Simultaneous pancreas-kidney transplantation (SPK) ameliorates the progression of microvascular diabetic complications but the procedure is associated with excess initial morbidity and an uncertain ...effect on patient survival when compared with solitary cadaveric or living donor renal transplantation. We evaluated mortality risks associated with SPK, solitary renal transplantation, and dialysis treatment in a national cohort of type 1 diabetics with end-stage nephropathy.
A total of 13,467 adult-type 1 diabetics enrolled on the renal and renal-pancreas transplant waiting list between 10/01/88 and 06/30/97 were followed until 06/30/98. Time-dependent mortality risks and life expectancy were calculated according to the treatment received subsequent to wait-list registration: SPK; cadaveric kidney only (CAD); living donor kidney only (LKD) transplantation; and dialysis wait-listed, maintenance dialysis treatment (WLD).
Adjusted 10-year patient survival was 67% for SPK vs. 65% for LKD recipients (P=0.19) and 46% for CAD recipients (P<0.001). The excess initial mortality normally associated with renal transplantation and the risk of early infectious death was 2-fold higher in SPK recipients. The time to achieve equal proportion of survivors as the WLD patients was 170, 95, and 72 days for SPK, CAD, and LKD recipients, respectively (P<0.001). However, the adjusted 5-year morality risk (RR) using WLD as the reference and the expected remaining life years were 0.40, 0.45, and 0.75 and 23.4, 20.9, and 12.6 years for SPK, LKD, and CAD, respectively. There was no survival benefit in SPK recipients > or =50 years old (RR=1.38, P=0.81).
Among patients with type 1 DM with end-stage nephropathy, SPK transplantation before the age of 50 years was associated with long-term improvement in survival compared to solitary cadaveric renal transplantation or dialysis.
Concentrations of polybrominated diphenyl ethers (PBDEs), pesticides, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons were measured in 136 fish from 14 remote lakes in 8 ...western U.S. National Parks/Preserves between 2003 and 2005 and compared to human and wildlife contaminant health thresholds. A sensitive (median detection limit, −18 pg/g wet weight), efficient (61% recovery at 8 ng/g), reproducible (4.1% relative standard deviation (RSD)), and accurate (7% deviation from standard reference material (SRM)) analytical method was developed and validated for these analyses. Concentrations of PCBs, hexachlorobenzene, hexachlorocyclohexanes, DDTs, and chlordanes in western U.S. fish were comparable to or lower than mountain fish recently collected from Europe, Canada, and Asia. Dieldrin and PBDE concentrations were higher than recent measurements in mountain fish and Pacific Ocean salmon. Concentrations of most contaminants in western U.S. fish were 1–6 orders of magnitude below calculated recreational fishing contaminant health thresholds. However, lake average contaminant concentrations in fish exceeded subsistence fishing cancer thresholds in 8 of 14 lakes and wildlife contaminant health thresholds for piscivorous birds in 1of 14 lakes. These results indicate that atmospherically deposited organic contaminants can accumulate in high elevation fish, reaching concentrations relevant to human and wildlife health.
The Link Between Nutritional Status and Insulin Sensitivity Is Dependent on the Adipocyte-Specific Peroxisome Proliferator–Activated
Receptor-γ2 Isoform
Gema Medina-Gomez 1 ,
Sam Virtue 1 ,
...Christopher Lelliott 1 ,
Romina Boiani 2 ,
Mark Campbell 1 ,
Constantinos Christodoulides 1 ,
Christophe Perrin 3 ,
Mercedes Jimenez-Linan 1 ,
Margaret Blount 1 ,
John Dixon 4 ,
Dirk Zahn 4 ,
Rosemary R. Thresher 4 ,
Sam Aparicio 4 ,
Mark Carlton 4 ,
William H. Colledge 1 ,
Mikko I. Kettunen 5 ,
Tuulikki Seppänen-Laakso 6 ,
Jaswinder K. Sethi 1 ,
Stephen O’Rahilly 1 ,
Kevin Brindle 5 ,
Saverio Cinti 2 ,
Matej Orešič 6 ,
Remy Burcelin 3 and
Antonio Vidal-Puig 1
1 Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital,
Cambridge, U.K.
2 Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy
3 Centre National de la Recherche Scientifique-UMR 5018, Paul Sabatier University, Toulouse, France
4 Paradigm Therapeutics, Cambridge, U.K.
5 Department of Biochemistry, University of Cambridge, Cambridge, U.K.
6 VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland
Address correspondence and reprint requests to Antonio Vidal-Puig, Department of Clinical Biochemistry, University of Cambridge/Addenbrooke’s
Hospital, Hills Road, Cambridge CB2 2QR, U.K. E-mail: ajv22{at}cam.ac.uk
Abstract
The nuclear receptor peroxisome proliferator–activated receptor-γ (PPARγ) is critically required for adipogenesis. PPARγ exists
as two isoforms, γ1 and γ2. PPARγ2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues,
where it is regulated more by nutritional state than PPARγ1. To elucidate the relevance of the PPARγ2 in vivo, we generated
a mouse model in which the PPARγ2 isoform was specifically disrupted. Despite similar weight, body composition, food intake,
energy expenditure, and adipose tissue morphology, male mice lacking the γ2 isoform were more insulin resistant than wild-type
animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARγ2 is not
the result of lipodystrophy and suggests a specific role for PPARγ2 in maintaining insulin sensitivity independently of its
effects on adipogenesis. Furthermore, PPARγ2 knockout mice fed a high-fat diet did not become more insulin resistant than
those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARγ2 is
required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARγ2 may be
necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.
BAT, brown adipose tissue
GTT, glucose tolerance test
HFD, high-fat diet
ITT, insulin tolerance test
IRS1, insulin receptor substrate 1
LC/MS, liquid chromatography/mass spectrometry
MRI, magnetic resonance imaging
PPARγ, peroxisome proliferator–activated receptor-γ
RPA, ribonuclease protection assay
SREBP1c, sterol regulatory element–binding protein 1c
WAT, white adipose tissue
Footnotes
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 21, 2005.
Received November 22, 2004.
DIABETES
We hypothesized that a strategy that reduced aortic manipulation would reduce the incidence of cognitive deficits in patients undergoing coronary artery bypass grafting compared with the ...“traditional” approach and that neurobehavioral outcomes with the reduced aortic manipulation strategy would approach those obtained with off-pump coronary artery bypass surgery.
Consenting high-risk patients (those with older age, diabetes, or hypertension) scheduled for coronary artery bypass grafting and cardiopulmonary bypass were randomly assigned to 1 of 2 aortic management protocols: (1) a traditional approach in which distal anastomoses were accomplished while the aorta was crossclamped but in which proximal anastomoses were sewn while a partial occlusion clamp was applied to the aorta (multiple aortic clamping group) or (2) a reduced aortic manipulation approach in which the aorta was clamped a single time with a reduced-pressure clamp (single aortic clamping group) and the partial occlusion clamp was not used. A contemporaneous group of patients undergoing off-pump coronary artery bypass surgery without cardiopulmonary bypass was also enrolled. Subjects in all 3 groups underwent neurologic and neuropsychological testing before and after surgery. After randomization, patients assigned to either approach could be changed to another strategy if the attending surgeon determined that patient safety demanded this change. The study design anticipated that surgical techniques would evolve over the course of patient enrollment and anticipated that some patients would have intraoperative echocardiographic findings that would demand that the traditional approach (eg, severe aortic atherosclerosis) or the reduced manipulation protocol (eg, severe ischemia or poor left ventricular function) be abandoned. Thus, an unequal distribution of patients was expected. By surgeon decision, 20 of 84 multiple aortic clamping patients crossed over to single aortic clamping, and 3 of 85 single aortic clamping patients switched to multiple aortic clamping. Eligible patients had a battery of neuropsychological tests before surgery and at 6 months after surgery. A 20% decrement in 2 or more tests was defined as a neuropsychological deficit.
MAC
OPCAB
SAC
Hospital mortality
3/67
(4%)
1/68
(1%)
0/102
(0%)
Hospital stroke
3/67
(4%)
1/68
(1%)
3/102
(3%)
Tested patients NPD 3-5 d
25/42
(60%)
33/47
(70%)
44/74
(60%)
Tested patients NPD 3-6 wk
25/49
(51%)
20/51
(40%)
27/85
(32%)
Tested patients NPD 6 mo
24/42
(57%)
13/41
(32%
⁎
)
22/74
(30%
⁎
)
MAC, Multiple aortic clamping;
OPCAB, off-pump coronary artery bypass;
SAC, single aortic clamping;
NPD, neuropsychological deficit.
⁎
P < .05 vs MAC.
A surgical strategy designed to minimize aortic manipulation can significantly reduce the incidence of cognitive deficits in coronary artery bypass grafting patients compared with traditional techniques. In this series, the results of the reduced aortic manipulation strategy were not significantly different from those in patients having off-pump coronary artery bypass surgery, thus emphasizing surgical technique as the primary cause of brain damage in coronary artery bypass grafting patients.
Global Positioning System (GPS) results from networks spanning the Eastern California shear zone and adjacent Sierra Nevada block, occupied annually between 1993 and 1998, constrain plate margin ...kinematics. We use an elastic block model to relate GPS station velocities to long‐term fault slip rate estimates. The model accounts for elastic strain accumulation on the San Andreas fault, as well as faults of the Eastern California shear zone. South of the Garlock fault, 14 mm/yr of dextral shear is distributed across the Eastern California shear zone. Some of this slip penetrates eastward into the Basin and Range, and a collective budget of 13 mm/yr is observed to the north at the latitude of Owens Lake. Model slip rates for two important faults, the Garlock and Owens Valley faults, significantly misfit geologic estimates. By referencing station velocities to stable North America we observe northward‐increasing deformation east of our regional GPS network. At the latitude of Mojave Desert, however, some of this deformation is ascribed to elastic strain accumulation due to a locked San Andreas fault and thus does not represent additional fault‐related, permanent deformation.
Objective: Acute hypogonadotropic hypogonadism (AHH) occurs frequently after TBI, as does chronic hypogonadotropic hypogonadism. However, AHH and persistent hypogonadotropic hypogonadism (PHH) after ...TBI are not well studied. The objective of this study was to characterize longitudinal hormone profiles and the impact of AHH and PHH on outcome.
Methods: In this prospective cohort study, men with severe TBI (n = 38) had serum gonadal and gonadotropic hormones measured during weeks 1-52 post-injury. AHH, PHH and/or early resolving hypogonadotropic hypogonadism (ERHH) were based on temporal hormone assessments. PHH and hormone profiles were then compared to multiple outcome measures 6-12 months post-TBI.
Results: AHH affected 100% of the population, while 37% subsequently developed PHH. Acute testosterone (TEST) and estradiol/testosterone (E2/TEST) ratios were associated with PHH and outcome. Over time, post-acute TEST and E2 levels for the ERHH group approached normal range, while levels for the PHH group remained low. Post-acute gonadotrophin levels were within the normal range for both groups. PHH, along with lower post-acute TEST and E2 profiles, was associated with worse functional and cognitive outcomes at 6 and 12 months post-injury.
Conclusions: These results support screening for post-acute secondary hypogonadism and further research to assess the mechanisms underlying PHH and associated functional and cognitive deficits.
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