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Improved Insulin Sensitivity and Resistance to Weight
Gain in Mice Null for the Ahsg Gene
Suresh T. Mathews,1,2Gurmant P. Singh,1Mollie Ranalletta,3Vivian J. Cintron,2Xiaoling Qiang,2
Anton Scott Goustin,2Kai-Lin Catherine Jen,4Maureen J. Charron,3Willi Jahnen-Dechent,5and
George Grunberger1,2
Fetuin inhibits insulin-induced insulin receptor (IR)
autophosphorylation and tyrosine kinase activity in
vitro, in intact cells, and in vivo. The fetuin gene
(AHSG) is located on human chromosome 3q27, re-
cently identified as a susceptibility locus for type 2
diabetes and the metabolic syndrome. Here, we explore
insulin signaling, glucose homeostasis, and the effect of
a high-fat diet on weight gain, body fat composition, and
glucose disposal in mice carrying two null alleles for the
gene encoding fetuin, Ahsg (B6, 129-Ahsgtm1Mbl). Fetuin
knockout (KO) mice demonstrate increased basal and
insulin-stimulated phosphorylation of IR and the down-
stream signaling molecules mitogen-activated protein
kinase (MAPK) and Akt in liver and skeletal muscle.
Glucose and insulin tolerance tests in fetuin KO mice
indicate significantly enhanced glucose clearance and
insulin sensitivity. Fetuin KO mice subjected to eugly-
cemic-hyperinsulinemic clamp show augmented sensi-
infusion rate (P ? 0.077) and significantly increased
skeletal muscle glycogen content (P < 0.05). When fed a
high-fat diet, fetuin KO mice are resistant to weight
gain, demonstrate significantly decreased body fat, and
remain insulin sensitive. These data suggest that fetuin
may play a significant role in regulating postprandial
glucose disposal, insulin sensitivity, weight gain, and fat
accumulation and may be a novel therapeutic target in
the treatment of type 2 diabetes, obesity, and other
insulin-resistant conditions. Diabetes 51:2450–2458,
consumption of a high-fat diet (2). Insulin resistance is
central to the pathophysiology of obesity and type 2
diabetes (3). Several physiological modulators of insulin
receptor (IR) function involved in the pathogenesis of
insulin resistance have been described, namely tumor
necrosis factor-?, PC-1 (plasma cell 1), Rad, protein ty-
rosine phosphatases, and ?2-HS-glycoprotein (?2-HSG)/
fetuin (4–8).
Human ?2-HSG/fetuin is a natural inhibitor of the insu-
lin-stimulated IR tyrosine kinase (TK) (8–13). Phosphor-
ylation status of ?2-HSG and rat fetuin is of critical
importance for TK inhibition (9,14). Nearly 20% of the
circulating ?2-HSG pool is phosphorylated on Ser-120 and
Ser-312 to ?1 mole phosphate per mole protein (15).
?2-HSG inhibits IRTK by reducing the Vmaxof the insulin-
stimulated IRTK reaction and increasing the half-saturat-
ing substrate concentration (S0.5) for ATP and the
exogenous substrate poly(Glu80Tyr20) (16). ?2-HSG pref-
erentially interacts with the activated IR and does not
require the proximal 576 amino acids of the IR ?-subunit
for its IR autophosphorylation/TK inhibitory activity (17).
Acute injection of human recombinant ?2-HSG inhibits
insulin-stimulated tyrosine phosphorylation of IR ?-sub-
unit and insulin receptor substrate (IRS)-1 in rat liver and
skeletal muscle (17). In a rat model of diet-induced obe-
sity, a significant increase in fetuin gene expression has
been observed (18). Evidence of IRTK inhibitory function
of human ?2-HSG and bovine, mouse, sheep, and pig fetuin
suggests a conserved function for fetuin homologs
(8,16,19,20). The human AHSG gene resides on chromo-
some 3q27, which recently has been mapped as a type 2
diabetes susceptibility locus (21). Kissebah et al. (22) have
demonstrated a quantitative trait locus on chromosome
3q27 strongly linked to the metabolic syndrome. Mice with
a targeted deletion of the fetuin gene (Ahsg) are fertile and
demonstrate no gross anatomical abnormalities except for
the presence of ectopic microcalcifications in a minority of
retired female breeders (23). In humans, no complete
?2-HSG deficiency has been found in extensive population
studies and clinical investigations (24).
To clarify the role of fetuin in insulin action, we ex-
plored glucose homeostasis in mice carrying two null
orldwide prevalence data indicate that type 2
diabetes has reached epidemic proportions
(1). Parallel to the rise in type 2 diabetes is a
rapid expansion of obesity, associated with
From the1Department of Internal Medicine, Wayne State University School of
Medicine, Detroit, Michigan; the2Center for Molecular Medicine and Genetics,
Wayne State University School of Medicine, Detroit, Michigan; the3Depart-
ment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York;
the4Nutrition and Food Science Department, Wayne State University, Detroit,
Michigan; and
Address correspondence and reprint requests to George Grunberger, Center
for Molecular Medicine and Genetics, Wayne State University School of
Medicine, University Health Center, 4H, 4201 St. Antoine Blvd., Detroit, MI
48201. E-mail: firstname.lastname@example.com.
Received for publication 22 February 2002 and accepted in revised form 3
May 2002.
2-DOG, 2-deoxyglucose; ?2-HSG, ?2-HS-glycoprotein; AIN, American Insti-
tute of Nutrition; BMR, basal metabolic rate; ERK2, extracellular signal–
regulated kinase 2; FFA, free fatty acid; GIR, glucose infusion rate; GTT,
glucose tolerance test; HF, high-fat; HOMA, homeostasis model assessment;
IR, insulin receptor; IRS, insulin receptor substrate; ITT, insulin tolerance test;
KO, knockout; LF, low-fat; MAPK, mitogen-activated protein kinase; PPAR-?,
peroxisome proliferator–activated receptor-?; PTP1B, protein tyrosine phos-
phatase 1B; S0.5, half-saturating substrate concentration; TG, triglyceride; TK,
tyrosine kinase; WGA, wheat germ agglutinin; WT, wild type.
5IZKF BIOMAT, Klinikum der RWTH Aachen, Aachen, Ger-
Page 2
alleles for Ahsg. Because fetuin inhibits insulin-induced IR
autophosphorylation and TK activity, it is hypothesized
that genetic ablation of fetuin results in enhanced insulin
signal transduction and increased whole-body insulin sen-
sitivity. Further, the consequence of this genetic manipu-
lation is examined in a model of acquired insulin
resistance, high-fat feeding.
Animals. Homozygous Ahsg knockout (Ahsg–/–) mice (23) from a mixed
background were backcrossed four generations into C57Bl/6J. Offspring (Ahsg
knockout [KO] and wild-type [WT] littermates [Ahsg?/?]) from the fourth
generation of the breeding protocol were used for this study. Mice were
housed on a 12-h light/dark cycle and fed a standard rodent food. All protocols
for animal use and euthanasia were reviewed and approved by the Animal
Investigation Committee of Wayne State University in accordance with
National Institutes of Health guidelines. For in vivo studies, animals were
anesthetized with ketamine (80 mg/kg) and xylazine (5 mg/kg) intraperitone-
ally (i.p.), and insulin (0.1, 1, and 10 ?mol/l) was injected through the portal
vein. Saline-injected animals served as controls. Liver and hindlimb muscles
were excised 1 and 3 min later, respectively, as described earlier (25).
Surgical procedures. Mice were anesthetized with an injection of pentobar-
bital (65 mg/g body wt i.p.), and an indwelling catheter was implanted as
described earlier (26). During a 2-day observation period, mice exhibiting
signs of illness were excluded from the study (two animals).
High-fat feeding. Mice (n ? 43) were housed four to five per hanging cage
with food and water available ad libitum. Within each genotype (KO and WT),
they were divided into high-fat (HF) and low-fat (LF) groups. The LF diet was
based on the American Institute of Nutrition (AIN)-93 mol/l formula (27) with
4% fat in the form of soybean oil. The HF diet was a modification of the AIN-93
mol/l formula with added soybean oil so that the final fat content was 40% by
weight. Carbohydrate, protein, and fat contents as a percentage of caloric
content were 75.9%, 14.1%, and 10% for LF and 26.17%, 15.06%, and 58.77% for
HF (Dyets, Bethlehem, PA). WT and KO mice were fed HF or LF diets for a
period of 9 weeks. Food intake and body weight were measured once a week.
For body composition analysis, internal organs were dissected and all visible
internal fat was removed and weighed. The remaining carcass was frozen for
carcass analysis (28). The carcass fat, designated subcutaneous fat, was
extracted by the method of Folch et al. (29). Total body fat was calculated as
the sum of subcutaneous fat and internal fat.
Partial purification of IR autophosphorylation and TK activity. IRs were
partially purified on wheat germ agglutinin (WGA)-agarose columns and
eluted with 0.3 mol/l N-acetylglucosamine. IR autophosphorylation of the
partially purified IR, in the presence or absence of insulin, was carried out by
the addition of [?-32P]ATP to a reaction mixture containing 5 mmol/l MnCl2, 50
?mol/l ATP, 50 mmol/l HEPES, pH 7.6, and 0.1% Triton X-100, and the proteins
were then separated on 7.5% SDS-PAGE. IRTK activity was assayed by
quantitation of phosphorylation on exogenous substrate, poly(Glu80Tyr20)
Metabolic studies. For glucose tolerance tests (GTTs), an oral (1 mg/g) or
i.p. (1.5 mg/g) glucose load was given after a 16-h fast to 10-week old male or
female WT and fetuin KO mice. Blood samples were taken at 0, 15, 30, 60, and
120 min from the tail vein. Glucose levels were measured with a Glucometer
Elite monitor (Bayer, Elkhart, IN). For insulin tolerance tests (ITTs), random-
fed female mice, all 10 weeks of age, were given an i.p. injection of 0.75 or 0.15
U/kg regular human insulin (Novo Nordisk, Clayton, NC) between 2:00 and
5:00 P.M. Blood samples were obtained at various time points from the tail
vein, and glucose levels were measured as described above. Insulin levels
were measured in plasma using rat insulin standards (Linco Research, St.
Charles, MO). To assess lipid levels, blood samples were obtained by
retro-orbital bleeds from overnight-fasted anesthetized mice. Fasting triglyc-
eride (TG) levels were measured in plasma by a colorimetric assay (Sigma),
and fasting free fatty acid (FFA) concentrations were determined using the
NEFA C kit (Wako Chemicals, Richmond, VA). Fasting levels of leptin were
assayed with a mouse leptin radioimmunoassay kit (Linco Research).
Euglycemic-hyperinsulinemic clamp. Clamp studies were carried out on
five male KO mice (3–4 months old) and five age- and sex-matched WT mice
(26,30). Food was removed 5–6 h before infusion. A bolus of [3-3H]glucose (50
?Ci) was administered at the start of each clamp over 1 min. For the
remainder of the clamp, [3-3H]glucose was infused at 12 ?Ci ? kg–1? min–1. A
continuous infusion of porcine insulin (Eli Lilly, Indianapolis, IN) was
administered at 100 mU ? kg–1? min–1. Plasma glucose was clamped at 90–110
mg/dl by infusing a 20% glucose solution. Glycemia was assessed on blood
obtained from the tail vein using a One Touch II Meter (LifeScan, Milpita, CA).
Steady-state glucose levels were achieved after ?80 min, at which point 10 ?l
blood was collected every 10 min for 40 min. The animals were then given a
bolus (24 ?Ci) of [14C]-labeled 2-deoxyglucose (2-DOG), which was flash-
injected through the catheter, and 10 ?l blood was collected at 2, 4, 6, 8, 10,
20, 30, and 40 min. At the end of the 40-min period, the animals were killed.
Tissues (brown and white adipose, heart, diaphragm, soleus, extensor digito-
rum longus, gastrocnemius, and skin) were rapidly removed and snap-frozen
in liquid nitrogen for further analysis. Whole-body glucose utilization and
tissue 2-DOG uptake were calculated as previously described (26,30). Muscle
glycogen content was determined by the amyloglucosidase method (31).
Antibodies. Antibodies against IR ?-subunit, phosphotyrosine proteins
(4G10), and extracellular signal–regulated kinase 2 (ERK2) were purchased
from Upstate Biotechnology (Lake Placid, NY). p44/42 mitogen-activated
protein kinase (MAPK) assay kit, phospho-p44/42 MAPK antibody, and
phospho-Akt antibody were purchased from New England Biolabs (Beverly,
Immunoprecipitations and immunoblotting. Liver and muscle tissues
were excised and homogenized in ice-cold buffer A (50 mmol/l HEPES, pH 7.4,
25 mmol/l NaPPi, 100 mmol/l NaF, 10 mmol/l EDTA, 10 mmol/l Na3VO4, 2
mmol/l phenylmethylsulfonyl fluoride, 1% Triton X-100, and 10 ?g/ml aprotinin
and leupeptin). Immunoprecipitations were carried out overnight at 4°C with
required antibodies followed by addition of protein A and G sepharose beads
(Oncogene, Cambridge, MA) for another hour at 4°C. Immunoprecipitated
proteins (IR ?-subunit, phosphorylated p44/42 MAPK) were washed, boiled in
SDS-sample buffer, separated on 7.5% SDS-PAGE, transferred to nitrocellulose
membrane (Schleicher and Schuell, Keene, NH), and developed using appro-
priate combinations of primary/secondary antibodies and chemilumines-
cence. Phosphorylation status of MAPK and Akt was assayed by Western
blotting using phospho-p44/42 MAPK antibody and phospho-Akt antibody,
respectively. Quantitation of ERK2, IR-? subunit, and Akt-1 were done to
normalize the phosphorylation data to protein loading. MAPK activity (phos-
phorylation of Elk-1) was assayed using a kit with two phospho-specific
antibodies (New England Biolabs).
Statistical Analysis. Data are presented as means ? SE. Statistical analyses
(Student's t test or ANOVA) were performed using GraphPad Instat (San
Diego, CA). Differences were considered significant if P ? 0.05. Quantitation
of data from Western blots and autoradiographs were done using UN-SCAN-IT
Gel Digitizing System (Silk Scientific, Orem, UT).
Increased IR autophosphorylation and tyrosine ki-
nase activity. Because ?2-HSG/fetuin inhibits insulin-
induced IR autophosphorylation and TK activity, we
examined the consequence of genetic ablation of fetuin on
basal and insulin-induced IR autophosphorylation status in
vitro (partially purified IR) and in vivo (liver and skeletal
muscle). IR purified from livers of fetuin KO mice showed
an approximate fourfold increase in basal IR autophos-
phorylation in vitro, compared with IR from livers of WT
mice (Fig. 1A, upper panel). Insulin (1 nmol/l) induced a
?2-fold increase in IR ?-subunit phosphorylation in KO
mice (14.26 ? 1.55-fold stimulation over WT basal [arbi-
trary scan units]) (Fig. 1A, lower panel) compared with
WT mice (8.56 ? 1.38 arbitrary scan units). Insulin-
induced IR autophosphorylation was similar at higher
insulin concentrations (10 or 100 nmol/l) in WT and KO
mice. Western blotting with an antibody against IR ?-sub-
unit confirmed equal amounts of IR loading in both WT
and KO lanes (Fig. 1A, lower panel). TK activity was
assayed in vitro in WGA-purified IR from KO and WT mice.
Basal TK activity was significantly increased (P ? 0.001) in
IR from KO mice (Fig. 1B), analogous to results of
receptor autophosphorylation. Next, autophosphorylation
of IR ?-subunit in liver and skeletal muscle, after in vivo
exposure to insulin (portal vein injection of 0.1, 1, or 10
?mol/l insulin), was assayed in age-, weight-, and sex-
matched WT and KO mice. Saline-injected mice served as
controls. Figure 1 shows representative blots of IR auto-
phosphorylation in liver (C, upper panel) and skeletal
Page 3
FIG. 1. IR autophosphorylation and TK activity. In vitro IR autophosphorylation (A) and IRTK activity (B) were determined from IRs partially
purified from liver membrane fraction on WGA. A: A representative autoradiograph of in vitro IR ?-subunit autophosphorylation (PY) (basal or
in the presence of 1, 10, or 100 nmol/l insulin) (upper panel). Four separate experiments were performed, with IRs purified individually from
livers of weight-matched, 8- to 10-week-old male WT and KO mice; n ? 4 per genotype. Western blot of IR ?-subunit confirmed equal loading of
IR (lower panel), and the result of the combined data of four separate experiments is shown (bar diagram). To assess the status of in vivo basal
and insulin-induced IR autophosphorylation, saline or insulin (0.1, 1, or 10 ?mol/l) was injected through the portal vein of weight-matched, 8- to
10-week-old male WT and KO mice. IR was immunoprecipitated from liver (C) or muscle (D) homogenates with anti–IR ?-subunit antibody and
immunoblotted with anti-phosphotyrosine antibody. Samples were normalized for loading by assaying total level of IR ?-subunit. The quantified
data (ratio of IR autophosphorylation to total level of IR ?-subunit) are shown as bar diagrams (mean ? SE; n ? 4 mice per genotype). *P < 0.05,
**P < 0.01, ***P < 0.001, WT vs. KO.
Page 4
muscle (D, upper panel). IR phosphorylation data in liver
and muscle were normalized to IR ?-subunit levels (Fig.
1C, lower panel, and D, lower panel), and the combined
data from four separate experiments are shown as bar
diagrams. A 2-fold increase in basal IR autophosphoryla-
tion in liver (P ? 0.05) and a ?1.5-fold increase (P ? 0.05)
in basal IR phosphorylation in skeletal muscle were ob-
served in fetuin KO mice. A significant increase (P ? 0.05)
in insulin-induced (1 ?mol/l) IR phosphorylation was
observed in skeletal muscle of KO mice, and a similar
increasing trend in insulin-induced IR phosphorylation
was observed in livers from KO mice.
Increased MAPK and Akt phosphorylation. To confirm
that the increased phosphorylation of IR in liver and
muscle of fetuin KO mice is manifested in increased
downstream signaling, phosphorylation status of p44/42
MAPK and Akt were assayed after in vivo exposure to
insulin (portal vein injection of 0.1, 1, or 10 ?mol/l insulin)
or saline in age-, weight-, and sex-matched WT and KO
mice. All assays were done in four to five mice in each
group; Fig. 2 shows a representative blot for each protein.
In liver, phosphorylation of MAPK was assayed by
phospho-p44/42 MAPK antibody and its activity by detect-
ing MAPK-induced phosphorylation of Elk-1. In livers of
KO mice, basal phosphorylation of p44/42 MAP kinase was
significantly increased (phospho-MAPK/ERK2 ratio for
KO, 1.54 ? 0.11-fold stimulation over WT; P ? 0.05) (Fig.
2A). Injection of insulin through the portal vein induced a
significant increase in p44/42 MAPK phosphorylation com-
pared with WT mice for every dose of insulin tested
(phospho-MAPK/ERK2 ratio with 10 ?mol/l insulin for KO,
3.78 ? 0.24-fold stimulation over WT basal; for WT, 2.23 ?
0.24-fold; P ? 0.001) (Fig. 2A). Reprobing the membrane
with ERK2 antibody confirmed equal sample loading (Fig.
2A). MAPK activity assayed in liver homogenates (by
active MAPK phosphorylation of Elk-1) demonstrated in-
creased basal and insulin-stimulated phosphorylation of
phospho-Elk-1, in concurrence with p44/42 MAPK phos-
phorylation (data not shown). Similarly, both basal (phos-
pho-Akt/Akt1 ratio for KO, 1.45 ? 0.15-fold stimulation
over WT; P ? 0.05) and insulin-induced (phospho-Akt/Akt1
ratio with 10 ?mol/l insulin for KO, 2.2 ? 0.09-fold
stimulation over WT basal; for WT, 1.57 ? 0.09-fold; P ?
0.01) phosphorylation of Akt, measured by phospho-Akt
antibody, was significantly increased in liver homogenates
of fetuin KO mice compared with WT mice (Fig. 2A). Equal
loading was confirmed using an antibody against Akt-1
(Fig. 2A).
In skeletal muscle, all tested doses of insulin induced
greater amounts of p44/42 MAPK phosphorylation in fetuin
KO mice compared with WT mice (phospho-MAPK/ERK2
ratio with 10 ?mol/l insulin for KO, 5.73 ? 0.34-fold
stimulation over WT basal; for WT, 3.23 ? 0.29-fold; P ?
0.01) (Fig. 2B). Equal loading of all lanes was confirmed
using an antibody against ERK2 (Fig. 2B). Insulin-induced
phosphorylation of Akt, measured by phospho-Akt anti-
body, was also increased in muscle (phospho-Akt/Akt1
ratio with 10 ?mol/l insulin for KO, 3.00 ? 1.19-fold
stimulation over WT basal; for WT, 1.63 ? 0.12-fold; P ?
0.001) (Fig. 2B) of fetuin KO mice compared with WT
mice. Equal loading was confirmed by similar concentra-
tions of Akt-1 (Fig. 2B). Basal phosphorylation of both
MAPK (KO, 2.65 ? 0.38-fold stimulation over WT; P ?
0.01) and Akt (KO, 1.38 ? 0.04-fold stimulation over WT;
P ? 0.01) was increased in skeletal muscle of KO mice. A
representative blot from four to five separate experiments
for each protein is depicted in Fig. 2B.
Enhanced glucose clearance and increased insulin
sensitivity in fetuin KO mice. Because fetuin KO mice
demonstrated increased insulin signaling, we examined
glucose clearance rates using GTTs and ITTs in 8- to
10-week-old KO and WT mice. Fetuin KO mice cleared
postprandial glucose from the blood with an increased
efficiency over WT mice during oral GTTs (1 mg/g).
Differences between WT and KO blood glucose values
were statistically significant (P ? 0.01) at the 15-, 30-, and
60-min time points (Fig. 3A). This experiment was re-
peated twice using different sets and sexes of animals (n ?
6/group) with similar results (data not shown). Although
fetuin KO mice, on average, have significantly lower body
weights (P ? 0.005) than age- and sex-matched controls
(10-week-old female WT, 15.5 ? 1.2 g, n ? 14; 10-week-old
female KO, 12.2 ? 0.9 g, n ? 17; P ? 0.001) (Table 1), the
body weights for KO and WT mice undergoing the oral
GTT were not statistically different (WT, 17.54 ? 2.21 g;
FIG. 2. Insulin signal transduction. A: Liver homogenates from saline-
or insulin-injected (0.1, 1, or 10 ?mol/l) weight-matched, 8- to 10-week-
old male WT and KO mice were resolved on SDS-PAGE, transferred,
and detected by chemiluminescence with antibodies against phospho-
MAPK or phospho-Akt. Membranes were stripped and blotted for ERK2
and Akt1, respectively, to normalize for sample loading. A representa-
tive blot (from four to five separate experiments) for each protein is
depicted. B: Hindlimb muscle homogenates were resolved on SDS-
PAGE, transferred, and detected by chemiluminescence with antibod-
ies against phospho-MAPK or phospho-Akt. Membranes were stripped
and blotted for ERK2 and Akt1, respectively, to normalize for sample
loading. A representative blot (from four to five separate experiments)
for each protein is depicted.
Page 5
KO, 15.84 ? 1.51 g; P ? 0.06) since the body weights of
some WT and KO mice overlap. However, to exclude the
possibility of body weight affecting the outcome of the
test, oral GTTs were also done on age-, sex-, and weight-
matched mice (WT, 16.44 ? 0.09 g, n ? 5; KO, 16.40 ?
0.28 g, n ? 5) with similar results (Fig. 3B). Further, GTTs
FIG. 3. Glucose and insulin tolerance tests in KO and WT mice. After an overnight fast, an oral glucose load (1 mg/g) (A and B) or i.p. glucose load (1.5
mg/g) (C and D) was given to 10-week-old fetuin KO and WT mice. Insulin tolerance tests were done on fed (random) mice using an i.p. injection of
0.75 units/kg (E) or 0.15 units/kg (F) regular human insulin. Blood glucose (A, B, C, E, F) or plasma insulin (D) was measured as described in RESEARCH
DESIGN AND METHODS. Results shown are from either male or female mice, as similar findings were observed in both male and female mice. Data are
means ? SE. *P < 0.05, **P < 0.01, ***P < 0.001, WT vs. KO.
Body weight, blood glucose, and plasma measurements in 10-week-old KO and WT mice
Wild type Knockout
Body weight (g)
Fasting blood glucose (mg/dl)
Fed blood glucose (mg/dl)
Fasting insulin (ng/ml)
Fed insulin (ng/ml)
Fasting FFAs (mEq/l)
Fasting triglycerides (mg/dl)
Fasting leptin (ng/ml)
17.9 ? 0.8 (11)
79.8 ? 5.9 (9)
120.2 ? 6.4 (11)
0.177 ? 0.01 (11)
0.213 ? 0.02 (7)
0.827 ? 0.06 (11)
59.52 ? 1.71 (12)
1.33 ? 0.07 (12)
13.9 ? 0.9 (10)
98.3 ? 7.7 (10)
107.0 ? 10.0 (10)
0.191 ? 0.01 (10)
0.187 ? 0.02 (8)
0.599 ? .03 (11)
42.31 ? 4.33 (11)
1.63 ? 0.46 (12)
Data are means ? SE (number of animals). Body weight, glucose, and insulin were measured in male mice; FFAs, triglycerides, and leptin
were measured in female mice.
Page 6
were also done with i.p. injections of glucose (1.5 mg/g;
mean WT body weight, 22.26 g; KO, 22.77 g) to exclude the
possibility of defective gastrointestinal absorption or ab-
sorption-related mechanisms. As in oral GTTs, diverging
curves were obtained for the i.p. GTTs, with KO mice
displaying significantly enhanced glucose disposal com-
pared with WT mice (P ? 0.05 for 15 min; P ? 0.01 for 30
and 60 min) (Fig. 3C). Plasma insulin concentrations after
an i.p. (Fig. 3D) or oral (data not shown) glucose load
demonstrated identical responses in KO and WT mice. To
confirm enhanced insulin sensitivity, ITTs were done on 8-
to 10-week-old male WT and KO animals fed ad libitum.
Using a single i.p. injection of regular human insulin
(Novolin) (0.75 units/kg), no differences were observed in
the clearance of glucose from the blood of WT and KO
mice (Fig. 3E). However, when a lower dose of insulin was
injected (0.15 units/kg), there was a ?45% drop in blood
glucose in KO mice at 30 min, versus ?30% in WT (P ?
0.05) (Fig. 3F).
Fasting or fed (random) blood glucose or plasma insulin
levels were not altered in male (Table 1) or female (data
not shown) KO mice. Fetuin KO mice demonstrate signif-
icantly lower levels of plasma FFAs and TG (P ? 0.001)
under fasting conditions than WT mice (Table 1). Fasting
levels of plasma leptin are not significantly altered in
fetuin KO mice compared with WT mice (Table 1). Levels
of FFAs, TG, and leptin were assayed only in females due
to blood sample limitations.
Increased whole-body glucose utilization and 2-DOG
uptake. Euglycemic (100 mg/dl) clamps were performed
on male fetuin KO mice and age-, sex-, and weight-
matched WT controls to assess glucose utilization under
hyperinsulinemic (100 mU ? kg–1? min–1) conditions.
Glucose infusion rates (GIRs) in fetuin KO mice were
higher (113.8 ? 6.4 mg ? kg–1? min–1) than those in WT
control mice (94.4 ? 7.1 mg ? kg–1? min–1) (P ? 0.077) (Fig.
4A). No differences in plasma insulin and plasma glucose
were detected between KO and WT mice (data not
shown). During the last 40 min of the euglycemic clamp, a
bolus of [14C]2-DOG was administered to determine glu-
cose uptake rates in individual tissues. Although no signif-
icant differences were identified between fetuin KO and
control mice in the tissues sampled, an increasing trend in
2-DOG uptake was observed in gastrocnemius muscle
(P ? 0.154) and soleus and white adipose tissue (P ?
0.168) of KO mice (Fig. 4B).
To assess the fate of glucose under insulin action,
glycogen content was measured in heart, hindlimb, and
liver at the end of the hyperinsulinemic clamp study.
Hindlimb glycogen content was ?1.9-fold greater in fetuin
KO mice (Fig. 4C), which is consistent with the increase in
2-DOG uptake. No significant differences between groups
were measured in heart and liver glycogen content.
Obesity resistance in fetuin-null mice. HF feeding
induces body weight gain and obesity (32,33) and is
associated with insulin resistance (34,35). Fetuin KO and
WT female mice were fed a HF diet (58.77% of calories
from fat) for a period of 9 weeks. At the end of the 9-week
period, WT mice on HF diet had significantly higher body
weight (P ? 0.005) than WT mice on a LF diet (Table 2).
Remarkably, KO mice (at 9 weeks) remained lean, with
body weights comparable to those of WT mice on a LF
diet. In WT mice, the HF diet produced a 15.83% increase
in body weight. Fetuin KO mice were substantially pro-
tected from diet-induced weight gain, with an average
increase in body weight of only 8.44%. The total caloric
intake (over 9 weeks) by WT and KO mice was not
different (WTHF, 6,045 ? 180 kcal; KOHF, 5,652 ? 499
kcal). The weight-to-length ratio was significantly higher in
WTHF mice (P ? 0.01) than in KOHF mice. Total fat
weight was significantly higher in WTHF mice than in
FIG. 4. Euglycemic-hyperinsulinemic clamp studies in conscious KO
and WT mice. Glucose infusion rate (A) and 2-DOG uptake in white
adipose tissue, soleus, and gastrocnemius muscles (B) were deter-
mined using the euglycemic-hyperinsulinemic clamp technique in
fasted 12- to 16-week-old male mice. Tissue glycogen content (C) was
assayed at the end of the euglycemic-hyperinsulinemic clamp. Results
are means ? SE for five animals per genotype. *P < 0.05, WT vs. KO.
Page 7
KOHF mice (P ? 0.01). Similar results were obtained when
expressed as percentage total fat (ratio of total fat weight
to body weight), with KOHF mice showing significantly
lower percentages (P ? 0.01) of total fat than WTHF mice.
The effect of HF diet on insulin levels and insulin
sensitivity was assessed in fetuin KO and WT mice. WTHF
mice showed significantly higher fasting insulin levels
(P ? 0.05) than KOHF mice (Table 2). Fasting blood
glucose concentrations did not differ in the four groups of
mice. In response to an i.p. glucose load (1.5 mg/g), no
impairment in glucose tolerance was observed in any of
the four groups (data not shown). Although the secretory
response of insulin was not altered, insulin levels at time
zero and at 30 and 60 min after the GTT were significantly
higher in WTHF than in KOHF mice (Fig. 5A). According to
homeostasis model assessment (HOMA) of insulin sensi-
tivity (fasting glucose [mmol/l] multiplied by fasting insu-
lin[?U/ml]divided by
demonstrated HOMA scores similar to those of WTLF
mice, indicating that KOHF mice retained their insulin
sensitivity (Fig. 5B), whereas WTHF mice showed signifi-
cantly higher HOMA scores (P ? 0.05), reflecting insulin
22.5) (36), KOHFmice
Decreased action of insulin in peripheral tissues is a
central feature of several common pathological states,
including type 2 diabetes, obesity, hypertension, and glu-
cocorticoid excess (3,37). Improving insulin sensitivity
offers a promising approach to the prevention, interven-
tion, and treatment of these pathological conditions. Sev-
eral animal models demonstrate a potential to increase
insulin sensitivity, namely Pik3r1–/–, PPAR-??/–(peroxi-
some proliferator–activated receptor-? heterozygous),
PTP1B Ex1–/–(protein tyrosine phosphatase 1B knock-
out), and transgenic Ucp-L mice (38–42). Fetuin has
irstatin (IR inhibitory) activity and interacts with the
activated IR (9,17,43). In this study, we used mice that
carry two null alleles for the Ahsg gene to examine the
hypothesis that deficiency of fetuin leads to increased IR
autophosphorylation and downstream insulin signaling,
thereby improving whole-body insulin sensitivity.
Fetuin KO mice exhibit increased insulin sensitivity, as
evidenced by augmented phosphorylation of IR, TK activity,
rates. The observed increase in basal IR phosphorylation (no
added insulin) and TK activity and moderate increases in
insulin-stimulated IR autophosphorylation in KO mice vali-
date the irstatin role of fetuin. The increased insulin-stimu-
lated signaling of downstream molecules (MAPK and Akt) in
KO mice also implicates increased IR activation. The discrep-
ancy of decreased IR phosphorylation at the highest insulin
concentrations (10 ?mol/l) may be due to IR downregulation
after in vivo insulin exposure or dose-/time-dependent ef-
fects. It may be noted that the observed dose-dependent
variations are similar in WT and KO mice.
The observed changes in insulin responsiveness, rang-
ing from mild to moderate, may be due to the altered lipid
metabolism or phosphorylation status of IR and other
downstream signaling molecules. Fetuin KO mice demon-
strate decreased body weight and resistance to diet-
induced obesity. This may be due to decreased fat stores
resulting from altered lipid metabolism or increased en-
ergy expenditure. Interestingly, other mouse models of
increased insulin sensitivity, such as PTP1B knockout
mice, PPAR? heterozygous mice, and mice that lack the
Klotho gene, also show significant reduction in size (39–
41,44). On the contrary, mice that are selectively insulin
resistant in muscle have an obese phenotype (45).
Oral and intraperitoneal GTTs and ITTs demonstrated
increased glucose clearance and improved insulin sensi-
tivity in fetuin KO mice; however, fasting glucose levels
were not significantly altered. Improved insulin sensitivity
has been shown to be associated with decreased fasting
insulin levels and decreased insulin secretion in response
to a glucose challenge (38,46,47). However, fetuin KO mice
did not show any difference in fasting or fed insulin levels.
In response to a glucose load, insulin levels were not
significant different. Fetuin KO mice demonstrated im-
proved insulin sensitivity, as assessed by ITT (0.15 units/
kg). This improved sensitivity of fetuin KO mice at low
insulin concentrations may be metabolically meaningful
considering the fact that basal IR phosphorylation is
elevated in KO mice.
Under euglycemic-hyperinsulinemic clamp conditions,
whole-body glucose disposal was increased in KO mice,
almost reaching statistical significance (P ? 0.077, n ? 5).
Alhough 2-DOG uptake into muscle of KO mice only
Body weight parameters, blood glucose, plasma insulin in WT and KO mice fed LF or HF diets
Genotype Diet
Body weight (g)
Weight/length (g/cm)
Liver weight (g)
Total fat weight (g)
Total fat (%)
Food intake (kcal)
Fasting glucose
Fasting insulin (ng/ml)
11 111110
28.1 ? 0.9a
2.85 ? 0.09a
1.07 ? 0.04
5.8 ? 2.1a
20.1 ? 0.6a
6,045 ? 180a
24.3 ? 0.9b
2.55 ? 0.07b
1.1 ? 0.04
3.4 ? 1.9b
13.5 ? 0.6b
3,505 ? 36b
24.4 ? 1.0b
2.5 ? 0.1b
1.00 ? 0.04
3.7 ? 2.1b
14.4 ? 0.6b
5,652 ? 499a
22.5 ? 0.9b
2.39 ? 0.08b
1.07 ? 0.03
2.62 ? 1.1b
11.4 ? 0.4b
3,713 ? 229b
93.64 ? 7.1
0.36 ? 0.03a(n?8)
83.64 ? 7.2
0.32 ? 0.01 (n?9)
84.91 ? 3.9
0.28 ? 0.01b(n?9)
80.8 ? 4.8
0.30 ? 0.01 (n?8)
Data are means ? SE. Fetuin KO and WT mice (females, 10 weeks old) were fed HF or LF diets ad libitum for 9 weeks and were monitored
weekly for food intake. End-of-study body weight parameters and total caloric intake are shown. Values were dissimilar superscript letters
(aorb) are significantly different from each other based on genotype or diet.
Page 8
showed a trend toward increased insulin effect compared
with WT mice, the glycogen content of hindlimb muscles
was increased significantly in the KO mice after the
hyperinsulinemic clamp study, indicating an increased
shunting of infused glucose to glycogen in skeletal muscle
(liver or heart glycogen content was not altered in KO
mice compared with WT mice). These data support the
increased glucose clearance rates observed during oral
and intraperitoneal GTT. It is possible that the increased
skeletal muscle glycogen content may be due to alter-
ations in GLUT4 expression/membrane localization or
modifications in glycogen metabolism.
Because an improved insulin sensitivity and lowered
plasma lipid content was observed in fetuin KO mice, it
was hypothesized that a high-fat diet would lead to less
insulin resistance and body weight gain in KO mice
compared with WT mice. KOHF mice had significantly
lower body weights compared with WTHF mice, and total
body fat content was significantly lower in KOHF mice.
Further, KO mice maintained insulin sensitivity even after
9 weeks of HF feeding, unlike WTHF mice, which became
hyperinsulinemic and less insulin sensitive, as evidenced
by HOMA scores. Because KO mice lack fetuin, IR auto-
phosphorylation can proceed more effectively, thus pre-
sumably maintaining normal glucose metabolism in spite
of HF feeding. Whether the resistance to weight gain is
related to the improved insulin sensitivity per se, in-
creased basal metabolic rate (BMR), or other non–BMR-
related energy expenditures is yet to be understood.
A second member of the fetuin family, fetuin-B, was
identified recently (48). Whether fetuin-B shares irstatin
activity with fetuin-A and whether such fetuin redundancy
could protect against the deleterious effects of gene dele-
tion is not known. Interestingly, mice deficient in PTP1B
demonstrate a phenotype similar to that of fetuin KO mice,
namely increased insulin sensitivity and IR phosphoryla-
tion, decreased adiposity, and resistance to weight gain
(40,41). This was not unexpected, since both fetuin and
PTP1B decrease IR phosphorylation.
In summary, this study provides the first direct evidence
that fetuin plays a critical role in clearance/uptake of
glucose from blood and in modulating insulin sensitivity.
Although the exact mechanism for fetuin's role in regulat-
ing insulin sensitivity is not understood, it may be medi-
ated by modulation of phosphorylation status of IR and
subsequent downstream signaling and by the alteration of
lipid metabolism. Furthermore, these studies identify fe-
tuin as a novel therapeutic target in the treatment of type
2 diabetes, obesity, and other insulin-resistant conditions.
This work was supported by the National Institutes of
Health (DK44382 awarded to G.G., DK47425 and HL58119
awarded to M.J.C., GM08167 awarded to K.-L.C.J., and F31
DK0952 awarded to V.J.C.), by the Wayne State University
Morris J. Hood Jr. Comprehensive Diabetes Center (re-
search fellowship grant awarded to S.T.M.), and by Deut-
sche Forschungsgemeinschaft (Ja562/5 awarded to W.J.-
D.). M.J.C. is a recipient of an Irma T. Hirschl career
scientist award.
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text:
Mandriva 2011 Out 156
from the fond-memories-of-mandrake dept.
We've improved Slashdot's video section; now you can view our video interviews, product close-ups and site visits with all the usual Slashdot options to comment, share, etc. No more walled garden! It's a work in progress -- we hope you'll check it out (Learn more about the recent updates).
...it was in fact a useful distro, it was compatible with most computers on the planet, all kinds of exotic hardware, I absolutely loved it.
But then it became Mandriva (aka Mandrivel...), economical support issues, fleeing contributors, and the support for obsolete hardware was coming apart until the distro became completely useless, first to fail was basic SoundCard support, even the soundblaster series...that worked fine under the Mandrake distro name...failed on several basic issues...such as...SOUND! -_-
One of the most wonderful things about Mandrake was that you could almost get 3D out-of-the-box, an Nvidia installer was just a click away *kind of like ubuntu today, but Mandrivel...? Things that worked before...broke, again because of the competent contributors fleeing (something about certain benevolent leaders...)
Ubuntu is going the same ways these days with UNITY, more splitting than unity if you ask me...everything is about tablets & touch screen, everyone wants to be modern...but what is modern? Have we forgotten all about functionality?
Administration: An ingenious abstraction in politics, designed to receive the kicks and cuffs due to the premier or president. -- Ambrose Bierce

subset: commoncrawl


text:
(503): View more from Oregon
Also CANADIAN LIPS TASTE OF MAPLE SYRUP AND APOLOGIES. SORRY.
Tap Here to view the Mobile Optimized TFLN
Also CANADIAN LIPS TASTE OF MAPLE SYRUP AND APOLOGIES. SORRY.
A stripper just invited me to her daughter's birthday. Where did my life go wrong?
I swear to god he's making pineapple onions and cheese. He thinks he's making eggs onions and cheese
And now you understand the importance of Saturday naps.
She just asked what would happen if you put a vacuum in your butt and turned it on. These are our conversations.
Doing bumps while the kids play upstairs. #bestnannyever
If we don't have crazy animal sex tonight at least twice, I'll know he's cheating on me.
I walked home with him, but I had to pee...so I did...as we walked. He was so drunk he didn't even notice. Good thing I was in a dress.
I'm tryin a pb and onion sandwich now
Did I mention I hooked up with another country star? I think I need some sort of trophy for each time, yah know? Or like a sash and I win a badge or patch for each person. Like a slutty Girl Scout.
i think i just asked a donut if it was ok
i was so high i thought the horse on my poster was running
i just tried to use a string cheese as a light source
Do I lose at life if I cry in a grocery store while buying a pregnancy test?
You know what's awkward? Being with your girlfriend and seeing her ex-boyfriend that she left for you while you've got a Ron Burgundy level awkward boner.


text:
are also receiving benefits already under SSI and/or SSDI, you are automatically eligible ..... account. If you are not a recipient of SSI and/or SSDI, but still meet the age of ..... eligible to open an ABLE account if you meet SSI criteria regarding significant functional
needs-based programs like Medicaid or SSI . And without this type of structure, if ..... amount will disqualify that person from SSI . They can requalify once the value drops ..... 100,000 and not be disqualified from SSI . You have a payback provision if you were
insurance company. Or if they raise the age at which a retiree can start receiving Medicare (like they did for my age bracket for SSI ), how would a senior get medical insurance for the years post-65 until Medicare begins? (I am pessimistically assuming
sister's trust account. She is 67 years old, disabled and not capable of earning any income (no pension, only a very meager SSI benefit). She has approx $110K in the trust account and this is all she will ever have so I am trying to set her account up
slowly getting on top of my finances. I still have a lot to learn, but will keep working on it, I promise. About me: I took SSI at 62, just before much of the literature seemed say, "Don't Do That!" It covers most of my monthly fixed expenses. I
payments for goods and services, reimbursements for food stamps, payments to those on public assistance programs such as TANF or SSI , payments for the big social insurance programs as Social Security OASI and disability, reimbursements to Medicare providers
The new [ really old ] CEO at JCP has resumed strong promotional activity and that may hurt other retailers [ SHLD, KSS, SSI , BON; TGT, GPS, TJX, ROST ]. http://online.barrons.com/article/SB50001424052748704895304578495232918053410
potentially lucrative escape option. Compare the SSI Convertible Income Strategy , a portfolio of converts assembled by SSI Investment Management, with key equity and ..... underlying shares. That's reflected by the SSI portfolio's low (0.44) correlation
provides Supplemental Security Income ( SSI ) to people who are 65 or older, or who are ..... assets." For 2010, the monthly federal SSI benefit is $674 for an individual, which ..... requirements may still be disqualified from SSI benefits because of the income earned by
increased 18.2% from the prior year, driven by premium increases in Georgia, membership growth (especially among high-premium SSI beneficiaries), and a shift from nonrisk to risk-based plans in South Carolina. Overall membership was up 6.7% from the


text:
In his recent Business Jet Traveler interview with Elite Aviation owner Chris Holifield, journalist Matt Thurber noted that "you don't see a lot of women-owned aviation businesses." Bizav, he said, is "a boys' club." It sure is, and so is the rest of the aviation world.
Commentary » Notes from the Editor
September 13, 2012
July 31, 2012
These days, everybody complains about the airlines–rotten food, TSA hassles, cramped seating, long delays, lost luggage. And while private jet travelers are a decidedly happier lot, they've been known to offer the occasional gripe as well–the charter flight lacked sufficient baggage space, the catering service overcharged, the FBO disappointed.
June 27, 2012
Recently, my wife and I attended a college-planning event at our son's high school. It doesn't seem all that long ago that Andre was 5 and we were taking notes at an orientation session for parents of new kindergarteners, but here we are. He's 17 now and, with a little luck and a lot of our money, he'll be heading off to college next year.
May 30, 2012
My relationship with rock and roll—which began when I was in grade school and watching American Bandstand in the 1950s—deepened in the next decade as the music and I hit our teenage years. I started collecting records, attending lots of concerts and eventually writing about popular music for magazines and newspapers.
May 2, 2012
Naturally, the editors of Business Jet Traveler hope that you'll find every article we publish to be tailor-made for your needs. But of course that's impossible: last time I checked, we had 35,633 subscribers and–beyond the fact that they presumably share an interest in business aviation–they're all different.
April 5, 2012
EDITOR'S NOTE: This blog concerns a survey that has now been completed and closed. Results will appear in the October/November 2012 issue of Business Jet Traveler.
March 6, 2012
Washington, D.C.–President Obama missed a major fundraising event yesterday due to cancellation of his JetBlue flight. The President had arrived on time at Washington National Airport in a Hertz rental car–a subcompact, according to his press secretary–and had been whisked through security.
February 6, 2012
Every now and then, I go through the voicemails on my office phone and delete the ones I no longer need. I usually end up trashing all of them–with the exception of two that I've held onto for years.
January 9, 2012
In my last blog post, I covered five of the most memorable moments from interviews I've conducted over the years for Business Jet Traveler. Here are another five. Just click on the names to read the full articles on Pascucci, Trump and Orman.
December 1, 2011
"We like to keep a low profile for our jet use." I can't tell you how many times I've heard variations on that line since I arrived at Business Jet Traveler in 2004. It has been a constant challenge to find business jet owners and passengers willing to be profiled in our pages and companies that will go on the record about their use of private aviation.
"I have an obligation to get you to your destination. You have an obligation to pay. What else is there? We don't need 24 pages of legalese."
-VistaJet founder and chairman Thomas Flohr, on the company's unusually brief, easy-to-understand contracts
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Hearts of Chaos
Lady Lucia draws on her untapped powers to defeat an evil force that threatens the world, a move that makes her betrothed--a feared shifter clan leader--uncomfortable, but also stirs in him a hunger for her.
Publisher: New York : Kensington Publishing Corp., 2014.
Characteristics: 343 pages ;,17 cm.
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text: For center Mike Ribeiro, the potency of Washington's league-leading power play is all about options. He and fellow center Nicklas Backstrom can pass to captain Alex Ovechkin for a devastating one timer near one of the faceoff circles. They can feed the puck to wing Troy Brouwer in front of the net. Or they swing it to defenseman Mike Green for a powerful slap shot from the point.


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text: Most film critics look down their noses at publicists, sizing them up the way sprinters size up hurdles. But maybe they could use some. Critics don't have anyone handling their PR, and as a consequence, their public image isn't so great. In a piece for the School Library Journal's C...Read More »


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MEDICAL FOUNDATION for the Care of Victims of Torture METHODOLOGY EMPLOYED IN THE PREPARATION OF MEDICO-LEGAL REPORTS ON BEHALF OF THE MEDICAL FOUNDATION Remit of the Medical Foundation The Medical Foundation, a registered charity in the human rights field, works exclusively with survivors of torture and organised violence, both adults and children. It has received some 43,000 referrals since it began in 1985. The Foundation exists to enable survivors of torture1 and organised violence2 to engage in a healing process to assert their own human dignity and worth. Our concern for the health and wellbeing of torture survivors and their families is directed towards providing medical and social care, practical assistance, and psychological and physical therapy. It trains health professionals and others to work with torture survivors, educates the public about torture, campaigns against torture and works to improve the legal framework regarding the treatment of asylum seekers and refugees. Testimony Taking It has been observed that in numerous instances that thoughtful, careful testimony taking and examination has a major therapeutic effect on victims of torture. For many it is the first time that they find the words to describe their ordeals. Putting unspeakable torture into words is an important step in rehabilitation. It was this observation among others that inspired the creation and development of the Medical Foundation for the Care of Victims of Torture in 1985. In some therapies the torture story is transformed into a testimony, to transform the survivor"s story of shame and humiliation into a public story about dignity and courage, returning meaning to life. It has been noted in a recent desk study review of the literature around Politically motivated torture and its survivors3 that "Although retelling the trauma story for reframing and reworking has been a central tenet in 1 The United Nations (UN), in the Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment (CAT) in 1984, adopted the following definition: "For the purpose of this Convention, the term "torture" means any act by which severe pain or suffering, whether physical or mental, is intentionally inflicted on a person for such purpose as obtaining from him or a third person information or a confession, punishing him for an act he or a third person has committed, or is suspected of having committed, or intimidating or coercing him or a third person, or for any reason based on discrimination of any kind, when such pain or suffering is inflicted by, or at the instigation of, or with the consent or acquiescence of, a public official or other person acting in an official capacity. It does not include pain or suffering arising only from, inherent in, or incidental to lawful sanctions" (United Nations, 1984). In addition the Medical Foundation is mindful of the case of Ireland vs. UK 1971.which determined that determined that certain interrogation techniques amounted to maltreatment but not torture. These included requiring a posture on the wall, hooding, noise, deprivation of sleep, diet of bread and water. Such cases would nevertheless fall within the Medical Foundation"s remit. 2 A WHO working group in 1986 introduced the concept of organized violence, defined as: "The inter- human infliction of significant, avoidable pain and suffering by an organized group according to a declared or implied strategy and/or system of ideas and attitudes. It comprises any violent action that is unacceptable by general human standards, and relates to the victims" feelings. Organized violence includes "torture, cruel, inhuman or degrading treatment or punishment" as in Article 5 of the United Nations Universal Declaration of Human Rights (1948). Imprisonment without trial, mock executions, hostage- taking, or any other form of violent deprivation of liberty, also fall under the heading of organized violence" (WHO, 1986; Geuns, 1987). 3 Jose Quiroga, MD and James M. Jaranson, MD, MA, MPH Torture: the Journal on Rehabilitation of Torture Victims and Prevention of Torture, Volume 15, No 2-3, 2005. 2 treatment, recovering memories of the torture must be done in a safe setting, with the appropriate timing, and with acknowledgement of cultural variations in the expression and interpretation of these memories. If done within a therapeutic setting, this can lead to anxiety reduction and cognitive change." Methodology of Medical Foundation Reports We consider that our approach differs from those of other writers of medico-legal reports in the UK. Two of the most important differences are that MF reports are processed through a series of quality control measures and that we do not produce a report every time that we are asked for one. First, new referrals are discussed by a multi-disciplinary panel of doctors, other clinicians and lawyers, at a meeting chaired by the Medical Foundation"s Legal Officer, at which all documents relevant to the case are studied before a decision is made as to whether to proceed to the next stage. Many cases are then referred for an assessment interview by a non-clinical caseworker, usually with legal training, to establish what (if anything) can be documented in a medico-legal report, for example to find whether scars are present, whether there are significant psychological sequelae and to establish a more detailed history of events if necessary. In this we are guided by the Manual on the Effective Investigation and Documentation of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment, the Istanbul Protocol, unanimously adopted by the UN General Assembly December 2000. Paragraph 160: "Witness and survivor testimony are necessary components in the documentation of torture. To the extent that physical evidence of torture exists, it provides important confirmatory evidence that a person was tortured. However, the absence of such physical evidence should not be construed to suggest that torture did not occur, since such acts of violence against persons frequently leave no marks or permanent scars." The multi-disciplinary panel will review the case again, as above, to decide whether a report might make a material difference to the case, and whether the case is within the remit of the Medical Foundation. That remit is broadly allied to the United Nations definition of torture and the WHO definition of organised violence, but it also takes account of the developing concept of collective violence. "The instrumental use of violence by people who identify themselves as members of a group – whether this group is transitory or has a more permanent identity – against another group or set of individuals, in order to achieve political, economical, or social objectives" (World Health Organisation, 2002). It should be noted, however, that this definition also covers a broad range of forms of violence including conflicts within and between countries, organised violent crime, and various forms of structural violence that may or may not be state perpetrated. Limitations upon the expertise and resources of the Medical Foundation generally exclude many forms of collective violence. Distinctions as to whether or not a report will be forthcoming may also be made between children and adults (the impact of violence upon children, whether actual or witnessed, may be different to that on an adult) and because of certain gender issues. An example of how our remit can apply differently according to gender might involve a case of sex trafficking where the victim found the police in her home country to be in collusion with those responsible for her situation. In these circumstances the 3 unwillingness or inability of the police to protect her would amount to a failure of state protection which would then potentially bring the case within our remit. Another example might be a victim of domestic violence where the perpetrator is a state agent and the victim found no opportunity for redress as he prevented her from seeking any official assistance. An example of a case not taken on might be one where torture has already been accepted in the first instance and refusal or the asylum claim now turns on other issues. In such cases, clearly, a medico-legal report would not make a material difference to the outcome of the case. Regrettably, given our limited resources, it has been our experience that "reasons for refusal letters" are very rarely sufficiently focused on the issues to say whether or not torture is accepted. Having decided that a case falls within the Medical Foundation"s remit, the panel will refer the case to an appropriate doctor. This doctor may be a generalist or a specialist, such as a paediatrician, gynaecologist or a psychiatrist. When appropriate the doctor will be assigned according to gender.4 The doctor makes the final decision on whether or not a report can be written, and may decline to write a report after seeing and assessing the patient for himself or herself. The majority of Medical Foundation doctors are volunteers, others are on salary. None are paid per report written. All Medical Foundation doctors are aware of the Civil Procedure Rule 35, which forms the basis of each of our doctors" declaration of his or her duty to the court. The doctor sees the subject of the report on a minimum of two occasions,5 more if needed. A full history and examination are undertaken and physical and psychological findings documented. Photographs or body diagrams of scars may be made if they would assist (e.g., where recent bruising might fade). Before taking the detailed history and conducting the examination, the doctor will familiarise herself with the papers provided to the Medical Foundation, (usually) by the subject"s legal representative. These papers guide our doctors as to the areas on which they should concentrate. However, it is important to note that the testimony of the subject given elsewhere does not form the basis for the doctor's history taking, which is always done independently. The whole of the subject"s testimony is assessed in the light of, among other things: health reported prior to and after torture, the history and detail given of the torture and the subject's affect and behaviour. Affect means the objective observation of their mood. Behaviour in this context means the manner of giving their account, the facial 4 Manual on the Effective Investigation and Documentation of Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment, the Istanbul Protocol, paragraph 153 "Ideally, an investigation team should contain specialists of both genders, permitting the person who says that they have been tortured to choose the gender of the investigator and, where necessary, the interpreter. This is particularly important when a woman has been detained in a situation where rape is known to happen, even if she has not, so far, complained of it." 5 We do not say 'patient' in this context because although every doctor must apply the professional rules of conduct as though the subject were his or her patient, the relationship is not the same as, for example, GP and patient. Nevertheless, the doctor-patient relationship should assert itself if, for example, there are health matters that ought properly to be notified, with consent, to the subject's GP. 4 expressions, body language and forms of speech as assessed by the doctor. There is no "normal" behaviour of a torture victim, but the doctor assesses their observations within her consideration of the person"s mental state in the overall context of the person"s speech content, culture of origin, family history, employment, levels of education, current state of health and apparent personality. For example, culture of origin and social background as well as severity of depressive illness can affect the level of eye contact made. During an assessment some cry a lot, some cry a little or not at all. It is not the number of tears shed but the total picture of the person gained during two different meetings that gives the doctor their impression of "behaviour". The specificity of the detail in an account, particularly sensory and geographical detail, as well as medical details of injuries received and the healing process of those injuries (e.g. how medically plausible is the account given of the healing process?) - all add to the often complex and detailed picture. It is our experience that, because doctors take their histories in ways quite different from lawyers or government officials, and because of the setting of a doctor's examination room compared to, say, the lawyer's busy offices or an interview room at the Home Office, a more detailed disclosure often results. Disclosure is sometimes significantly enhanced merely by the fact that the questions are put by a doctor, especially, we believe, if the doctor has had a level of specialist clinical training on interviewing survivors of torture and has gained experience from other such interviews of the immediate and long term impact of torture. Memory difficulties are explored in detail and with reference to established psychology research in this field.6 Further resources such as psychometric testing by a clinical psychologist are available if needed. An opinion is given on the examination in its entirety and not on isolated findings. It is not the role of the report writing doctor to assess credibility. However, doctors do not, even in their everyday practice, accept at face value everything they are told by their patients. For example, amounts of alcohol consumed, exercise taken or severity of pain reported - all these are carefully interpreted by a doctor in the light of their observations of the patient"s appearance, mobility and answers to questions exploring ability to function in everyday activities. During the examination Medical Foundation doctors critically assess the account given in relation to the injuries described and the examination findings, in the light of their own experience and the collective experience of colleagues at the Medical Foundation, and may decline to write a report if the account and findings do not correlate. Each report is read back to the subject to confirm details of the history have been accurately recorded. This process sometimes triggers further recall of details of the events as well as serving as a check that interpreter and doctor have understood the subject correctly. A senior doctor then reviews the report and a legal officer to check that all relevant aspects have been addressed appropriately before it is signed off. 6 Cohen J, Errors in Recall and Credibility: Can Omissions and Discrepancies in Successive Statements Reasonably Be Said to Undermine Credibility of Testimony? Medico-Legal Journal (2001) Vol. 69 Part 1, 25-34 and reprinted in International Journal of Refugee Law Vol .13 no3 2001 5 All Medical Foundation doctors understand and sign a declaration to the effect that the MLR is an expert witness report and that their duties to the court are those of an expert witness. Medical Foundation Doctors Medical Foundation doctors are mainly general practitioners, so their prior training and practice give them a valuable breadth of experience in all medical fields. Some have additional specialist qualifications and experience in fields such as paediatrics, dermatology, gynaecology and psychiatry. Victims of torture may have physical and psychological symptoms affecting many medical systems of the body, so a generalist approach is vital to their assessment. GPs are also trained and experienced in balancing the priorities of a patient"s requests, medical imperatives and finite health resources. Nowadays they act as the gatekeepers to the rest of medical care in the UK and, as such, are effectively neutral experts rather than advocates. This aspect of a doctor"s background and training are emphasised and enhanced during their induction and training with the Medical Foundation. The majority of modern GPs have extensive experience in psychiatry both as a result of some time spent during GP training working in psychiatry departments and as GPs, where over 60% of consultations have a psychological component and 80% of psychiatric patients are managed by GPs.7 GPs have to decide who is referred for counselling and who needs specialist psychiatric care. GPs initiate treatment with anti-depressants and assess patients for suicide risk to determine the need for acute admission. GPs see the full range of patients, including those not coping well with everyday life, the acutely bereaved, victims of assault and rape and those with major psychiatric diagnoses. They manage drug addicts and schizophrenics on a daily basis. Over the past 20 years the Medical Foundation has reached the conclusion that this experience can make a GP extremely well qualified to assess psychological symptoms in the context of a medico- legal report. New doctors to the Medical Foundation undergo further, more specialised training in the clinical conditions of asylum seekers and refugees generally and the more technical aspects of the documentation of scars and medico-legal report writing, with special reference to the Istanbul Protocol8 and our own in-house publications and library. Our doctors are also taught the specialist skills required in working with interpreters. It should be pointed out that the majority of interpreters we use are also trained in-house 7 "Primary care services, including social care services, carry the main responsibility for mental health care and treatment in the community. The majority of people with so-called "common disorders" and a significant number of people with severe and enduring mental illness are currently managed only in primary care. The National Institute for Clinical Excellence quotes a figure of 25% in their recently published guideline for people with schizophrenia receiving all or most of their care from the GP." Para 2.13. Fast-Forwarding Primary Care. Mental Health Graduate Primary Care Mental Health Workers Best Practice Guidance National Institute for Mental Health in England. Department of Health 2003. "Individuals with short term severe mental illness, such as severe depression, anxiety or panic disorder, generally respond well to treatment with drugs and psychological therapies, which can be provided in primary care (Standard two) with support from specialised services." National Service Framework for Mental Health, NHS launched in 1999. 8 Ibid., Istanbul Protocol 6 and are expected to bring a high level of skill and dedication to the demands of working with traumatised torture survivors. New doctors are supervised initially by experienced doctors, and all Medical Foundation doctors have an annual appraisal and attend one-day specialist academic meetings twice yearly as well as monthly lunchtime clinical meetings. All Medical Foundation doctors are actively encouraged to consult their colleagues on particular cases and more generally to share their thoughts and experiences with colleagues. Thus, whilst each report is the product of a specially trained doctor, it is also prepared on the basis of the Medical Foundation"s collective experience and expertise over more than 20 years of writing medico-legal reports for the courts. Professional and Expert Reports There has been considerable discussion of the relative weight that should be attached to "professional" and "expert" reports.9 Essentially an expert report is that of an impartial, experienced practitioner who sees the subject only for the purpose of preparing a report. In Medical Foundation cases, this is usually two appointments but may be more if the complexity of the case requires. A professional report is that provided by a clinician treating the patient. In Medical Foundation cases this is likely to be based on a number of treatment sessions over a prolonged period, as required by psychological therapies. We are aware that both types of report have been criticised; expert reports for being based on too short, and therefore on an apparently incomplete acquaintance with the subject, and the professional report for being based on too long, and therefore on a biased and subjective knowledge of the person who has now become the clinician"s patient. At the Medical Foundation we acknowledge both these points and the time constraints inherent upon all parties, including those preparing reports, in a system trying to make asylum decisions within a reasonable time frame. The majority of Medical Foundation reports are expert reports, and our doctors are trained to make as full an assessment as possible in the time available. In fact doctors" training tends to make them well able to assess critical points within the time available: "Does this patient need urgent transfer to hospital?" "Will they commit suicide before I can get them an appointment to see a psychiatrist?" This has become known as "see and treat" and has developed to a science within Accident and Emergency procedures10 Where a patient has already been in treatment for some time, or where it becomes apparent that a full picture of the impact of the trauma on them can emerge only during therapy, a professional report is preferred, as it will provide far better information for the court. In preparing professional reports a clinician is still aware of his or her duties to the court. Increasingly, the Medical Foundation may also produce an "interim" expert report setting out briefly what it is anticipated may emerge through a longer, therapeutic relationship. This accords with the New Asylum Model philosophy of seeking the best 9 AE FE (PTSD-Internal Relocation) Sri Lanka [2002] UKIAT 05237, HE (DRC – credibility and psychiatric reports) DRC CG [2004] UKIAT 00321 10 Guide to "see and treat" principles can be found at http://www.modern.nhs.uk/esc/8237/See%20&Treat.pdf 7 evidence available at the earliest opportunity. It may be that an interim report will be sufficient to allow the first instance decision maker or immigration judge to reach a decision. If not, then the interests of justice may be served by waiting for a further report.11 The Medical Foundation considers that it would be clinically inappropriate (to say the least) to create a culture of dependent patients, hanging onto therapy in the hope that the longer they spend in our care the greater their chance of asylum. However, some of those referred to us when first seen are simply too unwell, physically or mentally, for our doctors to complete their report in two sessions or so. In such cases an interim expert report or an expert report with recommendations that additional reports be obtained from treating professionals may be issued. In the latter case the interim report will generally specify the specialist area(s) of concern, such as neurology, clinical psychology, psychiatry, psychotherapy or counselling. Dr Juliet Cohen David Rhys Jones Head of Medical Services Refugee Policy Officer 2 June 2006 11 See the AIT Review Report April 2006. 6.30 "… we have heard arguments that the whole 6-week period is too short. For example the IAS told us that the four-week listing period for asylum cases was not conducive to the interests of justice in all cases. They added that some cases can be adequately prepared in such a timescale but many cannot. The timescale makes the commissioning of medical reports or country evidence almost impossible, for example. 6.31 We understand this concern and it will be important to keep this period under review. But the fact is that if there is a need for more time it remains open to the IJ to allow it. The 6-week timescale is provided for in the rules agreed by Parliament." 8 About the authors: Dr Juliet Cohen Dr Juliet Cohen is Head of Medical Services at the Medical Foundation and a GP, who qualified from the University of London in 1986. She has worked part time at the Medical Foundation since 1997. She has worked as a GP since 1990. Training included time spent working in general medicine, general surgery, A & E, neurology, geriatrics, paediatrics, obstetrics, gynaecology and genito-urinary medicine. Dr Cohen has worked overseas in Hong Kong for the British Red Cross at a Vietnamese detention centre and in Sydney for the Royal Australian Navy. In Sydney she also worked at a sexual assault referral centre, making forensic medical assessments of rape victims. Since 2001 Dr Cohen has worked as a GP with Specialist Interest to set up a mental health support service in Oxford for asylum seekers and refugees, bridging the gap between primary and secondary care. She has worked with the PCT on the referral pathway for mental health care in this group and has conducted seminars and training sessions for primary care staff in the Oxfordshire area. She has devised a computer template for primary care use to prompt better health care for asylum seekers and refugees. Research interests include sleep disorder, post traumatic stress disorder, late disclosure, capacity and suicide and self-harm in asylum seekers. Dr Cohen is responsible for the co-ordination and training of over 50 medical practitioners in the Medical Foundation"s London headquarters together with approximately 15 doctors in each of the Foundation"s Manchester and Glasgow offices. The overwhelming majority of Medical Foundation doctors are volunteers devoting between a day a week and a day a quarter of their time to the documentation of torture. She also organises the twice-yearly study days, in-house training and regular doctors' meetings at the Medical Foundation. In 2004-5 Dr Cohen has spoken at the Triennial World Police Medical Officers' Conference (assessing victims of torture), the Oxford Medico-Legal Society (credibility issues), the Asylum Support Adjudicators' meeting, (assessment and credibility) and at Imperial College Medical Ethics Course (physicians and human rights' abuses). Relevant Publications Errors of Recall and Credibility-can omissions and discrepancies in successive statements reasonably be said to undermine credibility of testimony? Medico-Legal Journal 2000 Vol. 69 (1), and reprinted in International Journal of Refugee Law 2001 David Rhys Jones David Rhys Jones has worked in the refugee field for over 20 years. First as counsellor in the Refugee Unit of UKIAS from 1986-1989 and then spending five years working with UNHCR in Hong Kong and Thailand on a number of legal projects concerning the determination of asylum claims for Vietnamese boat people. On returning to the UK in 1994 he joined the RLC where he became a manager of the advice and representations team. In 1996 he joined Glazer Delmar Solicitors. During this time David was also the 9 volunteer Legal Officer for the Association of Visitors to Immigration Detainees (AVID). David became AVID's first coordinator/Development Worker in February 2001. David was briefly a trustee of IAS in 2001; a post from which he resigned to work as a locum Legal Officer with Bail for Immigration Detainees (BID) for six months during which time he was a regular trainer with IAS on the subject of detention. He started work at the Medical Foundation for the Care of Victims of Torture in January 2002 and is now the Foundation"s Refugee Policy Officer. David is also a member of the Management Committee to the Jesuit Refugee Service (JRS) in the UK whose purpose is to accompany, to serve and to advocate on behalf of all asylum seekers from their first arrival until they are satisfactorily settled. David is a member of the steering committee and chairs the Advocacy Working Group of the Network of European Treatment and Rehabilitation Centres for Victims of Torture and Human Rights Violations. David co-trains Medical Foundation volunteer doctors on the legal aspects of medico- legal report writing and works with colleagues from torture/trauma centres elsewhere in Europe on related issues. Relevant Publications Medical Evidence in Asylum and Human Rights Appeals. International Journal of Refugee Law, Vol 3, No. 3, 381-410 published in 2004. (Co-author with Sally Verity Smith.) 10
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God Was Good To Judah
Judah's story is long, twisted and bizarre, so I will spare you the biblical references here and invite you to join me on a narrative. If you would like to read it (and I encourage you to), you will have to read it from Genesis–much of it.
Rough Start
Judah began life as something of a beduin and ended it as a guest of honor in Egypt, In between he had something of a troubled life. Born to a father who […]


text: TOP 10 Top 10 Fitness Top 10 Ways To Burn More Calories Back to Top ▲ Top 10 Ways To Burn More Calories 5 Get Down And Do 20 Share on Facebook Share on Twitter 0 Shares Thinkstock Performing short bursts of body-weight exercises whenever you have a free second is another great way to up your total daily calorie burn and strengthen your muscles. Every so often, get down and do 20 push-ups, bodyweight squats, crunches or, if you have a bar available, pull-ups. You'll also energize yourself in the process. Next Page TOP 10 9 8 7 6 5 4 3 2 1 Comments Show Comments More Like This Top 10 Dating Here Is The Definitive Guide To Flirting In 10 Simple Steps Read More Top 10 Dating 10 Signs That Dude, You're Seriously Spending Too Much Time On Facebook Read More Top 10 Better Man Take A Few Minutes To Watch The Ten Greatest Movie Fight Scenes Ever - You Won't Regret It Read More Top 10 Fitness Ten Things To Eat After You Hit The Gym Read More Top 10 Entertainment Avoid These 10 Horror Movies With Your Girl If You Ever Want To Get Close Again Read More Top 10 Dating 10 Surprisingly Effective Places To Meet Beautiful Women That You Might Have Overlooked Read More Promoted Around the Web Special Features Special Feature From Dating To Fitness, Over 75 Ways Men Are Winning 2015 Read More AskMen Exclusive Want To Win $1,000 To Stock Your Home Bar? Read More Special Feature 50 Ways To Look Better Than You Do Now. Smooth Up, Man. Read More


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Branch problems ...
Hello everyone! My first plumeria is looking really sad. The leaves and branches are all sagging a lot. It's in a large plastic planter and is outside in full sun. The branches are very top heavy and one hangs completely down (the middle thin branch). Any ideas what I can do? Trim it? Also, I just planted some succulents in the planter and I noticed that the roots are very near the surface, barely covered by soil. Is this normal? Thanks!!
Could be the tree isn't getting enough water; that would make the stems limber. Or it could be that's it's a naturally floppy variety like Aztec Gold.
You can always use green gardener's tape and tie the three branches together at a couple points or to a strong stake. I have a three-tip that was growing too wide so I just tied it in two spots and after the wood hardens the shape will stay in place.
I have one like that right now. I will be trimming it this spring when it is dormant. Trimming should help branching UNLESS it is a floppy one like Jen says, I.e. Aztec Gold.
I will be posting the same question, with a little twist. I can't tell from your picture, but my one plant with long branches, I notice that the branches have gotten thicker on the newer growth. I am curious if tis is because of my fertilizer. We will see what everyone thinks. Good luck. Jennifer


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NCAA BASKETBALL: MAR 13 SEC Tournament – Auburn v LSU
March 13, 2015 Auburn Tigers guard Antoine Mason (14) hangs on the rim after the slam dunk during the 2015 SEC Men's Basketball Tournament game between LSU and Auburn. Auburn upsets LSU 73-70 in OT at the Bridgestone Arena in Nashville, TN.
AuburnLSU20142015 basketball seasonAuburn UniversityBridgestone ArenaCollege basketballCollege sportsDivision 1 Men's BasketballMen's ChampionshipMen's College BasketballMusic CityNCAA Basketball TournamentNCAA Men's Basketball Tournament 2015NashvilleSECSoutheastern ConferenceTNTigersVictorycollege super fansdefeatfansFrank Mattia, from