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1.
J Paediatr Child Health ; 42(7-8): 445-51, 2006.
Article in English | MEDLINE | ID: mdl-16898883

ABSTRACT

AIM: To analyse patterns and trends in mortality from unknown causes (sudden infant death syndrome and unascertainable deaths) for all Aboriginal and non-Aboriginal infants born in Western Australia, 1980-2001. METHODS: Using total population linked data, we reviewed all post-mortem reports, including death scene investigations and final causes of death as ascertained by the coroner. Neonatal, post-neonatal and infant mortality rates attributed to unknown causes were calculated and the latter were analysed according to maternal age, geographical location, gestational age, sex and birthweight. Relative risks (95% confidence interval) for Aboriginal infants (compared with non-Aboriginal) were calculated. RESULTS: The proportion of deaths considered to be of unascertainable cause has significantly increased in recent years. In contrast to the non-Aboriginal population, there has been no significant decrease in deaths in the Aboriginal population and the overall relative risk for Aboriginal infants for the most recent years studied was 7.9 (95% confidence interval 5.1-12.2). The relative risk was significantly increased for most categories analysed. CONCLUSION: Reviewing post-mortem reports enabled identification of changes in the classification of deaths due to unknown causes. This provided a more accurate picture of the patterns and long-term trends of such deaths so that programmes can be developed to specifically target those groups most at risk. Adequately funded and evaluated education campaigns aimed at reducing the risk of sudden infant death syndrome among Aboriginal infants are required, as well as sustaining the current efforts that have been so successful for non-Aboriginal infants.


Subject(s)
Cause of Death/trends , Native Hawaiian or Other Pacific Islander , Sudden Infant Death/epidemiology , Databases, Factual , Humans , Infant , Longitudinal Studies , Western Australia/epidemiology
2.
Lancet ; 367(9524): 1758-66, 2006 May 27.
Article in English | MEDLINE | ID: mdl-16731271

ABSTRACT

BACKGROUND: Since there are known disparities between Aboriginal and non-Aboriginal populations in Australia, trends in infant mortality rates can be used to assess the effectiveness of programmes designed to improve the health of Aboriginal populations. We have examined mortality rates in these populations in Western Australia. METHODS: We used the most comprehensive and valid total population data available for an Australian state to determine all-cause and cause-specific mortality for Aboriginal and non-Aboriginal infants born in Western Australia from 1980 to 2001. FINDINGS: Overall, infant mortality rates fell in both populations, but less so in Aboriginal (from 25.0 in 1980-84 to 16.1 in 1998-2001) than in non-Aboriginal infants (from 8.4 in 1980-84 to 3.7 in 1998-2001) such that disparities between the two groups increased for all major causes of infant death. The relative risk for Aboriginal compared with non-Aboriginal infants rose from 3.0 (95% CI 2.5-3.6) to 4.4 (3.5-5.5), and there were significantly more potentially preventable deaths, such as those caused by infections (5.9 per 1000 livebirths vs 0.7 per 1000 livebirths, RR 8.5, 95% CI 7.1-10.2). Additionally, for Aboriginal infants, postneonatal mortality rates were higher than neonatal mortality rates (11.2 per 1000 livebirths vs 9.7 per 1000 livebirths), trend analyses showed that previous reductions in deaths due to preterm birth (4.3 per 1000 livebirths--1.4 per 1000 livebirths from 1980-97) were not sustained in the most recent years studied (3.5 per 1000 livebirths), and rates of sudden infant death syndrome did not fall significantly (4.9 per 1000 livebirths vs 4.7 per 1000 livebirths). INTERPRETATION: These increasing disparities between Aboriginal and non-Aboriginal infants, especially in remote areas, demand immediate action in partnership with Aboriginal communities, focusing on both access to primary health care and better living conditions. Implementation and assessment of policies to reduce the continuing social and economic disadvantage faced by Aboriginal families are vital.


Subject(s)
Infant Mortality/trends , Native Hawaiian or Other Pacific Islander , Population Surveillance/methods , Adolescent , Adult , Cohort Studies , Databases, Factual , Female , Humans , Infant, Newborn , Male , Maternal Age , Parity , Pregnancy , Western Australia/epidemiology
3.
Inflammopharmacology ; 12(5-6): 535-50, 2005.
Article in English | MEDLINE | ID: mdl-16259720

ABSTRACT

OBJECTIVE: To study the effect of hyaluronan on cell adhesion and recruitment both in vitro and in vivo, since hyaluronan both inhibits restenosis and is anti-inflammatory. When administered to animals undergoing angioplasty the recruitment of cells into the restenotic plaque is inhibited, as well as into inflammatory lesions. The recent discovery that ICAM-1 binds hyaluronan and exhibits the B(X(7))B HA binding motif, led us also to investigate whether cell adhesion could be modulated by hyaluronan. MATERIALS AND METHODS: Human neutrophils were adhered to human umbilical vein (HUVEC) or Ea.hy.926 HUVEC cells stimulated with phorbol myristate acetate (PMA) or tumour necrosis factor (TNFalpha). Neutrophil binding in vivo utilized FMLP-stimulated hamster cheek pouch post-capillary venules. RESULTS: Hyaluronan inhibited human neutrophil adhesion to both PMA and TNFalpha-stimulated HUVEC. Ea.hy.926 human immortal HUVECs expressed ICAM-1 in response to TNFalpha and PMA. E-selectin was also upregulated by 6 h with TNFalpha but not significantly with PMA. TNFalpha induced CD44 expression within 4 h, but PMA not significantly up to 6 h. However, specific binding of [125I]hyaluronan to Ea.hy.926 cells was increased by PMA-stimulation at 4 h. Neutrophil adhesion to PMA-stimulated Ea.hy.926 HUVECs was inhibited in a concentration dependent fashion by both anti-ICAM-1 and hyaluronan (1 ng/ml-10 microg/ml) at 4 h. At 1 mg/ml adhesion was stimulated by hyaluronan. Hyaluronan had no effect on neutrophil adhesion to resting Ea.hy.926 cells. Hyaluronan (25 mg/kg, i.v.) inhibited cell adhesion to FMLP-stimulated post capillary venules of the hamster cheek pouch, whilst leaving cell rolling unaffected. CONCLUSIONS: These results show that hyaluronan, at concentrations below those where intra-molecular associations occur, binds selectively to stimulated endothelial cells and inhibits neutrophil adhesion in vitro and in vivo via a mechanism which may involve molecules other than CD44, such as ICAM-1.


Subject(s)
Endothelial Cells/drug effects , Hyaluronan Receptors/metabolism , Hyaluronic Acid/pharmacology , Neutrophils/drug effects , Animals , Capillaries/drug effects , Capillaries/physiology , Cell Adhesion/drug effects , Cell Line , Cheek/blood supply , Cricetinae , Dose-Response Relationship, Drug , E-Selectin/metabolism , Endothelial Cells/cytology , Endothelial Cells/metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Intercellular Adhesion Molecule-1/metabolism , Iodine Radioisotopes , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Neutrophils/cytology , Neutrophils/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Time Factors , Tumor Necrosis Factor-alpha/pharmacology
4.
J Paediatr Child Health ; 41(12): 669-70, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16398872

ABSTRACT

The diagnosis of sudden infant death syndrome (SIDS) has undergone several changes in definition since first being recognised as a cause of death. Linked total population data from Western Australia enable investigations to determine changes in classifications of mortality for the infants of Aboriginal and non-Aboriginal mothers (Aboriginal and Torres Strait Islander people are referred to throughout this report as 'Aboriginal'). Data for recent years show a shift away from a classification of 'SIDS' towards a classification of 'unascertainable', particularly for Aboriginal infants. This has implications for the accurate translation of data into policy and practice.


Subject(s)
Infant Mortality/trends , Native Hawaiian or Other Pacific Islander/statistics & numerical data , Sudden Infant Death/epidemiology , Cause of Death , Humans , Infant , Population Surveillance , Risk Factors , Sudden Infant Death/diagnosis , Sudden Infant Death/ethnology , Western Australia/epidemiology
5.
Strahlenther Onkol ; 174(11): 580-8, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9830440

ABSTRACT

PURPOSE: Substantial clinical evidence shows the efficacy of low-dose radiotherapy in the treatment of a wide variety of benign conditions. However, experimental investigations into these empirically clinical observations remain scarce. We investigated in vivo low-dose radiation effects on chronic granulomatous tissue by using the air pouch model in mice. MATERIAL AND METHODS: Chronic granulomatous air pouches were induced in mice and dosed according to 4 protocols: group I: sham control; group II: 2 Gy on day 2; group III: 2 Gy on day 6; group IV: 5 daily doses of 0.5 Gy from day 2 to 6. On day 7 after granuloma induction the granuloma wet and dry weight was estimated, the vascular content was assessed by the formation of vascular casts incorporating carmine, the inducible nitric oxide synthase (iNOS)- and heme oxygenase 1 (HO-1)-expression in tissue homogenates was assessed by Western blot analysis, and the immunohistochemical localization of iNOS was carried out in cryostat sections of the granulomatous tissue. RESULTS: We did not observe any significant reduction in granulomatous tissue wet weight or dry weight following the different radiation treatments, which indicates that anti-proliferative effects in response to the low radiation doses used, are probably not involved in the effects of anti-inflammatory radiotherapy. A single dose of 2 Gy on day 2, as well as fractionated treatment with 5 x 0.5 Gy lead to an increase in vascularity. iNOS-expression in the homogenized granulomatous tissue was decreased, being most pronounced after single-dose irradiation with 2 Gy on day 2, early on in the acute phase of inflammation. In contrast, the HO-1-expression was increased in all irradiated groups. CONCLUSION: Low doses of radiation interfere with the NO- and the HO-1 pathway. Since NO contributes to several aspects of inflammation such as oedema formation and inflammatory pain, we put forward the hypothesis, that the inhibitory effect of low doses of ionizing radiation on the NO pathway is one radiobiological mechanism underlying the clinically observed efficacy of anti-inflammatory radiotherapy and might result in the reduction of swelling as well as relief of pain. Furthermore, the suppression of iNOS activity could be due to the increase in the stress protein HO-1 by low dose radiotherapy.


Subject(s)
Granulomatous Disease, Chronic/radiotherapy , Animals , Blotting, Western , Female , Granulomatous Disease, Chronic/metabolism , Granulomatous Disease, Chronic/pathology , Heme Oxygenase (Decyclizing)/analysis , Heme Oxygenase (Decyclizing)/metabolism , Immunohistochemistry , Inflammation/pathology , Mice , Nitric Oxide/analysis , Nitric Oxide/metabolism , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase/metabolism , Phantoms, Imaging , Radiation, Ionizing , Radiotherapy Dosage , Time Factors
6.
Int J Radiat Biol ; 74(3): 367-78, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9737539

ABSTRACT

PURPOSE: To investigate the hypothesis that modulation of the function of activated macrophages is one of the mechanisms of the clinically observed anti-inflammatory and analgesic efficacy of low-dose radiotherapy in the treatment of a variety of painful joint diseases with total doses between 1 and 6 Gy. MATERIALS AND METHODS: Metabolic activity, cell proliferation, reproductive integrity, nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression by unstimulated or [LPS/gamma-IFN-stimulated macrophages in vitro was investigated at different times after radiation doses ranging from 0.3 Gy to 10 Gy. In vivo, chronic granulomatous air pouches were induced in mice and either sham treated or irradiated with 2 Gy on day 2 or day 6, or with five daily doses of 0.5 Gy. On day 7, the iNOS expression was assessed by Western blot and localized by immuno-histochemistry in cryostat sections. RESULTS: In stimulated macrophages, metabolic activity, proliferation and reproductive integrity were not affected by radiation doses up to 10 Gy since they are apparently irreversible post-mitotic cells. However, a dose-dependent modulation of the NO pathway was observed with significant inhibition by the low radiation doses used in anti-inflammatory radiotherapy but with super-stimulation by the high radiation doses used in cancer therapy. CONCLUSIONS: The empirically based anti-inflammatory radiotherapy of benign diseases appears to act through specific modulation of different pathways of inflammatory reactions such as the nitric oxide pathway in stimulated macrophages.


Subject(s)
Macrophages, Peritoneal/radiation effects , Macrophages/radiation effects , Animals , Cell Division , Cell Line/radiation effects , Cell Survival , Cells, Cultured , Dose-Response Relationship, Radiation , Female , Gene Expression/radiation effects , Granuloma/enzymology , Immunohistochemistry , Inflammation/radiotherapy , Interferon-gamma , Lipopolysaccharides , Macrophage Activation , Macrophages/drug effects , Macrophages/metabolism , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred BALB C , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase Type II , Nitrites/analysis , Radiotherapy Dosage , Time Factors , Tumor Necrosis Factor-alpha/analysis
7.
Cancer Res ; 57(9): 1625-9, 1997 May 01.
Article in English | MEDLINE | ID: mdl-9134996

ABSTRACT

Topical diclofenac in 2.5% hyaluronan inhibits basal cell carcinoma, actinic keratosis, and murine colon-26 growth in vivo. colon-26 tumor growth was preceded by angiogenesis and reduced apoptotic and mitotic indices. Diclofenac reduced proliferation and viability in vitro, and stimulated apoptosis. Hyaluronan inhibited proliferation and viability at 1 mg/ml but was inactive below this level. Topical application of diclofenac inhibited tumor prostaglandin synthesis and retarded angiogenesis and tumor growth (ratio of treatment:control, 0.174). The mitotic index remained unaltered in vivo, whereas the apoptotic index and necrosis were increased. Topical vehicle exhibited slight antitumor and antiangiogenesis activity. The substantial quantities of diclofenac delivered locally in hyaluronan may exhibit antitumor activity in similar fashion to those seen in vitro and explain its clinical efficacy.


Subject(s)
Adenocarcinoma/drug therapy , Colonic Neoplasms/drug therapy , Cyclooxygenase Inhibitors/administration & dosage , Diclofenac/administration & dosage , Hyaluronic Acid/administration & dosage , Neovascularization, Pathologic/prevention & control , Administration, Topical , Animals , Apoptosis/drug effects , Cell Survival/drug effects , Mice , Mice, Inbred BALB C , Mitosis/drug effects , Pharmaceutical Vehicles , Platelet Endothelial Cell Adhesion Molecule-1/analysis
9.
Drug Metab Dispos ; 23(8): 832-9, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7493550

ABSTRACT

HFA134a (1,1,1,2-tetrafluoroethane) is a nonozone-depleting candidate to replace the chlorofluorocarbons used as propellants in metered-dose inhalers (MDIs) for pharmaceuticals that are widely used in the treatment of respiratory tract disease. As a means for ensuring the safety of such a compound for human use, it is necessary to establish that there is no excessive or unexpected accumulation in the body and in selected regions. A sensitive whole-body gamma-counting technique has been used with 18F-labeled HFA134a to measure the whole-body and regional absorption, distribution, and retention of HFA134a after administration in humans by single-breath inhalation. In seven healthy subjects, labeled HFA134a was rapidly eliminated by ventilation during the first few minutes, with an average of 9.6% of the radioactivity retained in the body at 5 min. This radioactivity cleared with an apparent terminal half-life of 1.5-4.2 hr to leave, on average, < 1% of the administered dose (< 750 micrograms, approximately 0.2 microCi) retained in the body at 5.8 hr. Disposition of radioactivity was independent of the position of label. Thus, there was no evidence of any significant degradative metabolism. On average, only 0.0056% of the administered dose appeared in the urine within the first 2 hr. Later samples contained no significant radioactivity. Inhaled HFA134a first distributed to all regions of the body and then cleared without evident accumulation in any specific region.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Aerosol Propellants/pharmacokinetics , Airway Obstruction/metabolism , Hydrocarbons, Fluorinated/pharmacokinetics , Administration, Inhalation , Adult , Aerosol Propellants/administration & dosage , Fluorine Radioisotopes , Half-Life , Humans , Hydrocarbons, Fluorinated/administration & dosage , Male , Middle Aged , Nebulizers and Vaporizers , Tissue Distribution , Whole-Body Counting
10.
Am J Clin Nutr ; 61(6): 1186-94, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7762516

ABSTRACT

We compared fat-free mass (FFM) and percentage body fat mass (BFM) values derived from total body potassium (TBK), bioelectrical impedance analysis (BIA), and dualenergy X-ray absorptiometry (DXA) in hypopituitary adults before and after 6 mo treatment with growth hormone. Before growth hormone treatment, FFM values from the three methods correlated strongly. FFM values from TBK were lower than FFM values derived from BIA and DXA (mean +/- SD: 53.7 +/- 14.3 compared with 49.1 +/- 9.2 kg, P < 0.0001; DXA compared with TBK: 54.7 +/- 16.4 and 49.2 +/- 9.7 kg, P < 0.0002). BFM values from TBK were significantly higher than the BIA-derived (P < 0.002) but not different from the DXA-derived values. There was no difference in FFM and BFM values derived from DXA and BIA methods. The differences between BIA and TBK methods and between DXA and TBK methods were observed in the obese but not in the nonobese subjects. The increase in FFM derived from BIA with growth hormone was greater than that derived from TBK ([median(range)]; BIA: +5.2(-0.1, +13.8) compared with TBK: +0.9(-4.8, +8.6) kg, P < 0.001, but the changes with placebo were not different. The changes in FFM and BFM derived from DXA was growth hormone and placebo were not significantly different from those derived by using TBK or BIA. We conclude that FFM and BFM values derived from TBK, BIA, and DXA correlate highly and that TBK-derived values for FFM are lower than those derived from BIA and DXA in obese patients.


Subject(s)
Body Composition/drug effects , Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Absorptiometry, Photon , Adipose Tissue/metabolism , Adult , Aged , Double-Blind Method , Electric Impedance , Female , Humans , Male , Middle Aged , Potassium/metabolism
11.
Clin Endocrinol (Oxf) ; 42(2): 179-89, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7704962

ABSTRACT

OBJECTIVES: The role of growth hormone in maintaining normal body composition and bone strength in adults has attracted much interest recently. We have assessed body composition and bone mass in GH deficient hypopituitary adults on conventional replacement therapy and compared them with matched controls. DESIGN AND SUBJECTS: A cross-sectional study of 64 growth hormone deficient hypopituitary adults (29 males and 35 females) on conventional replacement therapy and a large number of healthy control subjects matched for age, sex and body mass index (BMI). MEASUREMENTS: Skinfold thicknesses at two sites (triceps and subscapular), waist and hip girth circumferences were assessed by standard methods. Body composition was assessed using total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Bone mineral mass was assessed at the lumbar spine and the total body by DEXA. Not every patient and control participated in every measurement. RESULTS: Obesity was common in the hypopituitary patients; BMI (mean +/- SD) was 27.5 +/- 4.6 kg/m2 and body weight was 111.8 +/- 18.5% of the maximal ideal for height (P < 0.001). The sum of subscapular and triceps skinfolds was significantly higher in hypopituitary patients than in controls (men 46 + 15 vs 37 +/- 14 mm, P < 0.05; women 55 +/- 13 vs 47 +/- 17 mm, P < 0.05). Waist to hip circumference ratio was significantly greater in female hypopituitary patients than in matched controls but was not significantly different in men (men 0.94 +/- 0.07 vs 0.91 +/- 0.07, NS; women 0.84 +/- 0.09 vs 0.77 +/- 0.05, P < 0.001). The difference between patients and controls in the sum of skinfolds and the waist to hip ratio were present in non-obese (BMI < 26 kg/m2) subjects (21 patients and 32 controls). TBK corrected for body weight was significantly lower in hypopituitary patients (n = 44) than in controls (n = 31) (men 43.5 +/- 5.6 vs 50.1 +/- 5.9 mmol/kg, P < 0.003; women: 34.0 +/- 3.2 vs 40.6 +/- 5.3 mmol/kg, P < 0.0001). BIA-derived body water content (corrected for body weight) was significantly lower in hypopituitary patients (n = 56) than in controls (n = 57) (0.492 +/- 0.064 vs 0.545 +/- 0.067 l/kg, P < 0.0004). Percentage body fat derived from all the three methods was significantly higher in hypopituitary patients than in normal controls in both sexes (from TBK: men 34.7 +/- 9.4 vs 28.8 +/- 7.0%, P < 0.05; women 37.8 +/- 8.7 vs 30.4 +/- 9.7%, P < 0.01; from BIA: men 29.3 +/- 8.5 vs 23.2 +/- 8.4%, P < 0.01; women 34.6 +/- 8.1 vs 29.3 +/- 9.1% P < 0.01; and from DEXA: men 24.8 +/- 6.8 vs 20.4 +/- 6.1%, P < 0.05; women 38.9 +/- 7.9 vs 32.5 +/- 9.8%, P < 0.01). There was a significant difference between non-obese patients and controls in BIA-derived percentage fat in both sexes and in TBK-derived percentage fat in females only. Bone mineral density (BMD) of the lumbar spine in the L2-L4 region was lower in hypopituitary patients than in controls (men 1.116 +/- 0.129 vs 1.311 +/- 0.131 g/cm2, P < 0.0001; women 1.001 +/- 0.122 vs 1.131 +/- 0.138 g/cm2, P < 0.001). Spine BMD was also reduced in hypopituitary patients compared to the young adult and age and weight matched reference data. Total body BMD was significantly lower in patients than in controls (men 1.186 +/- 0.102 vs 1.250 +/- 0.080 g/cm2, P < 0.05; women 1.080 +/- 0.077 vs 1.149 +/- 0.073 g/cm2, P < 0.005). CONCLUSIONS: Hypopituitary adults on conventional therapy have abnormal body composition with increased fat content, reduced body water content and reduced bone mineral mass.


Subject(s)
Body Composition , Bone Density , Growth Hormone/deficiency , Hypopituitarism/physiopathology , Adipose Tissue , Adult , Aged , Body Mass Index , Body Water/chemistry , Cross-Sectional Studies , Female , Humans , Hypopituitarism/blood , Hypopituitarism/drug therapy , Male , Middle Aged , Obesity/physiopathology , Potassium/analysis
12.
Clin Endocrinol (Oxf) ; 42(1): 73-84, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7889635

ABSTRACT

OBJECTIVES: The physiological role of growth hormone in adult life has recently attracted increased interest. We have studied the clinical effects and the effects on body composition of prolonged replacement with biosynthetic human GH in a large number of hypopituitary adults. DESIGN: A randomized double blind placebo controlled trial for 6 months followed by an open trial of GH treatment for 12 months. GH daily dose was 0.04 (0.02-0.05) IU/kg s.c. PATIENTS: Forty GH deficient hypopituitary patients (19 M, 21 F; aged 19-67 years) on conventional replacement therapy were studied. MEASUREMENTS: Serum insulin like growth factor I (IGF-I), skinfold thickness, total body potassium, total body water (TBW), exercise tolerance and muscle strength, and well-being. RESULTS: During the 6-month double blind phase, two GH treated patients withdrew because of adverse events. Lean body mass (LBM) increased and percentage body fat (%BF) decreased on GH but not on placebo (P) (LBM: (GH: from 48.5 +/- 9.6 to 49.6 +/- 9.5 kg; P: from 50.9 +/- 9.2 to 50.1 +/- 9.0 kg, P < 0.05 GH vs P) and %BF (GH: from 34.7 +/- 11.4 to 34.2 +/- 10.7; P: from 37.4 +/- 7.6 to 38.7 +/- 8.1, P < 0.05 GH vs P)). TBW increased on GH (P < 0.01) but not on P. No change was observed in waist-to-hip ratio or in muscle strength. During longer-term follow-up combining the double blind and open phase components of the study, 34, 27 and 11 patients received GH for 6, 12 and 18 months respectively. Patients dropped out because of adverse events or lack of perceived benefit. Skinfold thicknesses decreased significantly at 6 and 12 months and the waist circumference at 6 months. Waist-to-hip ratio decreased significantly on GH at 12 months. LBM increased on GH treatment from 49.6 +/- 9.1 to 51.6 +/- 9.4 kg (P < 0.0006), 51.9 +/- 8.9 kg (P < 0.07) and 53.1 +/- 10.5 kg (P < 0.0001) at 6, 12 and 18 months respectively. Percentage body fat decreased on GH from 37.2 +/- 10.7 to 34.7 +/- 10.1 (P < 0.005), 35.1 +/- 12.8 (NS) and 34.5 +/- 8.6 (P < 0.04) at 6,12 and 18 months respectively. TBW also increased at 6 and 12 months of GH treatment. Exercise time increased significantly at 6, 12 and 18 months of GH treatment. Muscle strength in selected muscle groups increased significantly at 6, 12 or 18 months of GH treatment. Randomization resulted in the placebo group having a greater GHQ score (higher morbidity) than the GH group before therapy. Over the controlled phase, GHQ scores improved on placebo but not on GH and CPRS score was unchanged in either group. In the open phase, the GHQ score did not change on GH therapy but CPRS score improved at 6 and 12 months. CONCLUSIONS: Growth hormone replacement therapy in adults for 6 months increased lean body mass, total body water and exercise tolerance, and decreased body fat. Growth hormone replacement for longer than 6 months maintains the advantageous effects seen in shorter-term studies and may have additional effects on body fat distribution, muscle strength and psychological well-being.


Subject(s)
Growth Hormone/deficiency , Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Adult , Aged , Body Composition , Body Water , Double-Blind Method , Exercise , Female , Humans , Hypopituitarism/metabolism , Insulin-Like Growth Factor I/metabolism , Male , Middle Aged , Potassium/metabolism , Quality of Life , Sex Factors , Skinfold Thickness , Time Factors
13.
Int J Tissue React ; 17(4): 157-66, 1995.
Article in English | MEDLINE | ID: mdl-8867646

ABSTRACT

In a novel application, hyaluronan has been utilized as a delivery system for topical and i.v. therapeutics. Clinical trials and case reports show that topical diclofenac delivered in hyaluronan (HYAL CT-1101) is effective against basal-cell carcinoma and actinic keratosis. The effect of this drug formulation on tumour growth and angiogenesis, as well as granulomatous tissue angiogenesis, has been investigated experimentally. The evidence that hyaluronan has a permissive effect on the inhibition of granulomatous tissue angiogenesis by diclofenac (as assessed by the carminel/gelatin vascular casting method) when injected into the lesion or applied topically is reviewed. Topical diclofenac in hyaluronan also induces a regression of the existing neo-vasculature of granulomatous tissue when applied therapeutically. The diclofenac formulated in hyaluronan was also found to be profoundly effective against the development of subcutaneous Colon-26 tumours in syngeneic balb/c mice (T/C ratio after 12 days topical application of 0.174, p < 0.0001). Analysis of the tumour vasculature showed that vascular development was retarded by 12 days. This was shown by the reduction in the tumour density of carmine in the vascular casts, as well as reduced blood-vessel density visualized by rat anti-mouse CD31 immunohistology. Hyaluronan alone had a significant effect on tumour development with a 50% inhibition of tumour growth and only a transient reduction in vascularity. The effects noted when diclofenac is formulated in hyaluronan, and applied topically, could be related to trans-dermal delivery and deposition properties of hyaluronan, and to the binding properties of hyaluronan to areas of pathology with high expression of hyaluronan receptors such as RHAMM, ICAM-1, and CD44.


Subject(s)
Diclofenac/administration & dosage , Granuloma/physiopathology , Hyaluronic Acid , Neoplasms/blood supply , Neovascularization, Pathologic/drug therapy , Animals , Diclofenac/therapeutic use , Drug Delivery Systems , Humans
14.
Exp Physiol ; 78(5): 639-48, 1993 Sep.
Article in English | MEDLINE | ID: mdl-8240795

ABSTRACT

Muscle potassium (K+) content decreases during exercise. Previous studies, in humans, have used measurements of arteriovenous plasma potassium concentration differences (AV delta[K+]) and/or muscle biopsy to measure the loss of muscle K+ during exercise. In the current study a non-invasive method was developed to measure skeletal muscle K+ before and after exercise, using an isotope of K+, potassium-43 (43K+). Twelve subjects performed single-leg extension exercise for 2 h at 50% of their maximum predicted heart rate. The level of radioactivity from the quadriceps femoris was determined before exercise and during two periods post-exercise. After correction for counts arising outside the exercised muscle, we estimate a decrease in muscle K+ content of 3.2 +/- 1.55% (mean +/- S.E.M.) following exercise. The muscle K+ was not restored following 75 min of recovery. The decrease in muscle K+ following exercise in our study is considerably less than that suggested by previous studies using AV delta[K+] measurements but not so dissimilar from results obtained using muscle biopsy. We conclude that a small but significant loss of K+ occurs following prolonged dynamic exercise, and that complete recovery of muscle K+ is slow.


Subject(s)
Exercise/physiology , Muscles/metabolism , Potassium/metabolism , Adult , Heart Rate/physiology , Humans , Male , Muscles/chemistry , Muscles/physiology , Physical Exertion/physiology , Potassium/analysis , Potassium/physiology , Potassium Radioisotopes
15.
Q J Med ; 83(300): 283-94, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1321457

ABSTRACT

Lateral radiographs of the thoracic and lumbar spine were taken periodically in 49 patients with osteoporosis. Thirty patients were postmenopausal, and 19 nonmenopausal with osteoporosis due to steroids, male hypogonadism, alcoholism, thyrotoxicosis or unknown cause. Patients were studied before, during and after treatment with high calcium alone, or with combined calcium and sex steroids. Calcium was given as effervescent calcium lactate gluconate, and sex hormones as oestradiol valerate, testosterone oenanthate, or methenolone oenanthate. A total of 964 films covering 409 patient-years were available for measurement. On each vertebra, deformity due to loss of anterior height was measured and assigned to one of four grades. For the time interval between each consecutive pair of films, a patient's vertebral fracture rate score was calculated and expressed per thousand patient-years. In comparison with the corresponding pretreatment fracture rate score, both the postmenopausal and the nonmenopausal groups who had not received sex hormones previously, failed to show significant changes (p = 0.144; p = 0.017) on high calcium alone during mean periods of 4.3 and 2.8 years respectively. If the first 2 years on high calcium were excluded for the postmenopausal group, they still failed to show a reduction in fracture rate score (observed for a mean period of 5.0 years; p = 0.04). When treated with combined calcium and sex hormones, both postmenopausal and nonmenopausal groups showed a lower fracture rate score of 20 and 207 respectively when compared with the pretreatment levels of 1500 and 1697 (in mean treatment periods of 3.2 and 4.4 years; p less than 0.001 in each case). When given high-dose calcium alone, but after treatment with sex hormones as well, the postmenopausal group showed no change in fracture rate score from pretreatment (in a mean of 3.1 years; p = 0.069); however the nonmenopausal group still showed a significant reduction in fracture rate score from 1697 to 42 over a mean period of 2.3 years (p = 0.001). The postmenopausal group, after stopping all treatment, showed a higher fracture rate score of 1286 (in a mean of 2.6 years) than did those on combined calcium and sex hormones, in whom the fracture rate score was 20 (in a mean of 3.2 years; p = 0.008). A subgroup of 11 patients with osteoporosis of both the menopausal and nonmenopausal types, had data both before (in a mean of 5.5 years) and during (for a mean of 2.5 years) treatment with calcium alone; the fracture rate scores were 1473 and 918 (p = 0.247).(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Calcium/therapeutic use , Gonadal Steroid Hormones/therapeutic use , Osteoporosis/drug therapy , Spinal Fractures/prevention & control , Adult , Drug Therapy, Combination , Estradiol/analogs & derivatives , Estradiol/therapeutic use , Estrogens, Conjugated (USP)/therapeutic use , Female , Humans , Male , Methenolone/analogs & derivatives , Methenolone/therapeutic use , Middle Aged , Osteoporosis, Postmenopausal/drug therapy , Testosterone/analogs & derivatives , Testosterone/therapeutic use , Time Factors
16.
Br J Clin Pharmacol ; 32(2): 167-72, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1931467

ABSTRACT

1. We describe a new method that enables the tissue kinetics of picomolar concentrations of drugs to be measured in man. The method is based on the administration of a drug, labelled with a short-lived positron-emitting radioisotope, such as carbon-11 (t1/2 = 20.4 min, beta + = 99.8%) or fluorine-18 (t1/2 = 109.8 min, beta + = 96.9%), which is then detected in vivo by an array of 10 large uncollimated sodium iodide scintillation detectors, arranged as five opposing pairs, with each pair collecting data over one major organ or region of the body. 2. To illustrate the scope of the new method we report the results of administering [O-methyl-11C]-diprenorphine, an established radioligand for central opiate (mu, kappa, and delta) receptors and L-6-[18F]-fluoro-DOPA, a marker for dopaminergic neurons. 3. Only 2-10 muCi (74-370 kBq) of radioactivity are used and, as a consequence of the high specific activities with which carbon-11 and fluorine-18 labelled compounds can be prepared, the method requires less than a nanomole of drug to be administered. In many cases, this amount of drug might be considered low enough to avoid any adverse biological effect. Furthermore repeat studies are possible in many without delivering unacceptable radiation burdens. 4. The high sensitivity realised for both radioactivity and mass suggests a mean for determining the human biodistribution of a new drug at a very early stage in its development. This has potential benefit to drug discovery programmes and to ensuing drug therapies.


Subject(s)
Pharmacokinetics , Whole-Body Counting , Blood-Brain Barrier , Carbon Radioisotopes , Diprenorphine/analogs & derivatives , Diprenorphine/pharmacokinetics , Electrons , Fluorine Radioisotopes , Humans , Isotope Labeling , Levodopa/analogs & derivatives , Levodopa/pharmacokinetics , Tissue Distribution
17.
Am J Hum Genet ; 48(4): 769-82, 1991 Apr.
Article in English | MEDLINE | ID: mdl-2014800

ABSTRACT

Ten cases of small ring chromosomes which did not stain with distamycinA/DAPI and did not possess satellite regions associated with nucleolus-organizing regions are described. In situ hybridization with a battery of biotinylated pericentric repeat probes specific either for individual chromosomes or for groups of chromosomes allowed the identification of the chromosomal origin of these marker chromosomes. There was one example of a marker derived from each of chromosomes 1, 3, 6, 14, 16, 18, 20, 13 or 21, and the X, and there were two examples of markers derived from chromosome 12. One case possessed two markers, one derived from chromosome 6, and one derived from the X. The mechanism of generation of ring marker chromosomes is discussed. Five of seven cases who could be phenotypically assessed were abnormal. Three of these--the first with a ring chromosome derived from chromosome 1; the second with two markers, one derived from chromosome 6 and the other from the X chromosome; and the third with a ring chromosome derived from chromosome 20--each possessed distinctive facies. Additional cases with identified rings may allow the delineation of new chromosomal syndromes.


Subject(s)
Genetic Markers , Ring Chromosomes , Cells, Cultured , Chromosome Banding , Chromosomes, Human, Pair 20/ultrastructure , Chromosomes, Human, Pair 6/ultrastructure , Distamycins , Female , Humans , Infant, Newborn , Karyotyping , Male , Nucleolus Organizer Region , X Chromosome/ultrastructure
18.
Hum Genet ; 86(2): 187-90, 1990 Dec.
Article in English | MEDLINE | ID: mdl-2265831

ABSTRACT

In a large kindred in which the gene for central core disease is segregating, we have demonstrated linkage between the disorder and a marker on chromosome 19q. Marker D19S9 (p1J2) was linked to central core disease with a lod score of 6.4 at theta = 0.03 (support interval 0.01-0.14) thus localizing the gene for this disorder in or very close to 19q12-q13.2.


Subject(s)
Chromosomes, Human, Pair 19 , Genetic Linkage , Muscular Diseases/genetics , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Genes, Dominant , Genetic Markers , Humans , Lod Score , Male , Middle Aged , Pedigree , Restriction Mapping
19.
Am J Hum Genet ; 47(3): 493-8, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2393023

ABSTRACT

Nine cases are described of tetrasomy 18p resulting from the presence of an isochromosome 18p [i(18p)]. The initial diagnosis of i(18p) was by standard cytogenetic techniques and was confirmed by in situ hybridization with a biotinylated alphoid probe (L1.84) specific for the pericentric region of chromosome 18 and with a tritium-labeled chromosome 18 probe (B74) which hybridizes to the D18S3 locus situated at 18p11.3. The clinical features of the cases are summarized and shown to constitute a distinct and recognizable syndrome. Common features were low birth weight, a characteristic facies, neonatal hypotonia with subsequent limb spasticity, short stature, microcephaly, mental retardation, and seizure disorders. On the basis of size and cytogenetic banding a marker chromosome can be suspected to be an i(18p). In situ hybridization with the alphoid probe L1.84 provides confirmation of chromosome 18 origin. This more precise diagnosis will be an advantage in situations of pre- and postnatal diagnosis, since parents can be provided with a more confident prognosis for their child.


Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations/genetics , Chromosomes, Human, Pair 18 , Adolescent , Adult , Child , Chromosome Banding , Chromosome Disorders , Female , Humans , Infant, Newborn , Karyotyping , Male , Nucleic Acid Hybridization , Syndrome
20.
J Med Genet ; 27(3): 155-9, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2325088

ABSTRACT

Three patients with different marker chromosomes were screened by in situ hybridisation using biotinylated probes to chromosome specific pericentric repeats to determine the chromosomal origin of the marker. Each marker had a different origin, with one from each of chromosomes 1, 9, and 16. This is the first time that autosomal marker chromosomes consisting of a small ring have been shown to be derived from the pericentric heterochromatin of metacentric and submetacentric chromosomes. Evidence suggests that such markers are not associated with any significant risk of phenotypic abnormalities, but additional cases need to be studied.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 16 , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 9 , Heterochromatin/ultrastructure , Adolescent , Adult , Biotin , Child, Preschool , Chromosome Banding , Female , Genetic Markers , Humans , Karyotyping , Male
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