Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Nitrogen and phosphorus in soil solutions and drainage streams in Upper Teesdale, northern England: implications of organic compounds for biological nutrient limitation.

The availability of nitrogen (N) and phosphorus (P) to organisms is a fundamental control on the ecology of uplands in the British Isles, yet there has been relatively little consideration of the role of organic forms of these nutrients. N and P fractions in soil solutions and drainage streams were determined at monthly intervals over 1 year from Widdybank Fell, Upper Teesdale National Nature Reserve, an upland area of northern England. Nitrogen was present in inorganic and organic forms at relatively high concentrations, whereas P was mainly organic, with inorganic P concentrations near the detection limit (1 microg Pl(-1)). The highest concentrations of organic P occurred in 'pulses' during the spring. These pulses may have originated in the soil following drying and rewetting cycles, and appear to demonstrate hydrochemical connectivity between soils and streams. Seasonal changes in N:P ratio were estimated in various ways to assess when the availability of these elements was likely to influence organisms. Based on inorganic nutrients alone, marked P limitation would be expected throughout the year, but inclusion of organic nutrients suggests that some communities may become N-limited during the spring. This agrees with known seasonal changes in the biology of the cyanobacterium Rivularia, which dominates the main drainage streams. Our data highlight the importance of including organic nutrients when assessing biological nutrient limitation.

Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness.

Central hyposomatotropism and hypothyroidism have been inferred in long-stay intensive care patients. Pronounced hypoandrogenism presumably also contributes to the catabolic state of critical illness. Accordingly, the present study appraises the mechanism(s) of failure of the gonadotropic axis in prolonged critically ill men by assessing the effects of pulsatile GnRH treatment in this unique clinical context. To this end, 15 critically ill men (mean +/- SD age, 67 +/- 12 yr; intensive care unit stay, 25 +/- 9 days) participated, with baseline values compared with those of 50 age- and BMI-matched healthy men. Subjects were randomly allocated to 5 days of placebo or pulsatile iv GnRH administration (0.1 microg/kg every 90 min). LH, GH, and TSH secretion was quantified by deconvolution analysis of serum hormone concentration-time series obtained by sampling every 20 min from 2100-0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of gonadal and adrenal steroids, T(4), T(3), insulin-like growth factor I (IGF), and IGF-binding proteins as well as circulating levels of cytokines and selected metabolic markers were measured. During prolonged critical illness, pulsatile LH secretion and mean LH concentrations (1.8 +/- 2.2 vs. 6.0 +/- 2.2 IU/L) were low in the face of extremely low circulating total testosterone (0.27 +/- 0.18 vs. 12.7 +/- 4.07 nmol/L; P < 0.0001) and relatively low estradiol (E(2); 58.3 +/- 51.9 vs. 85.7 +/- 18.6 pmol/L; P = 0.009) and sex hormone-binding globulin (39.1 +/- 11.7 vs. 48.6 +/- 27.8 nmol/L; P = 0.01). The molar ratio of E(2)/T was elevated 37-fold in ill men (P < 0.0001) and correlated negatively with the mean serum LH concentrations (r = -0.82; P = 0.0002). Pulsatile GH and TSH secretion were suppressed (P < or = 0.0004), as were mean serum IGF-I, IGF-binding protein-3, and acid-labile subunit concentrations; thyroid hormone levels; and dehydroepiandrosterone sulfate. Morning cortisol was within the normal range. Serum interleukin-1beta concentrations were normal, whereas interleukin-6 and tumor necrosis factor-alpha were elevated. Serum tumor necrosis factor-alpha was positively correlated with the molar E(2)/testosterone ratio and with type 1 procollagen; the latter was elevated, whereas osteocalcin was decreased. Ureagenesis and breakdown of bone were increased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compared with placebo by an increment of +8.1 +/- 8.1 IU/L at 24 h (P = 0.001). This increase was only partially maintained after 5 days of treatment. GnRH pulses transiently increased serum testosterone by +174% on day 2 (P = 0.05), whereas all other endocrine parameters remained unaltered. GnRH tended to increase type 1 procollagen (P = 0.06), but did not change serum osteocalcin levels or bone breakdown. Ureagenesis was suppressed (P < 0.0001), and white blood cell count (P = 0.0001), C-reactive protein (P = 0.03), and lactate level (P = 0.01) were increased by GnRH compared with placebo infusions. In conclusion, hypogonadotropic hypogonadism in prolonged critically ill men is only partially overcome with exogenous iv GnRH pulses, pointing to combined hypothalamic-pituitary-gonadal origins of the profound hypoandrogenism evident in this context. In view of concomitant central hyposomatotropism and hypothyroidism, evaluating the effectiveness of pulsatile GnRH intervention together with GH and TSH secretagogues will be important.

Functionalism and holism: community nurses' perceptions of health.

This paper reports the results of a study that was designed to explore and examine the perceptions of two groups of newly qualified community nurses about the factors they considered to be embedded within the concepts of health, health-enhancing behaviours at individual, family and community levels and their 'innermost self'. The research was exploratory in nature, and included two sample groups: group 1 comprised 16 newly qualified health visitors; group 2 comprised 16 newly qualified community mental health nurses. Purposive sampling was used and data were collected using semi-structured interviews. The group of health visitors perceived health in terms of physical fitness and functional states. At a global level they perceived the need to provide education on health matters. They gave generously to 'charities' and perceived the 'inner self' as 'that part that matters'. The group of community mental health nurses perceived health in terms of holism and being states. Their concept of health was related to listening to each individual's perception of what is 'right' and 'health-enhancing' for them. At a global level they considered the protection of the ozone layer and the promotion of a just and equitable society which focused on the reduction of poverty, to be key health-enhancing activities. They perceived their 'innermost self' to be 'that part of me that makes life worth living', and the soul. The findings have implications for developing new and creative approaches for teaching the holistic concept of health and healing. Educational activities could be designed which strive to ensure that nurses themselves have safe and health embracing opportunities for exploring all the elements that are embedded within the topic of health. Their role in facilitating holistic health promoting activities for all clients also needs to be addressed.

Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells.

We report that transfection of insulin-like growth factor-binding protein-3 (IGFBP-3) cDNA in human breast cancer cell lines expressing either mutant p53 (T47D) or wild-type p53 (MCF-7) induces apoptosis. IGFBP-3 also increases the ratio of pro-apoptotic to anti-apoptotic members of the Bcl-2 family. In MCF-7, an increase in Bad and Bax protein expression and a decrease in Bcl-x(L) protein and Bcl-2 protein and mRNA were observed. In T47D, Bax and Bad proteins were up-regulated; Bcl-2 protein is undetectable in these cells. As T47D expresses mutant p53 protein, these modulations of pro-apoptotic proteins and induction of apoptosis are independent of p53. The effect of IGFBP-3 on the response of T47D to ionizing radiation (IR) was examined. These cells do not G(1) arrest in response to IR and are relatively radioresistant. Transfection of IGFBP-3 increased the radiosensitivity of T47D and increased IR-induced apoptosis but did not effect a rapid G(1) arrest. IR also caused a much greater increase in Bax protein in IGFBP-3 transfectants compared with vector controls. Thus, IGFBP-3 increases the expression of pro-apoptotic proteins and apoptosis both basally and in response to IR, suggesting it may be a p53-independent effector of apoptosis in breast cancer cells via its modulation of the Bax:Bcl-2 protein ratio.

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Acute lead poisoning: an unusual cause of hepatitis.

Four patients, aged 17 to 25 years, obtained lead and opium pills which had been stolen from retail pharmacists. They crushed them, suspended them in water an injected them intravenously. They developed general malaise, vomiting and constipation, and blood tests several weeks after injection of the pills showed raised alkaline phosphatase and aspartate transaminases. All four patients had negative tests for the hepatitis B surface antigen. Liver biopsy specimens showed persistent hepatitis in one and resolving hepatitis in the remaining three. Liver lead levels were grossly elevated in every case. The liver lead levels found it the patients described here were up to 35 times greater than levels which have been reported in industrial lead poisoning. It is postulated that the livers of patients with chronic lead poisoning are able to withstand this insult whereas in the cases described the overwhelming dose of lead was sufficient to cause hepatic damage.

Mezerein: antileukemic principle isolated from Daphne mezereum L.

An alcohol-water extract of Daphne mezereum L., a plant widely used in folk medicine for treating cancers, showed antileukemic activity against the P-388 lymphocytic leukemia in mice. Systematic fractionation of the extract has led to isolation and characterization of mezerein as the principal antileukemic component.

Interactions of oxygen at high pressure and radiation in Drosophila.

Oxygen at high pressure (OHP) and X-irradiation can interact in the fruit fly Drosophila melanogaster to potentiate toxic actions characteristic of one agent alone. 1000 kvp X-irradiation in doses of 30, 60, and 75 kr accelerated the acute immobilization of young male Drosophila by oxygen at 7.8 atm, up to rates twice that observed with such oxygen pressure alone. X-irradiation alone in these dosages did not acutely immobilize the Drosophila. X-irradiation during exposure to 7.8 atm pO(2) was more effective and consistent in producing this potentiation than was X-irradiation that preceded exposure to OHP. Acute OHP toxicity in young female Drosophila was not potentiated by 75 kr of X-irradiation. On the other hand, shortening of the life span of young male Drosophila by the above doses of X-irradiation was augmented significantly by a concurrent 40 min exposure to OHP (which alone did not significantly decrease life span). This shows, for the first time, that oxygen can affect not only the acute effects of radiation, but also the residual irreversible effects indicated by the life span shortening.