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101.
102.
Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity. 相似文献
103.
104.
Gable KL Maddux BA Penaranda C Zavodovskaya M Campbell MJ Lobo M Robinson L Schow S Kerner JA Goldfine ID Youngren JF 《Molecular cancer therapeutics》2006,5(4):1079-1086
In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers. 相似文献
105.
106.
Postprandial hypoglycaemia is increasingly recognised as a complication of gastric bypass surgery. While post-bypass hypoglycaemia
is often responsive to dietary modification, a subset of individuals develop life-threatening neuroglycopenia, with loss of
consciousness, seizures and motor vehicle accidents. Such patients require complex nutritional and medical management strategies
to reduce postprandial insulin secretion and stabilise glucose excursions, using medications including acarbose, octreotide
and diazoxide, and frequent monitoring of glucose values. In an article in this issue of Diabetologia, nationwide registry data from Sweden were used to assess the frequency of severe hypoglycaemia and potentially related diagnoses
(e.g. confusion, syncope, seizures, accidental death) following obesity surgery. Relative risk of hypoglycaemia and related
diagnoses were two- to sevenfold higher in the post-gastric bypass population, but absolute risk was small. While these data
underscore that hypoglycaemia is an important complication of gastric bypass, many questions regarding frequency, pathogenesis
and optimal therapy remain unanswered. Given that hypoglycaemia is usually evaluated in the outpatient setting, more precise
assessments of hypoglycaemia frequency will require prospective longitudinal studies in post-bypass cohorts. Until such data
are available, practitioners should have a higher awareness of symptoms consistent with neuroglycopenia in patients with a
history of bariatric surgery. Understanding the beneficial and challenging metabolic consequences of bariatric surgery is
a key imperative for the diabetes community, as such data may yield novel insights into mechanisms by which bariatric surgery
can lead to diabetes remission. 相似文献
107.
G Pandini R Vigneri A Costantino F Frasca A Ippolito Y Fujita-Yamaguchi K Siddle I D Goldfine A Belfiore 《Clinical cancer research》1999,5(7):1935-1944
The insulin receptor (IR) form hybrids with the closely related insulin-like growth factor-I (IGF-I) receptor (IGF-I-R). Because most human breast carcinomas overexpress both the IR and the IGF-I-R, we evaluated whether the insulin/IGF-I hybrid receptor (Hybrid-R) is also overexpressed in these tumors and what role it plays in breast cancer biology. Using specific ELISAs and Western blots, we measured Hybrid-R content and function in 8 human cultured breast cancer cell lines and 39 human breast cancer specimens. Hybrid-R content and function were also compared to the content and function of the IR and the IGF-I-R. Hybrid-R content exceeded the IGF-I-R content in >75% of breast cancer specimens and was directly related to the molar ratio of both the IR and IGF-I-R content, suggesting that Hybrid-R formation occurred by random assembly of IR and IGF-I-R half-receptors. Hybrid-Rs became tyrosine autophosphorylated when breast cancer cells were exposed to IGF-I but not when they were exposed to insulin. In cells with an elevated Hybrid-R content, Hybrid-R autophosphorylation in response to IGF-I exceeded IGF-I-R autophosphorylation, suggesting that most of the IGF-I effect occurred via the Hybrid-R. Furthermore, Hybrid-Rs mediated growth in response to IGF-I, as indicated by experiments with blocking antibodies to the IGF-I-R. These data indicated therefore that: (a) Hybrid-Rs are present and play a major role in mediating the IGF-I signal in breast cancer; (b) their expression is directly related to IR overexpression; and (c) potential therapies designed to block IGF-I actions in breast cancer must take into account the role of these Hybrid-Rs. 相似文献
108.
JA Grunt ID Schwartz C Buchanan CP Howard 《Acta paediatrica (Oslo, Norway : 1992)》1995,84(6):631-633
Seven children with significant idiopathic short stature (SISS) whose heights were significantly below the third percentile (SD score for height —2.5 to —3.5) and who had normal levels of growth hormone (GH) were treated with growth hormone releasing hormone (GH-RH) in a dose of 30 /μg/kg/day. Therapy was discontinued if patients failed to increase their rates of growth by more than 2.0 cm/year over their pre-therapy growth rate. Treatment was discontinued in two of the patients after 12 months but was continued in the other five for 24 months. These data demonstrate that some patients with SISS grow well during the first 2 years of treatment with GH-RH. 相似文献
109.
K. M. Kilbride F. L. Paveglio A. L. AltstattRID=""ID="" <E>Present address:</E> Chiswell Lane Silver Spring MD USA W. G. Henry C. A. JanikRID=""ID="" <E>Present address:</E> Palo Verde Albuquerque NM USA 《Archives of environmental contamination and toxicology》1998,35(2):236-248
Throughout the western United States, studies have identified various detrimental effects of contaminants to aquatic biota
from the use of agricultural drainage water for management of arid wetlands. However, little is known about the relative contributions
of contaminant loading from pollutants dissolved in water compared with those carried by drifting material (e.g., detritus) associated with drainage water. Consequently, we determined loading rates for contaminants dissolved in water and
those incorporated by drifting material for drainage (Diagonal Drain) as well as fresh (S-Line Canal) water used for wetland
management at Stillwater National Wildlife Refuge (SNWR), Nevada during the early, middle, and late periods of the irrigation
season (June through mid-November) in 1993. We found loading rates for trace elements throughout the irrigation season were
almost entirely (> 98%) associated with contaminants dissolved in the water rather than incorporated by drift. Although drift
contributed little to the total loading for trace elements to SNWR wetlands, contaminant concentrations were much greater
in drift compared with those dissolved in water. Loading rates for dissolved As, B, Hg, and total dissolved solids (TDS) differed
among periods for the Diagonal Drain. Along the Diagonal Drain, loading rates for dissolved As, B, Hg, Mo, unionized ammonia
(NH3-N), TDS, and Zn differed among its three sampling sites. B was the only trace element with differences in loading rates for
drift among periods from the Diagonal Drain. In contrast, loading rates for As, B, Cr, Cu, Hg, Se, and Zn in drift differed
among periods for the S-Line Canal. Along Diagonal Drain, loading rates in drift for B (middle and late periods), Cr, Cu,
and Zn differed among sites. Hg (xˉ ≥ 12.0 ng/L) and NH3-N (xˉ ≥ 0.985 mg/L) dissolved in water as well as B (xˉ ≥ 97.4 μg/g DW) and Hg (xˉ ≥ 0.461 μg/g DW) in drift from the Diagonal
Drain and S-Line Canal exceeded screening levels (SLs) for protection of aquatic biota throughout the irrigation season. Dissolved
As (xˉ ≥ 0.0426 mg/L) in water from the Diagonal Drain during all periods exceeded the SL for protection of aquatic biota.
Dissolved B (xˉ = 1.03 mg/L) in water from the Diagonal Drain during the early period exceeded the SL for protection of aquatic
biota.
Received: 18 September 1997/Accepted: 5 February 1998 相似文献
110.
To identify the predictive factors for testicular sperm extraction (TESE)
and to understand the pathology associated with TESE, we carried out a
prospective study in 40 consecutive men with azoospermia due to primary
gonadal failure. The main outcome measure was the retrieval of at least one
testicular spermatozoon. Endocrine and biophysical profiles, testicular
histology, Johnsen score and testicular spermatids were used as predictors
of sperm extraction. Spermatogenesis was quantified with the Johnsen score.
A variable pattern of spermatogenesis was common, being present in 20 (50%)
patients. Visualisation of testicular spermatids on testicular histology
showed a strong association with TESE (P < 0.0001). Statistically
significant differences were detected in plasma follicle stimulating
hormone (FSH) and testicular volume between patients who had
hypospermatogenesis and Sertoli cell-only or maturation arrest. There were
no significant differences in Johnsen score, biophysical and endocrine
profiles between the groups with successful and failed TESE. However, a
statistically significant trend occurred with changes in histological
pattern [chi2 for trend, P = 0.001; Pearson's coefficient (r) = 0.6],
Johnsen score (P = 0.022; r = 0.5), testicular volume (P = 0.01; r = 0.5)
and plasma FSH concentrations (P = 0.044; r = 0.4), albeit to a limited
degree. Difference in the interpretation of histological patterns with
different assessors was observed. The type of occupation or risk factors
for azoospermia showed no association with testicular pathology or TESE.
Variable histological patterns in different tubules in the same individual
may explain the poor correlation of TESE with endocrine and biophysical
profiles, Johnsen score and histological pattern. Differences in the amount
of tissue used for TESE and histopathology, and misinterpretation of
testicular histology rather than failure to quantify spermatogenesis may
explain the poor correlation between histological patterns and TESE.
Testicular spermatids predicted TESE. However, considerable overlap in
values means that no single variable can provide a perfect discrimination
between the groups with successful and failed TESE.
相似文献