Antibody responses to bovine parainfluenza virus type 3 (PIV3) vaccination and human PIV3 infection in young infants.

A phase 2 clinical trial was conducted to evaluate the antibody responses to bovine parainfluenza virus type 3 (bPIV3) vaccination in young infants. Three groups were tested as follows: placebo (n=66) and 10(5) (n=64) or 10(6) (n=62) TCID(50) of bPIV3. The vaccine or placebo was administered intranasally at ages 2, 4, 6, and 12-15 months, and serum specimens were collected at ages 2, 6, 7, 12-15, and 13-16 months. Serum hemagglutination inhibition (HI) and IgA antibody titers against bPIV3 and human PIV3 (hPIV3) were measured. The results indicate that antibody responses to bPIV3 vaccination are more likely to be detected by the bPIV3 IgA and HI assays than by the hPIV3 IgA and HI assays, that bPIV3-induced antibody response can be differentiated from hPIV3-induced antibody response most reliably by comparing bPIV3 and hPIV3 HI titers, and that bPIV3 vaccine prevents vaccine recipients from developing antibody profiles of hPIV3 primary infection.

Production and characterization of a Tie2 agonist monoclonal antibody.

The Tie2 receptor and its known ligands, the angiopoietins, play a critical role in endothelial cell differentiation during the process of angiogenesis. Recent experimental observations indicate that the agonistic ligand, angiopoietin-1, can stimulate endothelial cell sprouting and act as a chemo-attractant in vitro and induce increased and enhanced angiogenesis both alone and in conjunction with vascular endothelial growth factor (VEGF) in vivo. Here, we present a monoclonal antibody (MAb), which binds to the extracellular portion of the Tie2 receptor and elicits similar agonist effects. Upon MAb binding to the native Tie2 receptor of cultured human umblical vein endothelial cells (HUVEC), there is a rapid increase in receptor autophosphorylation with a concomitant enhancement in the recruitment and association of the signalling intermediates Grb2 and SH-PTP2. The antibody further demonstrates functional activity in vascular tissues. In vitro, the antibody promotes the survival of cultured HUVEC and elicits a dose dependent outgrowth and branching of microvessels from cultured explants of rat aorta. When administered in vivo, the antibody enhances the vascularization of subcutaneous Matrigel implants in mice. Together these data suggest that the antibody is capable of acting as a surrogate ligand for Tie2 and further confirms the role of Tie2 in the differentiation of endothelial cells during angiogenesis.

Safety of a trivalent live attenuated intranasal influenza vaccine, FluMist, administered in addition to parenteral trivalent inactivated influenza vaccine to seniors with chronic medical conditions.

We conducted a randomized, double-blind trial to evaluate the safety and tolerability of a live attenuated cold adapted trivalent intranasal influenza vaccine, FluMist, compared with intranasal placebo when given in addition to a licensed trivalent injected inactivated influenza vaccine (TIV). The study population consisted of persons 65 years of age and older with chronic cardiovascular or pulmonary conditions or diabetes mellitus. During the 7 days post-vaccination, sore throat was reported on at least one day by 15% (15/100) of FluMist recipients compared with 2% (2/100) of intranasal placebo recipients (p = 0.001). No other reactogenicity symptom was statistically associated with receipt of FluMist. Among this group, FluMist was safe and well tolerated when administered with TIV.

Long-term change in the bone mineral density of adults with adult onset growth hormone (GH) deficiency in response to short or long-term GH replacement therapy.

OBJECTIVE: Only two previous studies have assessed the effects of long-term GH replacement therapy on bone mineral density (BMD) in patients with adult onset GH deficiency. To date no study has looked at the long-term impact on BMD after a short course (6-12 months) of GH replacement. In two groups of patients with adult onset GH deficiency we have studied BMD either (a) after 3 years of continuous GH replacement or (b) 2 years after completion of a short course of GH. DESIGN: An open GH therapeutic study in which patients were recruited from a previous double-blind placebo-controlled study. The BMD status of all patients was unknown to the physician and patient at the time of recruitment. PATIENTS: Group A (n = 7, three females) all received GH replacement continuously for 3 years. Group B (n = 8, five females) included six patients who received GH replacement for 6 months and two who received GH replacement for 12 months with BMD being measured at 6-monthly intervals. METHODS: Single photon absorptiometry (SPA) and later single X-ray absorptiometry (SXA) were used to measure forearm cortical BMD. Dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine, trochanteric, femoral neck and Ward's area BMD. RESULTS: In group A lumbar spine and trochanter BMD had increased significantly from baseline by 3.7% (DXA: median change = 0.045 g/cm2; P = 0.028) and 4.0% (DXA: median change = 0.031 g/cm2; P = 0.046), respectively. There were non-significant decreases in femoral neck (1.9%) (DXA: median change = -0.02 g/cm2; P = 0.39), Ward's area (6.5%) (DXA: median change = -0.06 g/cm2; P = 0.09) and forearm (2.6%) (SPA/SXA: median change = -0.013 g/cm2; P = 0.18). In group B, compared with baseline, only trochanter BMD changed significantly, increasing by 5.9% (DXA: median change = 0.0485 g/cm2; P = 0.049). Lumbar spine (DXA: median change = -0.001 g/cm2) Ward's area (DXA: median change = 0.0135 g/cm2), femoral neck (DXA: median change = -0.005 g/cm2) and forearm cortical (SPA/SXA; median change = -0.01 g/cm2) BMD did not change significantly (P = 0.67, P = 0.57, P = 0.86 and P = 0.31, respectively). Median percentage changes compared with baseline were -0.1%, 1.8%, -0.5% and -2.1%, respectively. From the time of completion of GH therapy however, BMD increased significantly at lumbar spine, (median change = 0.023 g/cm2), Ward's area (median change = 0.03 g/cm2) and trochanter (median change = 0.056 g/cm2) (P = 0.036, P = 0.049 and P = 0.012, respectively) but not at the femoral neck (median change = 0.017 g/cm2; P = 0.31) or forearm (median change = 0 g/cm2; P = 0.75). CONCLUSION: Long-term GH replacement therapy for three years appears to have beneficial effects on bone in patients with adult onset GH deficiency particularly at the lumbar spine and trochanter; the effects on femoral neck and forearm cortical BMD, however, are less impressive. A short course (6-12 months) of GH replacement therapy results in an increase in trochanter BMD several years later, and after an initial decline in BMD whilst on GH replacement, lumbar spine and Ward's area BMD return towards their baseline values. These results emphasize that not all types of bone and skeletal sites respond to GH therapy identically. Furthermore a short course of GH replacement over 6-12 months may result in significant changes in BMD several years later.

Review of recommendations of the Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention, on varicella vaccine.

After US licensure of the Merck varicella vaccine for immunocompetent persons on 17 March 1995, the Advisory Committee on Immunization Practices finalized draft recommendations for varicella prevention in the public health sector. These recommendations call for routine vaccination of children at age 12-18 months with a single dose of the vaccine. Varicella vaccine preferably should be given to children at the same time they receive measles-mumps-rubella vaccine and may be given at the same time as other vaccines recommended at this age. Children ages 18 months to 12 years who have not been vaccinated as part of the routine schedule and who lack a reliable history of varicella should be vaccinated. Vaccination is desirable for persons > or = 13 years old without a reliable history of varicella. Special efforts should be made to assess the immunity of and to vaccinate susceptible persons who have close contact with persons at high risk for complications, including family contacts of immunocompromised individuals and health care workers.

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.

Neurosurgery in a patient with Creutzfeldt-Jakob disease after pituitary derived growth hormone therapy in childhood.

The case of a young man who had previously received pituitary derived growth hormone for treatment of radiation induced growth hormone deficiency is reported. He underwent neurosurgery for presumed recurrence of a posterior fossa tumour but was subsequently shown to have Creutzfeldt-Jakob disease, confirmed on necropsy. The risk of transmission of Creutzfeldt-Jakob disease by neurosurgical instruments is discussed. Since the occurrence of this case the Department of Health have issued guidelines concerning neurosurgery and ophthalmic surgery in patients who have previously received treatment with pituitary derived growth hormone and may therefore be at risk of developing Creutzfeldt-Jakob disease. Surgical instruments used on such patients should under no circumstances be reused, and should be destroyed after use.

Adult growth hormone deficiency and bone mass.

Bone mineral density (BMD) is reduced in adults with growth hormone (GH) deficiency and the decrease in BMD appears more marked if the GH deficiency is childhood onset rather than adult onset. Recent epidemiological studies suggest an increased fracture rate in GH-deficient adults. The skeletal response to GH therapy depends on the variety of GH deficiency, the type of bone studied and the duration of therapy. In the childhood-onset, GH-deficient adult there is either no change or a reduction in cortical and integral bone mass over the first 6 months, whereas at 6 months there is an increase in vertebral trabecular BMD. Subsequently there is a steady rise in BMD at all sites over the next 12-18 months. In the adult-onset, GH-deficient adult, the long-term results are more contentious. It is too early to determine whether GH therapy modifies fracture risk.

Child-care practices: effects of social change on the epidemiology of infectious diseases and antibiotic resistance.

The increasing number of mothers of young children in the work force and the resultant escalated use of child-care facilities has had a marked effect on the epidemiology of infectious diseases in young children. Children attending child care are at high risk for respiratory and gastrointestinal tract illnesses. The high prevalence of infectious diseases in the child-care setting is accompanied by high usage of antibiotics, which in turn has resulted in spread of antibiotic-resistant organisms. The infectious disease standards of the American Public Health Association/American Academy of Pediatrics guidelines were developed to prevent and limit transmission of infectious diseases in the child-care setting. Adherence to these standards is essential but will not completely eliminate the increased risk of infectious diseases in child-care settings. New challenges need to be addressed to assure that optimal health promotion and disease prevention is practiced in child-care settings. We approach the 21st century with a vast amount of medical knowledge, molecular technology, highly effective vaccines, and powerful antimicrobial agents. However, at the same time we face many unsolved serious problems, such as preventing or controlling the emergence and spread of antibiotic-resistant organisms that adversely affect our ability to treat infectious diseases. Further research is needed concerning the relations between child care, the use of antibiotics, and transmission of antibiotic-resistant organisms in order to design and implement the most effective strategies for preventing or controlling antibiotic resistance. The potential risk for transmission of HIV in the child-care setting also needs to be recognized, and procedures to prevent transmission of blood-borne pathogens need to be followed. Monitoring compliance with national standards for child-care facilities, dissemination of information concerning infectious diseases and use of antibiotics, and development and use of new vaccines are strategies which should be used to help protect the health of children in child-care environments.

Role of growth hormone and sex steroids in achieving and maintaining normal bone mass.

It is now established that adults with growth hormone (GH) deficiency, of childhood or adult onset, have reduced bone mass. GH deficiency is believed to interfere with acquisition of bone mass, although an alternative mechanism is required to explain the reduction in bone mass present in adults who acquire GH deficiency after peak bone mass has been achieved. GH replacement increases bone turnover and may increase bone mass in the longer term, although short-term studies show a decrease in bone mass which can be explained by an increase in bone resorption before new bone formation occurs. Abnormalities of GH secretion have also been implicated in the development of osteoporosis, but the effect of GH treatment on bone mass in such patients is disappointing. Sex steroids have an important role to play in the acquisition of bone mass, and reduced sex steroid levels during adolescence have a deleterious effect on bone mass. The importance of sex steroids in the maintenance of bone mass is illustrated by the development of osteopenia in men and women with hypogonadism, and by the preservation of bone mass by restoration of normal endogenous sex steroid levels, or by treatment with exogenous sex steroid. Sex steroids also influence circulating levels of GH and insulin-like growth factor-1, and the inter-action between these hormones is likely to be important in the acquisition and maintenance of normal bone mass.

Which adults develop side-effects of growth hormone replacement?

OBJECTIVE: Although the nature of the side-effects of GH replacement in adults are well described, the factors influencing their development are ill understood. The aim of this study was to determine whether there were any characteristics of adults with GH deficiency that predicted whether or not they developed side-effects of GH replacement. DESIGN: A 12-month study (double blind placebo controlled for the first 6 months and open for the second 6 months) of GH replacement (0.125 IU/kg/week for the first month and 0.25 IU/kg/week thereafter) in adults. PATIENTS: Sixty-three adults (27 men, 36 women, aged 34.9 +/- 1.4 (mean +/- SE, range 20.1-59.5 years)) with GH deficiency (peak serum GH response to provocative testing of less than 10 mU/l) who took part in a 12-month study of GH replacement. Twenty-five patients (40%) did not develop side-effects, 19 patients (30%) developed side-effects which did not necessitate a reduction in dose of GH, and 19 patients (30%) required a reduction in dose of GH because of side-effects. MEASUREMENTS: The three groups of patients were compared according to age, height, weight and body mass index (BMI) at entry into the study and to pretreatment peak serum GH response to provocative testing. They were also compared according to serum concentration of insulin-like growth factor (IGF)-I and IGF binding protein-3, and age-adjusted serum IGF-I standard deviation score (SDS), at entry into the study and by change in these measurements after 6 months of GH replacement. The patient's sex, whether GH deficiency was of childhood or adult onset, estimated duration of GH deficiency, presence or absence of additional pituitary hormone deficiencies, underlying pathological disorder and previous therapeutic interventions were also compared in the three groups of patients. RESULTS: Those patients who required a reduction in dose of GH because of side-effects were more likely to have a peak serum GH response of greater than 1 mU/l (P = 0.005) and to have adult onset GH deficiency (P = 0.04) than those who did not develop side-effects or who did not require a reduction in dose of GH because of side-effects. In addition, those who needed a reduction in GH dose were older (P = 0.002), heavier (P = 0.04) and had a greater BMI (P = 0.003) than those who did not develop side-effects. Those who developed side-effects but did not require a reduction in dose of GH had a greater increment in IGF-I SDS after 6 months of GH replacement than those who did not develop side-effects (P = 0.03). CONCLUSION: Side-effects of GH replacement are more likely to occur in older patients, in those with a peak serum GH response to provocative testing of greater then 1 mU/l, in those with a greater increment in serum IGF-I SDS whilst receiving GH replacement, in those with greater weight and BMI, and those with adult onset GH deficiency.

Factors influencing the desire for long-term growth hormone replacement in adults.

OBJECTIVE: Growth hormone replacement in adults may be considered beneficial by clinicians, but patients may not perceive any benefits. The purpose of this study was to determine whether there were any factors which influenced whether an adult wished to continue on long-term GH replacement after taking part in a study of GH replacement. DESIGN: A 12-month study (double-blind placebo controlled for the first 6 months and open for the second 6 months) of GH replacement (0.125 IU/kg/week for the first month and 0.25 IU/kg/week thereafter) in adults. PATIENTS: Sixty-three adults (27 men, 36 women, aged 34.9 +/- 1.4 (mean +/- SE, range 20.1-59.5) years) with GH deficiency (peak serum GH response to provocative testing less than 10 mU/l) who entered a 12-month study of GH replacement. Thirty patients (48%) wished to continue on GH replacement and 33 patients (52%) did not wish to continue on GH replacement after the study. MEASUREMENTS: Biochemical, anthropometric and demographic characteristics, and well-being, were compared in those patients who wished to continue on long-term GH replacement and in those who did not. In the two groups of patients the age, height, weight, body mass index, serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and IGF-I age matched standard deviation score (SDS) were compared at entry into the study, and changes in IGF-I, IGFBP-3 and IGF-I SDS were compared after 6 months of GH replacement. The patients were compared according to pretreatment peak serum GH response to provocative testing, sex, estimated duration of GH deficiency, whether GH deficiency was of childhood or adult onset, presence or absence of additional pituitary hormone deficiencies, underlying pathological disorder, previous therapeutic interventions, employment status, marital status and living arrangement, and according to development of side-effects of GH replacement and the requirement for reduction in dose of GH because of side-effects during the study. Scores on two questionnaire measures of well-being or distress, the Nottingham Health Profile (NHP) and the Psychological General Well-Being Schedule (PGWBS), were compared at entry into the study in the two groups, as were change in scores on these questionnaires after 6 months of GH replacement. RESULTS: Those who continued on GH replacement tended to have a greater severity of GH deficiency (median peak serum GH concentration 0.7 vs 2.3 mU/l, P = 0.06), tended to have greater distress in terms of energy (NHP, P = 0.06) and vitality (PGWBS, P = 0.06) at entry into the study and showed an improvement in energy during the study compared with no change in those who did not wish to continue on GH replacement (NHP, P = 0.06). CONCLUSION: Those adults who wished to continue on GH replacement tended to have a greater severity of GH deficiency, to experience more distress in terms of energy and vitality at entry into the study and to experience an improvement in energy after 6 months treatment with GH.

Mumps surveillance--United States, 1988-1993.

PROBLEM/CONDITION: CDC monitors the incidence of mumps in the United States through the passive reporting of cases to its National Notifiable Disease Surveillance System (NNDSS). REPORTING PERIOD COVERED: 1988-1993. DESCRIPTION OF SYSTEM: Weekly reports to the NNDSS from 48 states and the District of Columbia were used to calculate incidence rates for mumps. State immunization requirements were obtained from the U.S. Department of Health and Human Services. RESULTS: After the licensure of mumps vaccine in the United States in December 1967 and the subsequent introduction of state immunization laws in an increasing number of states, the reported incidence of mumps decreased substantially. The 1,692 cases of mumps reported for 1993 represent the lowest number of cases ever reported to NNDSS and a 99% decrease from the 152,209 cases reported for 1968. During 1988-1993, most cases occurred in children 5-14 years of age (52%) and in persons > or = 15 years of age (36%). Although the incidence decreased in all age groups, the largest decreases (> 50% reduction in incidence rate per 100,000 population) occurred in persons > or = 10 years of age. Overall, the incidence of mumps was lowest in states that had comprehensive school immunization laws requiring mumps vaccination and highest in states that did not have such requirements. INTERPRETATION: Because of the extensive use of mumps vaccine and the increased number of states that had enacted mumps immunization laws, the number of reported mumps cases decreased further since the marked decline that began during the early 1970s. The earlier shift in incidence from children of school ages to older persons that was noted during 1985-1988 continued until 1992, when the proportion of cases occurring in children of school ages increased and exceeded the proportions occurring in other age groups. ACTIONS TAKEN: All health-care providers are encouraged to a) report mumps cases to their local and state health departments for transmission to NNDSS and b) enact school immunization laws requiring mumps vaccination.

Characteristics of adults who wish to enter a trial of growth hormone replacement.

OBJECTIVE: It is possible that the degree of perceived well-being may influence the decision of an adult with GH deficiency to receive GH replacement. We have therefore sought factors which influenced whether or not such a patient wished to enter a study of GH replacement. DESIGN: Biochemical, anthropometric and demographic characteristics, and well-being, of patients who chose to enter a 12-month study of GH replacement at Christie Hospital NHS Trust were compared with those of patients who declined to enter the study. PATIENTS: Sixty-five adults with GH deficiency who entered a study of GH replacement and 33 adults with GH deficiency who were approached but who declined to enter the study. MEASUREMENTS: The two groups of patients were compared according to sex, age, height, weight, body mass index, peak serum GH response to provocative testing, estimated duration of GH deficiency, whether GH deficiency was of childhood or adult onset, presence or absence of additional pituitary hormone deficiencies, aetiology of GH deficiency, previous therapeutic interventions, employment status, marital status and living arrangement (65 entered vs 33 declined to enter). Well-being or distress was measured using the Nottingham Health Profile (NHP) (65 entered vs 20 declined to enter) and the Psychological General Well-being Schedule (PGWBS) (33 entered vs 19 declined to enter). RESULTS: Those who entered the study had significantly higher scores on the energy (P = 0.03) and emotional reaction (P = 0.02) subsections and on the total score (P = 0.04) of the NHP, indicating greater distress, and had a significantly lower score (P = 0.009) on the vitality subsection of the PGWBS, again indicating greater distress. Those who entered the study had a significantly lower prevalence of non-functioning pituitary adenoma (P = 0.02) but there was no other difference in biochemical, anthropometric or demographic characteristics between the two groups. CONCLUSION: Adults who enter a study of GH replacement exhibit greater distress on questionnaire assessment than those who decline to enter such a study. This bias must be considered when interpreting studies of the effect of GH replacement on well-being in adults.

Effect of growth hormone replacement on bone mass in adults with adult onset growth hormone deficiency.

OBJECTIVE: Previous studies of the effect of GH replacement on bone mass in adults with GH deficiency have produced conflicting results. We have studied the effect of 6 and 12 months of GH replacement on bone mass in adults with adult onset GH deficiency. DESIGN: Double blind placebo controlled study of GH replacement (0.125 IU/kg/week for the first month and 0.25 IU/kg/week thereafter) for 6 months and an open study for a further 6 or 12 months. PATIENTS: Twenty-two adults (10 men, 12 women), aged 41.5 +/- 2.1 years (mean +/- SE, range 23.6-59.5), with adult onset GH deficiency. MEASUREMENTS: Single-energy quantitative computed tomography was used to measure vertebral trabecular bone mineral density (BMD), single-photon absorptiometry (SPA) was used to measure forearm cortical and integral bone mineral content and BMD and dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine, femoral neck, trochanteric and Ward's triangle integral BMD. RESULTS: After 6 months of GH replacement (n = 21) there was a significant decrease in forearm cortical BMD (SPA: median change -0.009 g/cm2, P = 0.01), forearm integral BMD (SPA: median change -0.016 g/cm2, P = 0.03), lumbar spine BMD (DXA: median change -0.22 g/cm2; P = 0.003) and femoral neck BMD (DXA: median change -0.029 g/cm2, P = 0.006). After 12 months of GH replacement (n = 13) there was a significant decrease in lumbar spine BMD (DXA: median change -0.035 g/cm2, P = 0.002) from baseline. There was no significant increase in bone mass at any site after 6 or 12 months of GH replacement. Change in bone mass was not influenced by sex of the patient or by presence or absence of additional pituitary hormone deficiencies. CONCLUSION: The response of bone mass to 6 and 12 months of GH replacement in adults with adult onset GH deficiency is disappointing. Longer-term studies are required to determine whether prolonged GH replacement has a beneficial effect on bone mass.