Variation of the baseline characteristics and treatment parameters over time: an analysis of 15 years of growth hormone replacement in adults in the German KIMS database.

The purpose of this study is to examine potential implications of changes in the approach to adult growth hormone (GH) replacement (GHR) over the last 15 years. Therefore, we analysed the German KIMS database as one of the largest single country pharmacoepidemiological databases on adult GH deficiency (GHD). Based on the date of their first GH application patients were assigned to three intervals (1995-1999, 2000-2004, 2005-2009). A multivariate analysis of variance with interval and sex as independent variables was conducted. Differences were analysed with respect to IGF-I standard deviation score (SDS), quality of life, latency between GHD diagnosis and first GH dose, body mass index, waist-hip ratio, lipid profile, and GH dose. All analyses were conducted at baseline, 1 year, and 3 years of GHR. We detected significant associations between time interval and patient characteristics at baseline and with treatment effects. Recently, patients with less severe GHD (mean IGF-I SDS: -2.1, -1.6, -1.0 in the 1st, 2nd and 3rd interval; p = 0.000) are treated with lower GH starting doses (mean 0.30, 0.19, 0.21 mg/day in the 1st, 2nd and 3rd interval; p = 0.000). In the first time interval, IGF-I SDS was not normalized in females after 3 years of GHR. The results of our analysis demonstrate prominent changes in patient characteristics and handling of GHR. They highlight that approach to therapy and patient inclusion criteria change over time and may represent an important confounder for any analysis in epidemiological surveillance surveys.

Deriving reference values and utilities for the QoL-AGHDA in adult GHD.

BACKGROUND: Quality of life (QoL) measures are important in growth hormone (GH) deficiency (GHD) in adults. Ideally, for use in health economics, QoL should be expressed in utilities. The aim of this study was to obtain reference values and utilities for QoL of GHD in adults in Belgium and the Netherlands. METHODS: The study was conducted in three stages: (1) The Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) and the EQ-5D were administered in a representative sample of 6,875 individuals from the Belgian and 1,400 individuals from the general Dutch population. The EQ-5D(index) can be used to estimate utilities. Using a regression, utilities were predicted from the QoL-AGHDA. (2) QoL-AGHDA scores were obtained from 299 Belgian and 234 Dutch adult patients with GHD and no GH replacement. These scores were converted to utilities and compared the burden of disease with other patient groups. (3) To test the criterion validity, the 'standard' EQ-5D(index) was used in a subsample of 64 Dutch GHD patients and compared with the predicted utilities. RESULTS: We obtained data from 1,026 Belgian (response rate = 15%) and 1,038 Dutch respondents (response rate = 74%). The Belgian mean QoL-AGHDA value was 6.95 (90% range = 14.00), and the Dutch mean was 5.48 (range = 13.00). The R (2) of the regression model to predict the EQ-5D(index) was 0.360 (Belgium) and 0.482 (the Netherlands). We demonstrated a considerable burden of disease in GHD patients, comparable to patients with hypertension or with type II diabetes. The criterion validity was 0.407 (intraclass correlation, ICC). CONCLUSIONS: Interventions in GHD can now be evaluated more validly in Belgium and the Netherlands.

Effect of growth hormone replacement therapy on plasma brain natriuretic peptide concentration, cardiac morphology and function in adults with growth hormone deficiency.

OBJECTIVE: The impact of growth hormone (GH) replacement on plasma brain natriuretic peptide (BNP) in association with cardiac morphology and function in adults with growth hormone deficiency (GHD) was evaluated. SUBJECTS AND METHODS: Fifty nine adult patients with GHD (29 men, age 19-59 years) received a starting dose of 0.1-0.2 mg/day recombinant GH, which was subsequently adjusted to the 50th percentile of normal serum insulin-like growth factor (IGF-1) over a 6 month period. Plasma BNP and IGF-I levels before, 3 and 6 months after treatment were determined, as were the echocardiographic data, such as ejection fraction (EF), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), interventricular septal thickness (IVST), posterior wall thickness (PWT), left ventricular mass (LVM), E/A wave and deceleration time (DT). RESULTS: Mean plasma BNP levels (53.1+/-8 pg/ml) and echocardiographic parameters were within the normal range at baseline, although men had higher LVM, IVST, PWT, LVEDV and LVEDD, respectively. A significant decrease in plasma BNP was observed after 6 months (27+/-5.6 pg/ml, P<0.05). No significant changes in echocardiographic parameters were observed except for a mild tendency to increase in LVM, and a borderline decrease in DT (181+/-8.1 vs. 155+/-9 ms, P<0.01). CONCLUSIONS: Six months GH replacement therapy induced a significant decrease in plasma BNP levels despite the majority of patients having plasma BNP within the normal range at baseline. A borderline decrease in diastolic deceleration time was observed, the clinical significance of which is unclear.

From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum - a KIMS analysis.

OBJECTIVE: To describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD. DESIGN: Observational prospective study. METHODS: Baseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naïve prior to entry into the Pfizer International Metabolic Database (KIMS; 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (133 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD). RESULTS: IGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35% of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P<0.001) and pituitary disease duration (P<0.01). CONCLUSION: Both AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. Hypopituitarism in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

Cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement.

OBJECTIVE: The last decade has seen a proliferation in options for testosterone replacement. However, little is known as to the benefits of different treatment modalities. Our objective was to determine the testosterone prescription pattern and to examine the impact on various outcome measures. SUBJECTS AND METHODS: A total of 816 adult-onset hypopituitary males on stable pituitary replacement for at least 1 year were identified from the KIMS database. Patients were classified as either eugonadal (n = 106), or hypogonadal (n = 710) on intramuscular (IM, n = 558), oral (n = 74), transdermal (n = 61), and depot (n = 17) testosterone. RESULTS: After 1 year of stable pituitary replacement therapy, body composition, cardiovascular parameters, GH replacement and quality of life were not significantly different in androgen-replaced hypogonadal patients compared to eugonadal patients. There were no differences in outcome variables within the hypogonadal group according to the testosterone replacement regimen used and no difference in response to GH therapy. CONCLUSIONS: The majority of hypopituitary patients in the last decade have received IM testosterone. Body composition, cardiovascular parameters, GH replacement and quality of life were not different between eugonadal and hypogonadal patients and were not differentially affected by the mode of testosterone replacement. These findings are reassuring that there is no major difference in response to different testosterone replacement regimens.

A personal digital assistant application (MobilDent) for dental fieldwork data collection, information management and database handling.

OBJECTIVE: To develop a personal digital assistant (PDA) application for oral health assessment fieldwork, including back-office and database systems (MobilDent). DESIGN: System design, construction and implementation of PDA, back-office and database systems. METHODS: System requirements for MobilDent were collected, analysed and translated into system functions. User interfaces were implemented and system architecture was outlined. MobilDent was based on a platform with. NET (Microsoft) components, using an SQL Server 2005 (Microsoft) for data storage with Windows Mobile (Microsoft) operating system. The PDA devices were Dell Axim. RESULTS: System functions and user interfaces were specified for MobilDent. User interfaces for PDA, back-office and database systems were based on. NET programming. The PDA user interface was based on Windows suitable to a PDA display, whereas the back-office interface was designed for a normal-sized computer screen. A synchronisation module (MS Active Sync, Microsoft) was used to enable download of field data from PDA to the database. CONCLUSIONS: MobilDent is a feasible application for oral health assessment fieldwork, and the oral health assessment database may prove a valuable source for care planning, educational and research purposes. Further development of the MobilDent system will include wireless connectivity with download-on-demand technology.

Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database.

OBJECTIVE: To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma. DESIGN: Data from 447 patients, who had received radiotherapy (427 in addition to surgery), and 630 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement. RESULTS: Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-I and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment. CONCLUSIONS: This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

Estrogen replacement in women of fertile years with hypopituitarism.

BACKGROUND: What form of estrogen to prescribe a young hypopituitary woman with gonadal failure remains an open question despite evidence that oral estrogen therapy induces GH resistance and an increase in fat mass. METHODS: Using an international surveillance study of hypopituitary patients, we examined two questions: 1) What estrogen is prescribed to young women of fertile years with hypopituitarism? 2) Is there a difference in body composition or IGF-I levels dependent on the type of estrogen prescribed? RESULTS: Six hundred twenty-eight GH-deficient women, aged 18-50 yr, were identified. Three hundred thirteen had normal gonadal function, and 315 were receiving estrogen therapy; of these 14% were using transdermal estradiol, and 86% were taking an oral estrogen preparation (38% oral estradiol, 18% conjugated estrogens, and 30% ethinyl estradiol in the oral contraceptive). There was no difference in weight, waist/hip ratio, or body composition between the women taking different estrogen therapies. However, if the oral estrogen groups were combined, they showed less change in waist and hip measurement and had a greater waist/hip ratio after 1 yr of GH treatment compared with patients with normal gonadal function (0.85 vs. 0.83; P = 0.022). Patients taking ethinyl estradiol had lower age-adjusted IGF-I sd scores and required almost twice the GH dose to achieve an IGF-I sd score that remained lower than patients with normal gonadal function and patients receiving transdermal estradiol. CONCLUSIONS: 1) The majority of women of fertile years with hypo-pituitarism take oral estrogen replacement therapy. 2) Waist/hip ratio was greater in women taking oral estrogens, and there is indirect evidence that oral estrogens reduce the action of GH on fat mass. 3) Patients using the oral contraceptive had lower IGF-I levels and required twice the GH dose compared with patients receiving transdermal estradiol.

Intestinal pHi studied with continuous saline tonometry during ischaemia and reperfusion in the pig.

OBJECTIVE: To evaluate continuous saline tonometry for detection of progressive intestinal ischaemia and reperfusion in a porcine model. DESIGN: In eight anaesthetised pigs, small bowel mucosal pCO2 was recorded by means of two identical equipments for continuous saline tonometry and a standard tonometry balloon during ischaemia and reperfusion. RESULTS: Both systems of saline tonometry functioned stably during the four hour protocol ischaemia, although not significant until after 45 min for one of the tonometers. CONCLUSION: The equipment for continuous saline tonometry has a good reactivity, an accuracy comparable with standard tonometry.

Validation of a novel method for continuous saline tonometry in a porcine model.

Only intermittent and semi-continuous tonometric measurement of gastric and intestinal pHi is possible with the equipment available today. Earlier we developed a system for continuous saline tonometry and tested it in vitro. To assess the in vivo reliability of this method for continuous gastrointestinal saline tonometry, a standard tonometer for measurement of intestinal pCO2 and corresponding pHi was modified to allow continuous perfusion of physiological saline in a closed system and tested in a porcine model. In 11 anaesthetized and haemodynamically stable pigs, two continuous tonometry balloons were inserted into the distal small bowel, and a standard tonometry balloon was used as reference. To test long-term function of the continuous tonometers the research protocol lasted for eight hours. The two continuous saline tonometers performed well, and after an equilibration time of three hours the mean pHi values were stable between 7.35 and 7.43 and between 7.32 and 7.39 respectively. The standard tonometer measured stable pHi values. These preliminary studies indicate that continuous saline tonometry performs well over eight hours with a small bias and a good precision.

A new method for continuous tonometric pCO2 measurement--in vitro studies.

The available methods for tonometric pCO2 measurement only provide the possibility of performing intermittent registrations. A new method allowing continuous tonometric pCO2 measurement has been developed and tested in an in vitro model. A standard tonometer for intestinal pCO2 measurement was modified to allow continuous perfusion of the balloon with physiological saline solution in a closed system. The pCO2 in the system was determined in a specially constructed measurement chamber with a TCM20 percutaneous pCO2 monitor. In this in vitro model the tonometer balloon was placed in a saline bath with a constant pCO2 concentration and the measurements from the closed circulating system were compared with those obtained from a standard tonometer placed in the same bath. In 8 and 24 h experiments the circulating system measured the pCO2 value as accurately and reliably as traditional tonometry. This study indicates that the new method makes continuous monitoring of pCO2 possible.

GENEUS, a computer system for DNA and protein sequence analysis containing an information retrieval system for the EMBL data library.

We describe a comprehensive computer system, GENEUS, for extensive DNA, RNA and protein sequence analysis. The analysis system is developed for the DEC VAX/VMS computer and uses the EMBL Nucleic Acid Sequence Data Library. Help information is available on-line on terminal screen. To speed up system handling, a qualifier oriented user communication is employed. All results are stored on files making them accessible to the computer editor. An information retrieval system for the EMBL Nucleotide Sequence Data Library is also described. A defined data-base interface allows connection to other analysis programs.+

Search algorithm for pattern match analysis of nucleic acid sequences.

A new type of search algorithm to find biological information inherited in nucleic acid sequences was developed. The algorithm is of pattern match type and is based on the fact that genetic information often is a function of a predictable statistical occurrence of the four bases within parts of the sequence. The search algorithm compares the known statistical pattern of bases in e.g. a promoter, with an unknown sequence and calculates the statistical significance of the match at all positions in the unknown sequence. The program was tested on 54 published prokaryotic promoters. 44 or 49 could be found with 1 or 4 false answers, respectively. The program was also used on plasmid pBR322. All promoters functioning in an in vitro transcription system were found (tet, anti-tet, p4, bla and ori) except the so called p5 promoter. A search for donor and acceptor sites was performed in a human HLA genomic sequence that contains six introns. Five of the possible six donor and acceptor sites were found.

A filter fermenter-apparatus and control equipment.

Laboratory equipment for cultivation of microorganisms with the removal of cell-free medium is described. Separation is accomplished by filtration through a membrane which is built into a top-driven fermenter. A system is presented which controls the flow rate by automatic cleaning of the filter. Flow schemes for batch and continuous fermentations are shown. The filter fermenter is useful when studying continuous culture with feedback of biomass or processes where growth or product formation rates are influenced by inhibitory metabolites. Results are presented from experiments with Saccharomyces cerevisiae, Pedicoccus pentosaceus, and Zymomonas mobilis.