健康老年人血脂与甲状腺功能关系的研究

目的：观察健康老年人补充小剂量甲状腺激素（TH）后血脂水平的变化。方法：从健康老年人 为治疗组和对照组各60例。治疗组每日口服甲状腺片10mg,对照组每日口服Vit.B1 30mg，连服6个月,所有受试治疗前后均检测甲状腺功能指标包括高灵敏促甲状腺素（M－TSH）、游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）、总三碘甲状腺原氨酸（TT3）、总甲状腺素（TT4）、反T3（rT3)和血脂包括胆固醇 （TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C)、高密度脂蛋白（HDL－C）、载脂蛋白（apoAl)的水平并比较它们之间的关系。结果：服用甲状腺片后，治疗组TH水平有明显升高，TC、TG、LDL－C的水平也有不同程度的下降、HDL－C、apoAl的水平有轻度的升高。治疗组服药后与治疗组服药前及对照组服药前后比较有显性差异（P＜0．01）。结论：小剂量TH补充治疗可升高老年人血清TH水平和降低血脂水平，并可望有益于老年人高脂血症的治疗。     

Dose-response relationship between physical activity and dyslipidemia in youth

BACKGROUND:

The minimal and optimal amount of physical activity associated with cardiovascular health benefits in young people is unknown.

OBJECTIVE:

To determine the dose-response relationship between moderate-to-vigorous physical activity (MVPA) with high-risk low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride values in youth.

METHODS:

The study sample consisted of 1235 adolescents (12 to 19 years of age) from the 2003/2004 and 2005/2006 cycles of the United States National Health and Nutrition Examination Survey. Objective measures of MVPA were obtained over seven days with accelerometers. LDL cholesterol, HDL cholesterol and triglycerides were measured from a fasting blood sample. High-risk values for these lipids/lipoproteins were determined using age- and sex-specific thresholds. Logistic regression models were used to determine the dose-response relationships between MVPA and high-risk lipid levels.

RESULTS:

ORs for high-risk HDL cholesterol and triglyceride values decreased in a curvilinear manner with increasing minutes of MVPA. Compared with no MVPA (0 min), the ORs for high-risk HDL cholesterol values at 15 min, 30 min and 60 min per day of MVPA were 0.29 (95% CI 0.13 to 0.67), 0.24 (95% CI 0.10 to 0.64) and 0.21 (95% CI 0.07 to 0.61), respectively. The corresponding ORs for high-risk triglyceride values were 0.40 (95% CI 0.18 to 0.76), 0.22 (95% CI 0.06 to 0.66) and 0.10 (95% CI 0.01 to 0.51). There was no discernible dose-response relationship between MVPA and LDL cholesterol.

CONCLUSIONS:

Small amounts of MVPA were associated with a large reduction in the likelihood of having high-risk HDL cholesterol and triglyceride values in this representative sample of adolescents.     

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Streptozotocin (STZ) is used to induce diabetes in experimental animals. It has a variety of adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renal failure, and metabolic acidosis. STZ also has effects on the immune system, being associated with lymphopenia in rodents, the mechanism of which is not fully understood. We present data on a significant STZ-associated reduction in lymphocyte count in nonhuman primates. We report a significant reduction in absolute lymphocyte count; in 2 monkeys, the lymphopenia persisted for >100 d. However, a significant increase in absolute monocyte count was noted. Furthermore, an increase in serum monocyte chemoattractant protein-1 (MCP-1) was observed. The reduction in lymphocyte numbers may contribute to immunomodulation that may be beneficial to a subsequent islet graft, and may reduce the need for immunosuppressive therapy. The increase in monocytes and MCP-1, however, may be detrimental to the islet graft. Studies are warranted to explore the mechanism by which STZ has its effect.     

Streptozotocin-associated lymphopenia in cynomolgus monkeys

Streptozotocin (STZ) is used to induce diabetes in experimental animals. It has a varietyof adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renalfailure, and metabolic acidosis. STZ also has effects on the immune system, beingassociated with lymphopenia in rodents, the mechanism of which is not fully understood. Wepresent data on a significant STZ-associated reduction in lymphocyte count in nonhumanprimates. We report a significant reduction in absolute lymphocyte count; in 2 monkeys,the lymphopenia persisted for >100 d. However, a significant increase in absolutemonocyte count was noted. Furthermore, an increase in serum monocyte chemoattractantprotein-1 (MCP-1) was observed. The reduction in lymphocyte numbers may contribute toimmunomodulation that may be beneficial to a subsequent islet graft, and may reduce theneed for immunosuppressive therapy. The increase in monocytes and MCP-1, however, may bedetrimental to the islet graft. Studies are warranted to explore the mechanism by whichSTZ has its effect.     

Dose-response curves for treatment with biosynthetic human growth hormone

We have studied the effect of varying doses of biosynthetic human GH on the growth response over the first year of therapy in 90 short prepubertal children (67 males and 23 females, aged 3.1-12.9 years). As pretreatment height velocity was the predominant determinant of response, the children were divided into three groups on the basis of their pretreatment height velocity standard deviation scores (SDS). Group A (n = 27) had pretreatment height velocity SDS between +1.3 and -0.8 (short normal growing children), group B (n = 35) between -0.9 and -2.0 (moderate GH insufficiency) and group C (n = 28) less than -2 (severe GH insufficiency). Within each group, the dose of GH administered was the dominant factor in the regression. At a mean dose of 16 units/m2 body surface area per week, the change in height velocity SDS over the first year of therapy was +2.9 (95% confidence interval (CI) 2.4, 3.5) in group A, +4.3 (95% CI 3.9, 4.6) in group B and +7.0 (95% CI 6.0, 8.0) in group C. These values translate into increases in growth rate of 2.2, 3.4 and 5.5 cm/year for an 8-year-old in each group respectively. These results have important implications in planning the treatment of children with GH insufficiency.     

The interaction between growth hormone and the thyroid axis in hypopituitary patients

Alterations in the hypothalamo‐pituitary‐thyroid axis have been reported following growth hormone (GH) administration in both adults and children with and without growth hormone deficiency. Reductions in serum free thyroxine (T4), increased tri‐iodothyronine (T3) with or without a reduction in serum thyroid‐stimulating hormone secretion have been reported following GH replacement, but there are wide inconsistencies in the literature about these perturbations. The clinical significance of these changes in thyroid function remains uncertain. Some authors report the changes are transient and revert to normal after a few months or longer. However, in adult hypopituitary patients, GH replacement has been reported to unmask central hypothyroidism biochemically in 36–47% of apparently euthyroid patients, necessitating thyroxine replacement and resulting in an attenuation of the benefit of GH replacement on quality of life in those who became biochemically hypothyroid after GH replacement. The group at highest risk are those with organic pituitary disease or multiple pituitary hormone deficiencies. It is therefore prudent to monitor thyroid function in hypopituitary patients starting GH therapy to identify those who will develop clinical and biochemical features of central hypothyroidism, thus facilitating optimal and timely replacement.     

Pulse wave velocity and morphological changes associated with early atherosclerosis progression in the aortas of cynomolgus monkeys

To determine the time course of changes in arterial stiffness and corresponding morphology during atherosclerosis progression, we determined pulse wave velocity (PWV) in cynomolgus monkeys fed atherogenic (test) and control diets over an 18-month period. At 6-month intervals, thoracic and abdominal aortic PWVs were determined with a pressure transducer retracted down the aorta in 5 cm increments. Iliac artery PWV was determined from the abdominal aortic pressure to a noninvasive femoral pulse. Groups of individual cardiac cycles, triggered by the ECGs, were sampled on a computer and the velocities (PWV) of the pulse wave fronts were calculated. There was no significant difference between groups until 18 months when test animal PWVs in the thoracic (7.44 +/- 0.83 m X s-1) and abdominal (8.52 +/- 0.67 m X s-1) aorta were significantly greater than those of controls (5.02 +/- 0.51 and 6.24 +/- 0.53 m X s-1, respectively), indicating increased arterial stiffness. There was no change in iliac PWV, 10.96 +/- 0.74 m X s-1 for 18-month test compared with 9.44 +/- 0.89 m X s-1 for controls. Constant infusion of nitroprusside and noradrenaline lowered and raised blood pressure and PWV in all groups, and PWV changes due to drug-induced pressure changes were greater in atherosclerotic than in control arteries. Systolic pressure of 18-month test and pulse pressure of 12- and 18-month test groups were significantly greater than controls under all drug conditions, also indicating increased vessel stiffness. Morphometric evaluation of histological aortic cross sections revealed early, noncomplicated atherosclerosis showing gradual increases in the ratio of intimal to medial cross-sectional area in the thoracic (1.24 +/- 0.30 after 18 months) and abdominal (1.70 +/- 0.42 after 18 months) aortas, compared with control ratios of essentially zero. The fraction of the internal elastic lamina covered with atherosclerotic lesions, and maximal intimal thickness also showed significant increases during the test diet period. These data show that early atherosclerosis resulted in aortic but not iliac stiffening which was detected by increased PWV before development of significant stenotic lesions.     

老年人甲状腺激素与钙、磷代谢及骨代谢关系的研究

目的 探讨老年人甲状腺激素(TH)水平与钙、磷代谢及骨代谢关系。方法 选择健康老年治疗组和对照组各60例。治疗组口服甲状腺片10mg·d~(-1),对照组口服VitB_1 30mg·d~(-1),连服6月,所有的受试者治疗前后均检测TH包括促甲状腺激素(TSH)、游离三碘甲状腺原氨酸(FT_3)、游离甲状腺素(FT_4)、总三碘甲状腺原氨酸(TT_3)、总甲状腺素(TT_4)、反三碘甲状腺原氨酸(rT_3)和血钙(Ca)、血磷(P)代谢以及骨代谢生化指标包括骨钙素(BGP)、骨碱性磷酸酶(BALP)、I型前胶原羧基肽(PICP)及尿羟脯氨酸/肌酐(Hop/Cr)、尿胶原吡啶交联/肌酐(Pyd/Cr)的水平并比较它们之间的关系。结果 治疗组TH水平有明显升高,血清Ca、BGP、BALP、PICP的水平也有明显升高,而P的水平、Pyd/Cr、Hop/Cr值则有一定程度的降低,与治疗前比较有显著性差异。对照组服药前后各项指标无显著性差异。结论 给予老年人小剂量的TH补充治疗,可升高血清中TH水平和Ca、BGP、BAL、PICP的水平,降低P的水平、Pyd/Cr、Hop/Cr值,对骨的形成有利。     

Aging-related changes in release of growth hormone and luteinizing hormone in female rhesus monkeys

A decline in somatic function with aging in women is associated with a decrease in GH release and a loss of estrogen after menopause. As an initial step to establish a monkey model for the neuroendocrine mechanisms underlying somatopause and menopause, we have conducted three experiments in unrestrained aged (approximately 25.7-yr-old) and young (approximately 5.4-yr-old) female rhesus monkeys. GH release was pulsatile, and mean GH release and pulse amplitude were significantly lower in aged monkeys than in young monkeys. Injection of GHRH alone, GH-releasing peptide-2 alone, or the combination of both induced an increase in GH release in both age groups. The mean LH level, pulse amplitude, and baseline LH levels were significantly higher in aged animals than in young animals. Both estrogen and IGF-I levels were lower in aged than young monkeys. These results suggest that in female rhesus monkeys 1) there is a clear decline in circulating GH and IGF-I levels with aging; 2) GHRH and GH-releasing peptide-2 stimulate GH release synergistically; and 3) circulating LH levels increase as estrogen decreases with aging. These results indicate that the rhesus monkey is an excellent model for studies of the neuroendocrine mechanisms of aging.     

The linear relationship between changes in childhood growth velocity and topical glucocorticoid dose.

The concept of therapeutic indices for glucocorticoid treatment of rhinitis and asthma requires demonstration of the dose dependency of benefits and side effects. Therefore, we examined the relationship between glucocorticoid dose and changes in growth velocity (delta GV). The literature was reviewed for articles where the net delta GV could be calculated among steroid and parallel placebo, active treatment, or baseline run-in periods. Steroid dose and delta GV were analyzed by linear regression for 5 rhinitis and 19 asthma studies using topical budesonide, beclomethasone, fluticasone and mometasone, parenteral steroids, and nonsteroid comparitors. Dose dependency was established between 0 and the equivalent of 2000 micrograms/day of beclomethasone (r2 = 0.60). delta GV was not significantly affected by 200 micrograms/day of BDP or less. Nasal and bronchial administrations appeared to give equivalent responses. Growth suppression occurred within 2 weeks, and may be linked to a delay in the onset of puberty. The physiology of these effects was discussed.     

Effects of growth hormone on neonatal growth in nursing rhesus monkeys

The effects of recombinant human GH treatment of either nursing mothers or their infants on neonatal growth in rhesus monkeys was determined. Growth rates of infants treated daily from birth with GH (INFGH; n = 9; 100 micrograms/kg, sc) were compared to those of infants given saline (INFc; n = 10), infants whose mothers received saline from the second trimester of pregnancy through 7 weeks postpartum (CON; n = 9), infants of mothers who received GH during pregnancy only from the second trimester to parturition (PRG; n = 8), infants of mothers who received GH during lactation only from parturition through 7 weeks postpartum (LAC; n = 9), and infants of mothers who received GH during the second trimester of pregnancy through 7 weeks postpartum (PRG/LAC; n = 8). Mothers receiving GH were given 250 micrograms/kg, sc, Monday, Wednesday, and Friday. Infants were allowed to nurse ad libitum. Although infant birth weights were similar among the six groups, body weights at 7 weeks of age were significantly greater in PRG/LAC infants (0.77 +/- 0.03 kg) compared to those in CON (0.66 +/- 0.02 kg), INFc (0.62 +/- 0.03 kg), LAC (0.62 +/- 0.04 kg), and INFGH infants (0.62 +/- 0.01 kg), with infants of PRG mothers intermediate (0.71 +/- 0.02 kg) between them. By 35 weeks of age, after infants had been weaned by their mothers, body weights were similar among all groups. Serum concentrations of insulin-like growth factor-I (IGF-I) rose significantly in all infants during the study period. Although IGF-I levels did not vary significantly among the treatment groups, average concentrations of IGF-I were significantly related to weight gains. Analyses of milk composition revealed that total protein, lactose, and IGF-I levels were similar among groups, whereas the percentage of fat in the milk was significantly higher in PRG/LAC mothers. Milk protein content was significantly related to weight gain. These data suggest that neonatal body weight gain can be accelerated in nursing infants whose mothers have received GH from at least the second trimester of pregnancy through the lactational interval. Since infants of mothers receiving GH during lactation only were not different from controls, the effect of GH in this treatment paradigm may be mammogenic rather than galactopoietic per se.     

Existence of multiple forms of follicle-stimulating hormone within the anterior pituitaries of cynomolgus monkeys

Ovariectomized cynomolgus monkeys were treated with physiological levels of estradiol and progesterone. A reduction in serum levels of FSH was observed after steroid exposure. Anterior pituitary homogenates were prepared from monkeys after 0, 12, 24, or 36 h of exposure to estradiol and progesterone and quantitated for FSH activity by radioreceptor assay (RRA) and RIA. Pituitary FSH activity (expressed as RRA/RIA) increased with duration of exposure to steroids. Forms of FSH within these pituitaries were separated by the column isoelectric focusing technique, chromatofocusing. All pituitary homogenates tested contained FSH isohormones that eluted at similar isoelectric points. Each FSH isohormone exhibited a mol wt similar to that of a purified FSH standard, but differed in ability to displace labeled FSH from a biological receptor preparation. FSH forms with basic isoelectric points exhibited greater RRA/RIA values than forms with more acidic isoelectric points. The relative proportion of the more basic FSH forms increased within pituitary tissue with duration of exposure to steroids. All FSH forms were secreted by pituitary cells in culture. The biochemical basis for the microheterogeneity appears to be the degree of sialic acid incorporation into the FSH molecule. The results of these studies demonstrate that the cynomolgus monkey pituitary responds to the surrounding hormonal milieu by altering the relative proportions of FSH forms present within that gland.     

人甲状腺激素受体相互作用蛋白15与甲状腺激素受体的相互作用

目的　确立人甲状腺激素受体相互作用蛋白 15 (hTRIP15 )与甲状腺激素受体 (TR)的相互作用及其作用方式。方法　应用酵母双杂交技术及半乳糖苷酶定性或定量测定。结果　将构建质粒 (BD TRIP15与AD TR)共转化AH10 9酵母细胞后 ,在高严格度选择的培养基 (SD Leu Trp Ade His) 10天克隆长出 ,相比阳性对照质粒 (BD P5 3 +AD Tag)共转后 3天克隆生长。将构建载体及对照载体转化Y187酵母菌株 ,检测LacZ报告基因的表达 (β gal单位 ) ,阳性对照质粒 (BD P5 3 +AD Tag)为 14 9.5 7± 0 .5 1,BD TRIP15 +AD TR为 3 .2 3± 10 .15 ,加入T3 后为 2 .0 2± 0 .0 8,而阴性对照质粒 (BD P5 3 +AD LamC)仅为 0 .0 2± 0 .0 1β gal单位 ,且T3 呈剂量依赖方式抑制两者的相互作用。结论　hTPIR15能与TR共相互作用 ,T3 呈剂量依赖方式抑制两者间的作用 ,仅在超大剂量时才可完全阻断hTRIP15与TRα间的作用。     

Growth response relationship between growth hormone dose and short term growth in patients with Turner's syndrome

Short stature is a common feature of Turner's syndrome. We studied the dose-response relationship between short term linear growth and GH dose using the lower leg-measuring device. Three doses of GH (0.05, 0.15, and 0.45 U/kg, three times weekly) were given sc for 1-month treatment periods. Lower leg growth rate increased significantly during treatment with the 0.15 and 0.45 U/kg doses [1.8 +/- 0.2 (+/- SEM) and 1.7 +/- 0.3 mm/4 weeks). The higher dose of 0.45 U/kg was no more effective than the 0.15 U/kg dose. Serum somatomedin-C levels increased after treatment with each of the three doses of GH, but did not differ in any of the three dosage groups. We conclude that 0.15 U/kg GH, three times weekly, stimulates short term growth in patients with Turner's syndrome. Longer term studies are required to determine if this increased growth rate is sustained.     

Dose-response studies with biosynthetic human growth hormone (GH) in GH-deficient patients

Increasing doses of biosynthetic human GH (R-hGH) were given sc to seven GH-deficient patients for three consecutive 14-day periods (2, 4, and 6 IU/day at 2000 h), followed by 14 days of no GH therapy. At the end of each period each patient was hospitalized for frequent blood sampling from 2000 to 1100 h the following day. A dose-dependent increase in serum GH and serum insulin-like growth factor I (IGF-I) levels occurred. However, the time course of the serum IGF-I concentrations was different on the four occasions; there was a significant fall in the evening when no therapy was given (P less than 0.01), a significant increase after injections of 2 IU R-hGH, and constant levels during treatment with 4 and 6 IU R-hGH. Plasma glucose levels were within the normal range, with a significantly lower fasting level (at 0400 h) when no GH was given. Breakfast induced a plasma glucose rise when GH was administered, but no rise without GH, and a postprandial serum insulin response that was GH dose dependent. GH therapy increased serum FFA (P less than 0.05) and blood 3-hydroxybutyrate levels, but had no effect on blood alanine or lactate or serum triglyceride and cholesterol levels. We conclude that the serum IGF-I response to GH is dose dependent, and that a GH replacement dose of 2 IU/day (equalling 1.5 IU/m2.day) is insufficient to maintain normal diurnal serum IGF-I levels. Furthermore, a GH-independent diurnal variation in serum IGF-I in these patients is suggested. This GH preparation also has diabetogenic and lipolytic actions.     

血清促甲状腺激素与甲状腺癌的关系

越来越多的证据显示,血清促甲状腺激素(TSH)是预测结节性甲状腺肿患者发生甲状腺癌的独立危险因素.即使血清TSH水平在正常范围内,结节性甲状腺肿患者发生甲状腺癌的风险也随着血清TSH水平的升高而逐渐增加.高水平的TSH与甲状腺癌的高发生率以及晚期甲状腺癌关系密切.血清TSH抑制治疗能降低肿瘤进展高危患者的复发率和死亡率.血清TSH在甲状腺癌的发展过程中起着非常重要的作用.     

Prolonged survival of porcine hepatocytes in cynomolgus monkeys

BACKGROUND & AIMS: Management of patients with liver failure can be a significant medical challenge, and transplantation of the liver is the only definitive therapy. Whole liver allotransplantation is limited by a shortage of human donors and the risks of the surgery in those most ill. Transplants consisting of xenogeneic hepatocytes might overcome these problems, and work in rodents indicates that such transplants can correct some metabolic deficiencies and can prevent the complications and mortality associated with hepatic failure. As a prelude to clinical application, we tested the feasibility of hepatocyte xenotransplantation in nonhuman primates. METHODS: One to 2 billion hepatocytes from outbred swine were transplanted into the spleens of cynomolgus monkeys using conventional immunosuppression to control rejection. Duration of graft function was determined based on assay for porcine albumin. RESULTS: Following a single infusion, xenogeneic hepatocytes functioned for more than 80 days and, following re-transplantation, for more than 253 days. Engraftment in the spleen was confirmed 40 days after transplantation by asialoglycoprotein receptor-directed nuclear scanning. The humoral immune response to the transplanted porcine cells had no discernible impact on the survival of the grafts. CONCLUSIONS: Xenotransplantation of hepatocytes should be explored as a readily available, minimally invasive form of therapy for hepatic failure.     

Relation between phenotype and intra-cellular thyroid hormone effect in patients with altered peripheral thyroid hormone sensitivity

OBJECTIVE We wished to ascertain whether different phenotypic appearances in patients with altered cellular sensitivity to thyroid hormones were related to the type of altered intra-cellular thyroid hormone effect. DESIGN Blood samples were obtained from two members of a family suffering from generalized thyroid hormone resistance (GTHR) for hormone assays and examination of the cellular thyroid hormone effect, and the results compared with results from other families with signs of altered peripheral thyroid hormone sensitivity. PATIENTS Two members of a family with thyroid hormone resistance and nine normal persons were studied. MEASUREMENTS Basal thyroid hormone function tests were measured. The thyroid hormone effect on mononuclear blood cells was determined by measuring the thyroid hormone stimulated oxygen consumption and glucose uptake. RESULTS The two family members appeared phenotypically normal except for nodular goitre. Thyroid hormone stimulated glucose uptake was depressed whereas thyröid hormone stimulated oxygen consumption was normal. CONCLUSION Comparison of the present results of the cellular examination in two patients with GTHR, with the results obtained in other families with altered peripheral thyroid hormone sensitivity, suggest that the classic GTHR (phenotype: normal or with goitre) is linked to impaired thyroid hormone stimulated glucose uptake, whereas in patients with osteopetrosis, the thyroid hormone insensi-tivity seems located at the mitochondrial level (impaired thyroid hormone stimulated oxygen consumption).