investigated using a different maze (8-arm radial maze) but with the same reinforcement (food), no difference was found between capsaicin-and vehicle-treated rats. In both groups a trial number-related increase of the responding efficiency and a decrease in the mean running time were observed. Neonatally treated rats behaved also similarly in aversive conditioning. However, their learning performances were much better than those of untreated rats. These results confirm that neonatal exposure to painful stimuli later improves active avoidance performance. Capsaicin treatment did not have any effect on the latency of nociceptive response in the hot-plate test.

Tenotomy prevents the functional improvement of a muscle reinnervated with a chronically severed nerve.

During the early stages of nerve implantation, we followed the dynamic properties of the lateral gastrocnemius muscle of the rat, reinnervated with an acutely or chronically severed peroneal nerve. The aim of this study was to ascertain whether 1) the better functional recovery of a muscle reinnervated by a chronically severed foreign nerve is present from the onset of reinnervation, and 2) whether such functional improvement is due to the conditioning lesion effect. Our results indicate that better functional recovery is already apparent one week after nerve implantation, and it is due to the conditioning lesion effect, since tenotomy prevents such improvement. The tenotomy effect underlines the fact that some environmental factors concerning the target tissue, and not only the predegenerated nerve, are involved in the conditioning effect.

Redox state, antioxidative activity and lipid peroxidation in erythrocytes and plasma of chronic ambulatory peritoneal dialysis patients.

Red blood cells and plasma reduced and oxidized glutathione levels, glutathione peroxidase (GSH-Px) activity, thiobarbituric acid reactants (TBAR) of both chronic ambulatory peritoneal dialysis (CAPD) patients and a matched control group were investigated in this study. Oxidized and reduced pyridinic nucleotides in red blood cells (RBC), in which NADPH is a direct expression of hexose monophosphate shunt function, were also studied. The results obtained indicate that RBC and plasma are exposed to oxidative stress in CAPD. This condition is characterized by a decreased GSH/GSSG ratio, particularly evident in RBC as a consequence of the GSSG accumulation. Lipid peroxidation is increased, as indicated by raised TBAR levels, and reduced pyridinic nucleotides are decreased. Increased GSH-Px levels and unmodified or slightly increased GSH content were observed in the RBC but not in plasma, which showed decreased GSH and unmodified peroxidase activity. Peroxidase correlated positively with TBAR levels in the RBC lysates. In a subgroup of patients treated with erythropoietin (vs. untreated patients and controls) no differences were observed in the glutathione-related parameters studied. These data suggest that a mechanism for adaptation to oxidative conditions may be present in CAPD and its effects on RBC integrity are discussed in comparison with the hemodialysis conditions previously studied.

The structure of sleep is related to the learning ability of rats.

Using electroencephalographic methods, rats learning or not learning a two-way active avoidance task were found to differ significantly in the structure of sleep determined the day before training. The main differences concerned (i) synchronized sleep episodes followed by wakefulness, which were longer and fewer in learning rats; (ii) paradoxical sleep episodes, which were longer in learning rats. Significant correlations were present between the number and/or the average duration of synchronized sleep episodes followed by wakefulness or by paradoxical sleep and the number of avoidances or escapes scored in the training session. Power spectral analysis indicated that the relative output in the 6-7-Hz region was higher in learning rats, notably during short episodes of synchronized sleep followed by paradoxical sleep. As two-way active avoidance training induces comparable modifications in postacquisition sleep (Ambrosini et al., Physiol. Behav., 51, 217-226, 1992), the features of preacquisition sleep which prevail in learning rats might directly determine their capacity to learn. Alternatively, they might reflect the existence of a genetic determinant independently conditioning the ability to learn.

L-acetylcarnitine enhances functional muscle re-innervation.

The efficacy of L-acetylcarnitine and L-carnitine treatment on motor re-innervation was analyzed by evaluating different muscular parameters describing functional muscle recovery after denervation and re-innervation. The results show that L-acetylcarnitine markedly enhances functional muscle re-innervation, which on the contrary is unaffected by L-carnitine. The medial gastrocnemius muscle was denervated by cutting the nerve at the muscle entry point. After 20 days the sectioned nerve was resutured into the medial gastrocnemius muscle, and the extent of re-innervation was monitored 45 days later. L-acetylcarnitine-treated animals show significantly higher twitch and tetanic tensions of re-innervated muscle. Furthermore the results, obtained by analysing the twitch time to peak and tetanic contraction-relaxation times, suggest that L-acetylcarnitine mostly affects the functional re-innervation of slow motor units. The possible mechanisms by which L-acetylcarnitine facilitates such motor and nerve recovery are discussed.

Vagal afferent innervation of the pylorus and the upper small intestine studied in the rat with the horseradish peroxidase technique.

The neuronal tracer horseradish peroxidase was injected into different segments of the gastrointestinal in the rat, in order to study the vagal afferent innervation. In the nodose ganglia the extent of labeling was greater in the experiments on the gastric antrum and pylorus than in the experiments on the first part of the small intestine. Vagal afferents are scarce in the upper duodenum and originate mainly from the left nodose ganglion.

Vagal afferent innervation in regenerated rat liver.

The possible presence of neural sprouting in the afferent neurons of regenerated rat liver after hepatectomy was investigated by retrograde transport of horseradish peroxidase. This experiment was carried out to see if the increase in hepatic parenchyma could provide an adequate stimulus for the sprouting process. The study was limited to the vagal afferents, particularly the left ones, because they are the principal contributors to hepatic afferent innervation in the rat. The results show that neural sprouting does not occur in regenerated rat liver after 3 weeks. In fact, the number of intensely labeled neurons in the left nodose ganglia of hepatectomized rats was significantly smaller than in controls. This could be due to a lessened availability of horseradish peroxidase to nerve terminals because of the increased non-innervated hepatic mass. There was no difference between right nodose ganglia neurons in hepatectomized and control animals. This could be a consequence of their possible distribution in hepatic areas not involved in the regenerative process.

On the nature of the afferent fibers of oculomotor nerve.

The oculogyric nerves contain afferent fibers originating from the ophthalmic territory, the somata of which are located in the ipsilateral semilunar ganglion. These primary sensory neurons project to the Subnucleus Gelatinosus of the Nucleus Caudalis Trigemini, where they make presynaptic contact with the central endings of the primary trigeminal afferents running in the fifth cranial nerve. After complete section of the trigeminal root, the antidromic volleys elicited in the trunk of the third cranial nerve by stimulating SG of NCT consisted of two waves belonging to the A delta and C groups. The area of both components of the antidromic volleys decreased both after bradykinin and hystamine injection into the corresponding cutaneous region and after thermic stimulation of the ipsilateral trigeminal ophthalmic territory. The reduction of such potentials can be explained in terms of collision between the antidromic volleys and those elicited orthodromically by chemical and thermic stimulation. Also, capsaicin applied on the nerve induced an immediate increase, followed by a long lasting decrease, of orthodromic evoked response area. These findings bring further support to the nociceptive nature of the afferent fibers running into the oculomotor nerve.

Capsaicin-sensitive vagal afferent neurons innervating the rat pancreas.

The vagal afferent innervation of the rat pancreas was investigated by the use of retrograde axonal transport of horseradish peroxidase (HRP) injected into the pancreas through the common bile duct. Many labeled neuronal somata were found in the right and left nodose ganglia. The size distribution of the labeled neuronal population in the nodose ganglia was examined and compared with that obtained from rats pretreated with capsaicin. In rats treated neonatally with capsaicin the smallest neurons (up to 200 micron2) were completely absent and those belonging to the second and third classes (200-300, 300-400 micron2) were reduced in both vagi.

Influence of atrophy on the efficiency of muscle reinnervation.

The effectiveness of motor reinnervation carried out after an interval of 20 days between nerve transection and reimplantation onto a foreign muscle was studied in the rat. Sixty days after reimplantation the compound action potential, the maximal indirect twitch and tetanic tensions, and weight loss were evaluated. The functional data demonstrated an incomplete recovery which differed from the complete functional restoration observed in an acutely denervated muscle reinnervated with a chronically severed nerve. Time-dependent changes induced in the muscle by denervation seem therefore to influence the efficacy of motor reinnervation.

Thyroid function tests in patients undergoing maintenance dialysis: characterization of the 'low-T4 syndrome' in subjects on regular hemodialysis and continuous ambulatory peritoneal dialysis.

Thyroid function tests were evaluated in 38 patients on regular hemodialysis (HD), in 36 on continuous ambulatory peritoneal dialysis (CAPD) and in 39 healthy controls. A significant reduction in total thyroxine (TT4), total triiodothyronine (TT3), reverse (rT3), and free T4 (fT4) mean levels and normal TSH, free T3, TBG and albumin concentrations was found in both HD and CAPD patients. A 'low-T4 syndrome' (serum T4 less than 5 micrograms/dl) was found in 9 CAPD (25%) and 20 HD (53%) patients, but none of them had fT4 levels below the normal laboratory range. The only striking difference between low-T4 HD and low-T4 CAPD patients was the significantly lower TBG and albumin serum levels in CAPD group. Low-T4 HD displayed normal TBG levels but enhanced fT4/TT4 and fT4/TT4 X TBG ratios. We concluded that: the abnormalities in thyroid function tests in patients on long-term dialysis (HD and CAPD) do not express the existence of a true hypothyroidism; a different pathogenesis of the low-T4 syndrome in the CAPD and HD groups may be hypothesized: in the former it could be attributed to a reduction in serum-binding capacity for thyroid hormones, in the latter the relative increase in fT4 percentage despite normal TBG levels suggests either the presence of T4-TBG-binding inhibitor(s), or structural abnormalities of thyroid-hormone-binding proteins.

Differential distribution of vagal afferent neurons from the rat liver.

Selective injection of horseradish peroxidase (HRP) into the left and median lobes (LM) and into the right and caudate (RC) lobes of the liver is followed by labeling of neuronal somata in the right and left nodose ganglia. The size distribution of the labeled neuronal population shows that the afferent neurons from the two parts of the liver can be grouped in two corresponding classes; a third class is apparent following injection into the LM lobes. Small neurons are more numerous after injection into the LM lobes, whereas large ones are labeled in the left nodose ganglion after injection into the RC lobes. It is suggested that the two parts of the liver may have a different functional role in conveying afferent signals.

Capsaicin-sensitive afferent vagal neurons innervating the rat liver.

The effects of neonatal capsaicin treatment on the vagal afferent neurons innervating the liver have been studied in the rat. The smallest neurons (up to 180 microns 2) innervating the left and median lobes and the right and caudate lobes of the liver are completely destroyed by neonatal capsaicin administration and the number of neurons up to 300 microns 2 is reduced. It is suggested that the capsaicin-sensitive neurons in the nodose ganglion innervating the liver may be involved in nociception.

Control of uremic neuropathy by equilibrium peritoneal dialysis.

Motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNVC) and distal motor latencies times (DMLT) were evaluated both in upper and lower limbs in three groups of 15 patients of comparable age, treated respectively by extracorporeal dialysis (HD), continuous ambulatory peritoneal dialysis (CAPD) and combined peritoneal dialysis (CPD) for comparable sufficiently long periods. Moreover, MNCV was monitored longitudinally in two groups of patients shifted from CAPD to HD and vice versa. The results show a significant superiority of peritoneal dialysis and particularly of CAPD with respect to HD in controlling uremic neuropathy.