Peptide:glycosaminoglycan hybrid hydrogels as an injectable intervention for spinal disc degeneration.

Degeneration of the spinal discs is a major cause of back pain. During the degeneration process, there is a loss of glycosaminoglycans (GAGs) from the proteoglycan-rich gel in the disc's nucleus, which adversely alters biomechanical performance. Current surgical treatments for back pain are highly invasive and have low success rates; there is an urgent need for minimally-invasive approaches that restore the physiological mechanics of the spine. Here we present an injectable peptide:GAG hydrogel that rapidly self-assembles in situ and restores the mechanics of denucleated intervertebral discs. It forms a gel with comparable mechanical properties to the native tissue within seconds to minutes depending on the peptide chosen. Unlike other biomaterials that have been proposed for this purpose, these hybrid hydrogels can be injected through a very narrow 25 G gauge needle, minimising damage to the surrounding soft tissue, and they mimic the ability of the natural tissue to draw in water by incorporating GAGs. Furthermore, the GAGs enhance the gelation kinetics and thermodynamic stability of peptide hydrogels, significantly reducing effusion of injected material from the intervertebral disc (GAG leakage of 8 ± 3% after 24 h when peptide present, compared to 39 ± 3% when no peptide present). In an ex vivo model, we demonstrate that the hydrogels can restore the compressive stiffness of denucleated bovine intervertebral discs. Compellingly, this novel biomaterial has the potential to transform the clinical treatment of back pain by resolving current surgical challenges, thus improving patient quality of life.

Reversible sequestration of nitric oxide by hemoglobin during hemodialysis in end-stage renal disease.

BACKGROUND: During hemodialysis, patients whose plasma concentrations of nitric oxide (NO) products increase reportedly experience hypotension. Therefore, whether NO bound to hemoglobin (Hb) could contribute to various clinical and laboratory changes during hemodialysis was explored in patients with end-stage renal disease (ESRD). METHODS: Ten patients were studied during 3 hemodialysis treatments with samples of blood analyzed for RBC nitrosyl Hb (HbNO), L-arginine, asymmetric dimethylarginine (ADMA), plasma nitrite+nitrate (NOx), and buffy coat NO synthase (NOS) activities. RESULTS: HbNO before and during hemodialysis varied considerably. Those with higher predialysis levels had lower HbNO values during dialysis, whereas HbNO levels in those with lower levels before dialysis increased. Plasma NOx did not correlate with HbNO, but change in HbNO in the first hour and change in NOx in the first 2 hours correlated with drop in diastolic and systolic blood pressures (BP), respectively. HbNO concentrations increased in patients with >35% drop in systolic BP, whereas in those with <35% drop, HbNO concentrations decreased. HbNO levels adjusted by the hematocrit showed a drop in HbNO for the <35% group and a >3-fold increase in the >35% group. HbNO levels were higher in men than in women, and levels and changes correlated with the hematocrit, skin temperatures, plasma ADMA, arginine, and buffy coat NOS. CONCLUSIONS: In patients with >35% drop in systolic BP, NO was scavenged by Hb in the circulating RBCs, undoubtedly attenuating the degree of hypotension. These data indicate that the amount of NO that is scavenged or released by Hb in the circulating RBCS during dialysis is highly variable and reversible. Various predialysis factors relate to the concentration of HbNO before and during dialysis, which in turn influence clinical findings that occur during the interdialytic period.

Preterm premature rupture of membranes: aggressive tocolysis versus expectant management.

The objective of our study is to determine whether aggressive tocolysis in patients with preterm premature rupture of membranes between 24 and 34 weeks gestation improves neonatal outcome. Patients with documented preterm premature rupture of membranes between 24 and 34 weeks gestation were prospectively randomized to group I, aggressive tocolysis with intravenous magnesium sulfate, or to group II, no tocolysis. The lecithin/sphingomyelin ratio was determined upon hospital admission and every 48-96 hours until delivery. Both groups received weekly steroids and antibiotics pending culture results and were promptly delivered when chorioamnionitis, fetal stress, or an Lecithin/sphingomyelin ratio of > or = 2.0 occurred. The study group involved 145 patients. No statistically significant differences between groups I (n = 78) and II (n = 67) were observed regarding demographic characteristics, gestational age at enrollment or at delivery, latency, development of clinical chorioamnionitis, birth weight, number of days in neonatal intensive care unit, days on oxygen or ventilatory support, frequency of hyaline membrane disease, necrotizing enterocolitis, intraventricular hemorrhage, neonatal sepsis, or neonatal mortality. Our data suggest that tocolysis in patients with preterm premature rupture of membranes does not significantly improve perinatal outcome.

Evaluation of hemodialysis patients treated with erythropoietin.

We evaluated 20 hemodialysis patients who had been treated with erythropoietin (Epo). All patients had hemoglobin levels below 8.5 g/dL. They were randomized to receive either Epo (100 U/kg) or placebo three times per week for 12 weeks. All patients on Epo had a significant (P less than 0.001) elevation of hematocrit levels (19.7% v 35.7%). They also had a significant (P less than 0.05) increase in midweek predialysis blood urea nitrogen (BUN) levels, 27.8 versus 29.6 mmol/L (78 v 83 mg/dL), and serum phosphorus, 1.8 versus 2.1 mm/L (5.7 v 6.6 mg/dL). Protein catabolic rate also increased significantly (P less than 0.05). No changes were seen in the levels of serum creatinine and potassium, but episodes of hyperkalemia were more frequent in patients on Epo. No changes were seen in patients on placebo. When hematocrit increased, the clearance of blood-water for urea decreased 9%, and the clearance of creatinine, potassium, and phosphorus decreased 15%. Patients on Epo increased both their appetite and protein intake. More frequent episodes of hyperkalemia and elevated phosphorus level resulted from a combination of increased intake and decreased dialyzer clearance. We may need blood-water clearance to calculate Kt/V.

Altered vascular reactivity in sickle hemoglobinopathy. A possible protective factor from hypertension.

Patients with sickle cell anemia have considerably less hypertension than the black population in general. Factor(s) offering "protection" from hypertension in these patients remain unknown. Hormonal and hemodynamic parameters involved in blood pressure regulation were evaluated in normotensive, stable sickle cell patients and black nonsickle normotensive controls. There was no difference in systolic, diastolic, or mean arterial blood pressure between the two groups. The characteristic hemodynamic findings of increased cardiac index, renal plasma flow, and plasma volume were observed in the sickle cell patients. Urinary sodium excretion was comparable on an ad libitum, high sodium, and low sodium diet. In contrast, plasma renin activity was greater in sickle cell patients at all levels of sodium intake in both supine and upright positions. These findings suggested possible altered vascular responsiveness to endogenous angiotensin II. Plethysmography revealed that sickle cell patients had greater forearm blood flow than normal controls and black nonsickle chronic anemic controls at rest, during cold stimulation, and during exercise. Forearm vascular resistance was significantly lower in the patients and did not increase with cold-induced, sympathetic-mediated stimulation. To assess these findings more directly, the pressor response to the exogenous administration of graded doses of angiotensin II and norepinephrine was measured. There was a marked decrease in the pressor response to angiotensin II but not to norepinephrine in the sickle cell patients. The findings in these studies indicate fundamental differences in blood pressure control in the sickle cell patient, probably at the vascular level.

Long-term effects of cyclosporine on renal function in liver transplant recipients.

The long-term effects of cyclosporine on renal function were evaluated in eleven liver transplant recipients over a 6-26-month follow-up period. Renal hemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF]) fell 60% postoperatively, subsequently improved, and stabilized at 45-60% of normal despite continued drug administration. Tubular sodium transport studies during water diuresis suggested that the proximal tubule is a major site of cyclosporine nephrotoxicity. In contrast to the acute effects of cyclosporine on renal function, the fraction of glomerular filtrate reabsorbed in the proximal tubule was less in the patient group while the fractional excretion of sodium, potassium, and phosphate was increased. When the fraction of filtered sodium reabsorbed in the diluting segment was examined as a function of sodium delivery, functional impairment occurred in the diluting segment as well. Eight renal biopsies performed in six patients 4-29 months posttransplantation showed only mild to moderate changes, predominantly vascular, which correlated poorly with corresponding renal function. These data showed that long-term cyclosporine administration produced early and persistent depression of both hemodynamic and tubular function. A functional rather than structural mechanism appears to be more significant during this period of observation.