Variable region expression in the antibody responses of infants vaccinated with Haemophilus influenzae type b polysaccharide-protein conjugates. Description of a new lambda light chain-associated idiotype and the relation between idiotype expression, avidity, and vaccine formulation. The Collaborative Vaccine Study Group.

Haemophilus influenzae b polysaccharide (Hib PS)-protein conjugate vaccines differ chemically and immunologically. To determine whether anti-Hib PS variable region expression might differ according to vaccine formulation, infants were vaccinated at 2, 4, and 6 mo of age with Hib PS coupled to either meningococcal outer membrane protein complex (Hib PS-OMPC) or tetanus toxoid (Hib PS-T), or Hib PS oligomers coupled to a mutant diphtheria toxin (Oligo-CRM). Two anti-Hib PS idiotypes were measured in sera obtained after the third injection: HibId-1, expressed by anti-Hib PS antibodies having the kappa II-A2 variable region, and HibId-2, a newly defined cross-reactive idiotype associated with a subset of anti-Hib PS antibodies having lambda VII variable regions. HibId-1 was present in 33, 68, and 64% of infants given either Hib PS-OMPC, Oligo-CRM, or Hib PS-T, respectively (P < 0.001). The respective values for HibId-2 were 47, 18, and 10% (P = 0.001). Subjects who were vaccinated with Hib PS-OMPC or Hib PS-T and who produced detectable HibId-1-positive antibody, had significantly higher mean antibody avidity than subjects who did not produce HibId-1 positive antibodies. In contrast, Oligo-CRM evoked high avidity anti-Hib PS antibodies, irrespective of the idiotypic profile. These findings indicate fundamental differences in both variable region content and antibody quality elicited by different Hib PS conjugate vaccines.

The effect of somatostatin on postresectional ileal hyperplasia.

After somatostatin infusion in rats, the proliferative activity in ileal crypts was examined under a variety of circumstances known to influence mucosal behaviour. The anticipated hyperplastic response to resection was inhibited by somatostatin treatment, not only under conditions of intestinal continuity but also in isolated segments of ileum. These results suggest that postresectional ileal hyperplasia is humorally mediated and is explicable on the basis of somatostatin suppression of trophic gut hormones. However, a direct effect of somatostatin and other secondary effects cannot be excluded.

Renal, endocrine, and hemodynamic effects of human brain natriuretic peptide in normal man.

Brain Natriuretic Peptide (BNP) is a recently identified hormone which is secreted by the human heart and circulates in plasma. To determine the effects of pathophysiological levels of human BNP (hBNP), we have studied the integrated renal, hormonal, and hemodynamic response in six normal men receiving 2-h infusions of synthetic hBNP (2.0 pmol/kg.min) or placebo in random order. Steady state levels of hBNP (20-30 pmol/L), achieved at 90-120 min, were similar to levels observed in mild heart failure. Compared to placebo infusions, hBNP induced a greater than 2-fold increase in sodium excretion (P = 0.014) and suppressed plasma aldosterone (P < 0.004) to levels less than 50% of placebo values. These changes were associated with an increase in both plasma (P = 0.028) and urine excretion (P < 0.004) of cGMP. Effects on blood pressure were not statistically significant but increases in both heart rate (P < 0.0001) and plasma albumin (P = 0.007) after cessation of hBNP infusions indicate significant hemodynamic effects of hBNP. High MCR (5.8 +/- 0.7 L/min) yet slow disappearance rate (mean t1/2 22.6 min) indicate that hBNP has a large volume of distribution in humans. These studies show that hBNP, at plasma levels observed in patients with mild heart failure, has potentially important natriuretic, endocrine, and hemodynamic effects which are similar to those observed with comparable infusion rates of ANF.

Reduced bone mineral density in patients with adult onset growth hormone deficiency.

We have demonstrated previously that adults with isolated GH deficiency of childhood onset have a reduced bone mineral density (BMD) of vertebral trabecular bone [quantitative computed tomography (QCT): median Z score -1.3, P < 0.01, n = 12] and of cortical bone in the forearm [single photon absorptiometry (SPA): median Z score -2.9, P = 0.001, n = 7]. We have now examined BMD in 26 patients (13 men, 13 women), aged between 23.6 and 59.5 (mean 42.4) yr, with adult onset GH deficiency, defined as a GH response of less than 5 micrograms/L to provocative testing, of at least two years duration. BMD was measured using QCT for vertebral trabecular bone, dual energy x-ray absorptiometry (DXA) in the lumbar spine and femoral neck, and SPA in the forearm. There was a highly significant reduction in QCT (median Z score -1.07, P < 0.00005), in DXA of the lumbar spine (median Z score -0.76, P = 0.0001) and in SPA of the forearm (median Z score -0.86, P = 0.0001) but not in DXA of the femoral neck (median Z score -0.38, P = 0.35). There were no significant differences in Z scores between those patients with isolated GH deficiency and those with GH and gonadotrophin deficiency. There was a significant positive correlation between age at which BMD was measured and Z score (the older the patient, the higher the Z score) for QCT (r = 0.38, P < 0.05) and SPA (r = 0.48, P < 0.01) with a trend to a positive correlation for DXA of the lumbar spine and femoral neck. Patients were grouped according to estimated duration of GH deficiency (less than 5 yr, n = 7; 5-10 yr, n = 10; greater than 10 yr, n = 9). These groups did not show a significant difference in BMD at any site. We conclude that patients with adult onset GH deficiency (isolated or in conjunction with other pituitary hormone deficiencies) have a reduced BMD. Age at development of GH deficiency may be more important than duration of GH deficiency in determining the degree of reduction in bone mass. The impact of GH treatment on BMD in adults with adult onset GH deficiency requires investigation.

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency.

The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.

WR-2721 protection of pneumonitis and fibrosis in mouse lung after single doses of x rays.

The radioprotective effect of WR-2721 has been studied in mouse lung after single doses of radiation. Using the breathing rate assay and lethality, radioprotection was assessed at monthly intervals between 3 and 18 months after irradiation during both pneumonitis and chronic fibrosis. The degree of radioprotection was greater for fibrosis than for pneumonitis using both assays. In replicate experiments, dose modifying factors (DMF's) ranging from 1.2 to 1.4 were obtained for pneumonitis and 1.5 and 1.6 for fibrosis. The differences in DMF's for the two phases of lung damage were significant. A difference in the time course of expression of damage was seen in both the breathing rate and lethality assays between mice irradiated with and without WR-2721: the damage ended sooner in the drug-treated mice. This difference is best explained by protection of all damage after 5 months by WR-2721. No evidence of drug toxicity was found. We conclude that WR-2721 protects against chronic lung fibrosis caused by radiation at least as well as against the earlier appearing pneumonitis after single doses of radiation. Thus, if WR-2721 is dose modifying and if late tissue complications are dose limiting in clinical radiotherapy, then a therapeutic benefit would be obtained by the use of this drug in clinical radiotherapy, provided that the radioprotection of tumors did not exceed a factor of 1.5-1.6.

Brain natriuretic peptide: natriuretic and endocrine effects in essential hypertension.

OBJECTIVE: Documentation of the renal, hormonal and haemodynamic effects and plasma clearance of human brain natriuretic peptide (BNP) given (in a dose inducing increases in plasma BNP concentrations to pathophysiological levels) to patients with essential hypertension. DESIGN: Six male patients with untreated, uncomplicated, mild-to-moderate essential hypertension underwent placebo-controlled single-blind studies in balanced random order. Human BNP (2 pmol/kg per min) and vehicle were given as constant intravenous infusions in a volume of 15 ml/h for 2 h. Continuous recording of intra-arterial blood pressure and heart rate, together with serial blood samples (for hormone assays) and 30-min urine collections, were obtained throughout the studies from 90 min before commencement of infusions to 90 min after completion of infusions. RESULTS: Achieved intra-infusion plasma BNP immunoreactivity (20-30 pmol/l) was similar to levels previously observed in heart failure. Plasma cyclic GMP was increased. Sodium excretion rose to 2.5-fold placebo values. Plasma aldosterone fell to 50% of placebo values. Blood pressure and heart rate were unchanged. The metabolic clearance rate (5.0 +/- 0.4 l/min) and plasma half-life (19.5 min) indicated that BNP has a large volume of distribution (141 +/- 16 litre). CONCLUSIONS: In essential hypertension pathophysiological plasma concentrations of human BNP have significant acute effects promoting natriuresis and suppressing plasma aldosterone. These effects are similar to those of ANP, but the plasma half-life and volume of distribution of BNP are considerably greater than those of atrial natriuretic peptide. These two hormones may play separate complementary roles in fluid volume and blood pressure homeostasis.

Subdural effusion and its relationship with neurologic sequelae of bacterial meningitis in infancy: a prospective study.

One hundred thirteen infants, aged 1 to 18 months, were screened systematically and serially using transillumination for the presence of subdural effusion during acute bacterial meningitis due to Haemophilus influenzae type b, Streptococcus pneumoniae, or Neisseria meningitidis. Effusion developed in 44 (39%) of the patients during the course of treatment. Young age, rapid onset of illness, low peripheral white blood cell count, and high cerebrospinal fluid levels of protein and bacterial antigen were associated with a higher likelihood of developing effusion. Although patients with effusion were more likely to have neurologic abnormalities both at the time of admission and at completion of therapy, and were more likely to have seizures during the course of treatment, there was no greater incidence of seizures, hearing loss, neurologic deficits, or developmental delay on longterm follow-up (median follow-up interval 5.5 years) in patients with effusion. Specific invasive therapy is not indicated in infants with meningitis and subdural effusion who are otherwise improving.

Exocrine pancreatic function in mediastinal teratomata: an aid to preoperative diagnosis?

The diagnosis of teratoma may be made by demonstration of high amylase content in fluid aspirated from anterior mediastinal lesions. In 2 cases of mediastinal teratoma proteolytic enzyme activity was evident at the time of operation. A diagnosis of mediastinal teratoma was aided in 2 subsequent cases by demonstration of elevated amylase activity in the aspirated fluid before definitive operation.

Domiciliary gallows traction for femoral shaft fractures in young children. Feasibility, safety and advantages.

Over 15 years (1967 to 1982) 140 uncomplicated femoral shaft fractures in children under four years of age were successfully treated using Bryant's traction. Forty of these children were treated after the introduction of the domiciliary management policy in 1976; 13 children were managed at hospital and 27 were managed at home. No significant complications occurred. The advantages to the family, and the safety and economy of domiciliary management lead us to recommend its adoption in favourable cases. Treatment at home relies on an efficient and experienced home nursing service. Possible complications of the injury and treatment with recommendations to prevent them are discussed.

Violent deaths among alcoholics. A descriptive study.

In a follow-up study of 1289 alcoholics 6-9 years after treatment, 52 had died by violent means. Suicide and homicide were the leading causes of violent death, with deaths in fires and pedestrian accidents also occurring with some frequency.

Familial intussusception.

We report a father and two sons who each suffered from recurrent acute ileocolic intussusception in childhood, suggesting that there may in some cases be a genetic predisposition to the condition. This might have an anatomical basis.

Human chorionic gonadotrophin and laparoscopy in the treatment of impalpable testes.

The object of this preliminary retrospective study was to assess the use of human chorionic gonadotrophin (HCG) in the treatment of impalpable testes. Eleven children were found to have an impalpable testis, and in two cases neither testis was palpable. After HCG injections, 10 testes were palpable (67%), two of which were in the scrotum. During laparoscopy, three testes were found to be absent (20%) and two were found to be intraabdominal (13%). During surgery, seven testes were found in the inguinal canal, close to the deep ring (47%). The other was found at the superficial ring. The authors conclude that HCG injections are valuable in the treatment of impalpable testes; the treatment resulted in palpable testes in 83% of their cases in which one testis was present.

Plasma interleukin-6 and tumour necrosis factor levels as predictors of disease severity and outcome in necrotizing enterocolitis.

Plasma tumour necrosis factor (TNF) and interleukin-6 (IL-6) levels of 18 infants with necrotizing enterocolitis (NEC) were measured at the time of diagnosis or on transfer to a paediatric surgical unit. Whereas TNF levels were similar for infants managed medically (stage II, n = 8) and surgically (stage III, n = 7), IL-6 levels were significantly higher in stage III cases (mean, 3,127 pg/mL [95% CI, 1,809 to 4,445 pg/mL]) than in stage II (mean, 127 pg/mL [95% CI, 10 to 329 pg/mL]; P = .001). Neither TNF nor IL-6 level predicted eventual outcome. Plasma IL-6 may be useful as an indication for operation in NEC.

The effect of complete excision on stage III neuroblastoma: a report of the European Neuroblastoma Study Group.

UNLABELLED: Current opinion is divided about the value of excisional surgery in Evans stage III neuroblastoma. AIMS: To evaluate and correlate the survival of patients with stage III neuroblastoma with the effectiveness of the surgical excision, as assessed by (1) the surgeon (resection data) at the time of operation and (2) the pathologist (excision data). METHODS: The ENSG (European Neuroblastoma Study Group) database of 202 patients from 29 centres with proven stage III were analysed. The data include all patients with neuroblastoma diagnosed between 1982 and 1992 and their subsequent follow-up. RESULTS: Patients were grouped according to the extent of resection (100%, 75% to 99%, and < 75%) and the completeness of excision (complete, microscopic residual, macroscopic residual). There were 123 with resection data, a subgroup of 104 with excision data, and 27 with no excision. There was no statistically significant difference (log rank test) in overall survival (p = 0.11) or event-free survival between the resection subgroups, even when the data from patients without resection were included. Complete excision was associated with a highly significant survival advantage, in terms of overall survival (P = .007) and event-free survival (P = .006). This effect is most obvious among patients with the worst prognosis: older children and those with an abdominal tumour. CONCLUSION: Histological confirmation of complete excision confers a significant survival advantage for patients with stage III neuroblastoma and justifies a painstaking attempt at complete resection.

The role of parental disciplinary practices in the development of depression and alcoholism.

Awareness of child abuse has been growing over the past several decades as more cases have come to the attention of medical personnel and school and police authorities. Information-gathering systems have become more effective, and the long-term deleterious effects of abusive treatment have been brought into focus (American Humane Association 1981; Strauss et al. 1980). Cases which come to the attention of the authorities probably represent only the most blatant and severe instances of abuse. However, since Kempke and colleagues (1962) originally described the "battered child syndrome," descriptions of child abuse have been broadened to include maltreatment other than physical abuse resulting in injury (Martinez-Roig et al. 1983; Smith and Hanson 1974; Wolff 1981). Indeed, Strauss and colleagues contend that even mild forms of physical punishment should be considered abusive because they would be illegal if directed toward adults or strangers. The current paper examines retrospectively the relationship between disciplinary practices experienced in childhood, both mild and severe, and the experience of major depressive episodes and alcoholism in adulthood in a general population sample, in whom disorder tends to be untreated and mild.

Bone mineral density is reduced in female but not male subjects with Addison's disease.

AIMS: Bone mineral density (BMD) may be potentially reduced in Addison's disease as a result of excessive glucocorticoid replacement, loss of adrenal androgens or concomitant gonadal or thyroid disease. We have examined clinical and biochemical parameters, and BMD in a group of subjects with Addison's disease. METHODS: Fourteen patients (9 female mean age 56 years, 5 male mean age 56.6 years) with primary adrenocortical failure (median duration 8.5 yrs) on replacement therapy were studied. Four had hypothyroidism on thyroxine doses (0.1 to 0.15 mg/d). Seven of the 9 females were post menopausal. Mean plasma cortisol levels were calculated from at least five samples in each subject drawn between 3 and 5 hours post dose, and the cortisol replacement dose calculated per unit body mass (mg/kg). BMD was measured by dual energy X-ray absorptiometry (DEXA) at femoral neck and lumbar spine (L2-4) and compared with local reference data. RESULTS: For women (n = 9) at L2-4 the mean Z score was -1.21 (95% CI -1.69, -0.73), and at femoral neck -0.57 (95% CI -1.15, 0.00). For men (n = 5) at L2-4, the mean Z score was 1.32 (95% CI -0.86, 3.50) and at femoral neck 0.62 (95% CI -0.18, 1.42). For all patients, there was no significant correlation between mean plasma cortisol and Z scores at L2-4 and femoral neck, r = -0.003 and -0.095 respectively; and between duration of Addison's disease and mean Z scores at L2-4 and femoral neck r = -0.043 and 0.143 respectively. CONCLUSIONS: Women with Addison's disease therefore have a greater than expected reduction in BMD. We postulate that this may be related to loss of adrenal androgens.

Plasma cytokine levels in necrotizing enterocolitis.

Plasma concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6) were measured by ELISA in samples taken from 24 infants with necrotizing enterocolitis (NEC) between 0 and 306 h from diagnosis. TNF was detected (> 10 pg/ml) in 71% samples with a mean of 48 pg/ml (95% CI 42 to 55 pg/ml) and did not vary with either time from diagnosis or severity of disease. IL-6 was raised during the first 48 h with a significant difference between stage II (mean 127 pg/ml, 95% CI 10 to 329 pg/ml) and stage III (mean 3127 pg/ml, 95% CI 1809 to 4445 pg/ml, p = 0.001). Postoperative plasma IL-6 concentration fell to similar levels seen in stage II (mean 150 pg/ml, 95% CI 37 to 283 pg/ml, p = 0.79). We conclude that plasma concentration of IL-6 rather than TNF reflects the clinical severity of necrotizing enterocolitis and that the relative level of these cytokines has important implications for the use of anti-cytokine therapy in NEC.

Necrotizing enterocolitis--multisystem organ failure of the newborn?

Evidence of failure of organ system other than the gastrointestinal tract was reviewed in a series of 46 infants treated for necrotizing enterocolitis (NEC) at a regional combined medical and surgical neonatal unit. Respiratory failure was identified in 42 infants (91%), renal failure in 39 (85%), cardiovascular failure in 15 (33%) and hepatic failure in 7 (15%). The number of systems involved correlated with both severity of disease and outcome. Onset of failure in the above systems was closely related to the diagnosis of NEC and 29 cases predated the clinical onset. We conclude that NEC is part of a syndrome of multisystem failure and that this has important implications for the treatment of NEC.