Jean Gueris

On the pathogenesis of so-called idiopathic hypercalciuria

Abstract Forty-seven patients were identified as having persistent hypercalciuria during a period of low calcium intake ( Type 2 patients were divided into two subtypes on the basis of their response to the administration of methylchlorothiazide and 25-hydroxyvitamin D 3 (25(OH)D 3 ). Type 2a patients responded to either treatment with little change in serum calcium, an increase in serum phosphate and a decrease in serum immunoreactive PTH concentration. They were classified as having suppressible hyperparathyroidism secondary to a primary renal calcium leak. Type 2b patients responded to both thiazide and 25(OH)D 3 therapy with an increase in serum calcium concentration and no decrease in immunoreactive PTH. They were classified as having nonsuppressible normocalcemic hyperparathyroidism and underwent successful parathyroid surgery. However, they had persistent postoperative hypercalciuria, and several had suppressible hyperparathyroidism several years after their successful parathyroid surgery. On the basis of these facts, type 2b patients were also considered to have a long-standing primary renal calcium leak that led initially to secondary hyperparathyroidism but eventually to tertiary or nonsuppressible hyperparathyroidism.

Inflammatory cytokine response in patients with septic shock secondary to generalized peritonitis

Objectives: The aims of this study were the following: a) to assess the proinflammatory cytokine (tumor necrosis factor [TNF]‐α, interleukin [IL]‐1, and IL‐6) response in patients with septic shock secondary to generalized peritonitis; and b) to evaluate the influence of bacteremic status, type of peritonitis (acute perforation or postoperative), and peritoneal microbial status (mono‐ or polymicrobial) on cytokine expression and mortality. Design: Prospective study. Setting: Surgical intensive care unit of a university hospital. Patients: Fifty‐two consecutive patients with septic shock caused by generalized peritonitis. Interventions: Routine blood tests, blood cultures, and cytokine assays were performed during the first 3 days after onset of shock. Measurements and Main Results: Serum TNF‐α and IL‐6 concentrations were measured by using a radioimmunoassay, and IL‐1 concentrations were measured by using ELISA. Median serum concentrations on day 1 were: TNF‐α, 90 pg/mL; IL‐1, 7 pg/mL; and IL‐6, 5000 pg/mL. TNF‐α and IL‐6 concentrations decreased significantly between the first and third days of septic shock (p = .0001), whereas IL‐1 concentrations remained low. The decrease in IL‐6 tended to be more pronounced in the survivors group (p = .057). Median TNF‐α serum concentrations were higher in bacteremic compared with nonbacteremic patients (151 vs. 73 pg/mL, p = .003). TNF‐α, IL‐1, and IL‐6 serum concentrations and mortality were not different between acute perforation vs. postoperative peritonitis and mono‐ versus polymicrobial peritonitis. Conclusions: The systemic release of TNF‐α and IL‐6 during septic shock caused by generalized peritonitis was maximal on day 1 and decreased rapidly during the next days. No systemic release of IL‐1 was observed. IL‐6 serum concentrations remained higher in patients who subsequently died. Among the different features of peritonitis studied, only bacteremia influenced the systemic cytokine response (higher TNF‐α).

High tumor necrosis factor serum level is associated with increased survival in patients with abdominal septic shock: A prospective study in 59 patients

BACKGROUND In several studies including patients with septic shock of various origins, high serum cytokine levels have been reported to correlate with poor outcome. The aim of this prospective study was to assess the prognostic value of cytokine serum levels in a group of patients with perioperative septic shock of digestive origin. METHODS From January 1992 to December 1994, 59 patients were evaluated (mean age, 68 +/- 15 years). From the first day of septic shock to day 7, blood was drawn every day to measure the conventional biologic parameters (white blood cell count, platelet count, hematocrit, blood urea nitrogen level, serum electrolytes level, pH, blood gases, serum lactate level, coagulation parameters, liver function tests) and tumor necrosis factor (TNF), interleukin-1, and interleukin-6. RESULTS No difference was observed between the 26 survivors and the 33 nonsurvivors with regard to age, gender, and cause of sepsis. On admission, mean platelet count was significantly higher in the survivors than in the nonsurvivors (260 +/- 142 versus 177 +/- 122 10(9)/L; p = 0.01). Mean blood urea nitrogen level was significantly lower in the survivors than in the nonsurvivors (9.6 +/- 9 versus 12 +/- 7 mmol/L; p = 0.04). No difference was observed between survivors and nonsurvivors for the other conventional biologic parameters and for serum interleukin-1 and interleukin-6 levels. Mean serum TNF level tended to be higher in survivors than in nonsurvivors (565 +/- 1325 versus 94 +/- 69 pg/ml; not significant). In the group survivor 9 (35%) of 26 patients had a serum TNF level greater than 200 pg/ml versus 2 (6%) of 33 patients in the nonsurvivor group (p < 0.02). Survival was noted in 6 (100%) of 6 patients who had both a serum TNF level greater than 200 pg/ml and a platelet count greater than 100.10(9)/L versus 1 (11%) of 9 in patients with neither of these criteria (p < 0.01). CONCLUSIONS In our patients with abdominal septic shock, high serum TNF levels were associated with increased survival. The high serum level of TNF may reflect the efficacy of peritoneal inflammatory response against abdominal sepsis. Although this possibility must be further explored, a score combining the serum TNF level and platelet count could be helpful for the prognostic assessment of patients with abdominal septic shock.

The effect of 1α(OH)D3 and 1α,25(OH)2D3 on the bone in patients with renal osteodystrophy

Abstract Six patients with chronic renal disease and variable degrees of renal osteodystrophy were treated for three weeks with either 1α,25-dihydroxyvitamin D 3 (1α25(OH)D 3 ) or 1α,hydroxyvitamin D 3 (1α(OH)D 3 ) and both the biochemical and osseous responses measured. The most consistent changes seen were an increase in serum calcium concentration to normal, a decrease in immunoreactive parathyroid hormone toward normal, an increase in the extent of the calcification front and a decrease in the extent of fibrous dysplasia in the marrow cavity. Two important parameters which did not change significantly were the serum alkaline phosphatase activity and the osteoid volume. These data, in conjunction with that from previous studies, indicate that therapy with 1α,25(OH) 2 D 3 or 1α(OH)D 3 does not heal the osteomalacia of renal osteodystrophy, but that it does suppress the secondary hyperparathyroidism, and ameliorate the osteitis fibrosa seen in patients with chronic renal disease. They raise the likelihood that additional factors, such as metabolites of vitamin D other than 1α,25(OH) 2 D 3 , play a role in regulating bone formation and/or mineralization.

Morphine-induced sensitization of locomotor activity in mice: effect of social isolation on plasma corticosterone levels.

This study examined the influence of social isolation on behavioural sensitization to the locomotor effect of morphine and the link between this behaviour and plasma corticosterone concentrations. Four weeks isolation induced an increase in the locomotor effect of morphine. In social and isolated mice, repeated administrations (6) of morphine (one injection every 3 or 4 days) followed by 3 h in an actimeter induced behavioural sensitization to the locomotor effect of morphine. No interaction was observed between social isolation and behavioural sensitization to morphine. Resocializing previously isolated mice for 3 weeks reduced the morphine-induced locomotor effect without altering the behavioural sensitization. Corticosterone plasma levels were more increased (416%) in mice isolated 5 weeks than in mice isolated for 2 weeks (243%) and they return to the control levels following 3 weeks of resocialization. Since there was no interaction between the increase in morphine locomotor effect induced by social isolation and the morphine-induced behavioural sensitization, it is suggested that each of these two events acts independently. Whether or not a common mechanism (plasma corticosterone levels?) partly underlies both effects, the result resembles a simple additive effect.