bluuebunny/crossref_metadata_2025 huggingface dataset:
An AIF orthologue regulates apoptosis in yeast
Authors: Wissing Silke , Ludovico Paula , Herker Eva , Büttner Sabrina , Engelhardt Silvia M. , Decker Thorsten , Link Alexander , Proksch Astrid , Rodrigues Fernando , Corte-Real Manuela , Fröhlich Kai-Uwe , Manns Joachim , Candé Céline , Sigrist Stephan J. , Kroemer Guido , Madeo Frank
Published: September 2004

Apoptosis-inducing factor (AIF), a key regulator of cell death, is essential for normal mammalian development and participates in pathological apoptosis. The proapoptotic nature of AIF and its mode of action are controversial. Here, we show that the yeast AIF homologue Ynr074cp controls yeast apoptosis. Similar to mammalian AIF, Ynr074cp is located in mitochondria and translocates to the nucleus of yeast cells in response to apoptotic stimuli. Purified Ynr074cp degrades yeast nuclei and plasmid DNA. YNR074C disruption rescues yeast cells from oxygen stress and delays age-induced apoptosis. Conversely, overexpression of Ynr074cp strongly stimulates apoptotic cell death induced by hydrogen peroxide and this effect is attenuated by disruption of cyclophilin A or the yeast caspase YCA1. We conclude that Ynr074cp is a cell death effector in yeast and rename it AIF-1 (Aif1p, gene AIF1).
βIVΣ1 spectrin stabilizes the nodes of Ranvier and axon initial segments
Authors: Lacas-Gervais Sandra , Guo Jun , Strenzke Nicola , Scarfone Eric , Kolpe Melanie , Jahkel Monika , De Camilli Pietro , Moser Tobias , Rasband Matthew N. , Solimena Michele
Published: September 2004

Saltatory electric conduction requires clustered voltage-gated sodium channels (VGSCs) at axon initial segments (AIS) and nodes of Ranvier (NR). A dense membrane undercoat is present at these sites, which is thought to be key for the focal accumulation of channels. Here, we prove that βIVΣ1 spectrin, the only βIV spectrin with an actin-binding domain, is an essential component of this coat. Specifically, βIVΣ1 coexists with βIVΣ6 at both AIS and NR, being the predominant spectrin at AIS. Removal of βIVΣ1 alone causes the disappearance of the nodal coat, an increased diameter of the NR, and the presence of dilations filled with organelles. Moreover, in myelinated cochlear afferent fibers, VGSC and ankyrin G clusters appear fragmented. These ultrastructural changes can explain the motor and auditory neuropathies present in βIVΣ1 −/− mice and point to the βIVΣ1 spectrin isoform as a master-stabilizing factor of AIS/NR membranes.
The SH3–SAM Adaptor HACS1 is Up-regulated in B Cell Activation Signaling Cascades
Authors: Zhu Yuan Xiao , Benn Sally , Li Zhi Hua , Wei Ellen , Masih-Khan Esther , Trieu Young , Bali Meenakshi , McGlade C. Jane , Claudio Jaime O. , Stewart A. Keith
Published: September 2004

HACS1 is a Src homology 3 and sterile alpha motif domain–containing adaptor that is preferentially expressed in normal hematopoietic tissues and malignancies including myeloid leukemia, lymphoma, and myeloma. Microarray data showed HACS1 expression is up-regulated in activated human B cells treated with interleukin (IL)-4, CD40L, and anti–immunoglobulin (Ig)M and clustered with genes involved in signaling, including TNF receptor–associated protein 1, signaling lymphocytic activation molecule, IL-6, and DEC205. Immunoblot analysis demonstrated that HACS1 is up-regulated by IL-4, IL-13, anti-IgM, and anti-CD40 in human peripheral blood B cells. In murine spleen B cells, Hacs1 can also be up-regulated by lipopolysaccharide but not IL-13. Induction of Hacs1 by IL-4 is dependent on Stat6 signaling and can also be impaired by inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and nuclear factor κB. HACS1 associates with tyrosine-phosphorylated proteins after B cell activation and binds in vitro to the inhibitory molecule paired Ig-like receptor B. Overexpression of HACS1 in murine spleen B cells resulted in a down-regulation of the activation marker CD23 and enhancement of CD138 expression, IgM secretion, and Xbp-1 expression. Knock down of HACS1 in a human B lymphoma cell line by small interfering ribonucleic acid did not significantly change IL-4–stimulated B cell proliferation. Our study demonstrates that HACS1 is up-regulated by B cell activation signals and is a participant in B cell activation and differentiation.
Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1α and Attenuates Subsequent T Lymphocyte Transendothelial Migration
Authors: Rao Ravi M. , Betz Travis V. , Lamont Deanna J. , Kim Michael B. , Shaw Sunil K. , Froio Richard M. , Baleux Françoise , Arenzana-Seisdedos Fernando , Alon Ronen , Luscinskas Francis W.
Published: September 2004

Leukocyte trafficking to sites of inflammation follows a defined temporal pattern, and evidence suggests that initial neutrophil transendothelial migration modifies endothelial cell phenotype. We tested the hypothesis that preconditioning of human umbilical vein endothelial cells (HUVEC) by neutrophils would also modify the subsequent transendothelial migration of T lymphocytes across cytokine-stimulated HUVEC in an in vitro flow assay. Using fluorescence microscopy, preconditioning of HUVEC by neutrophils was observed to significantly reduce the extent of subsequent stromal cell–derived factor-1α (SDF-1α [CXCL12])-mediated T lymphocyte transendothelial migration, without reducing accumulation. In contrast, recruitment of a second wave of neutrophils was unaltered. Conditioned medium harvested after transendothelial migration of neutrophils or supernatants from stimulated neutrophils mediated a similar blocking effect, which was negated using a specific neutrophil elastase inhibitor. Furthermore, T lymphocyte transendothelial migration was inhibited by treatment of HUVEC with purified neutrophil elastase, which selectively cleaved the amino terminus of HUVEC-bound SDF-1α, which is required for its chemotactic activity. The reduction in T lymphocyte transendothelial migration was not observed using a different chemokine, ELC (CCL19), and was not reversed by replenishment of SDF-1α, indicating endothelial retention of the inactivated chemokine. In summary, transmigrating neutrophils secrete localized elastase that is protected from plasma inhibitors, and thereby modulate trafficking of other leukocyte subsets by altering the endothelial-associated chemotactic activities.
Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells
Authors: Rivino Laura , Messi Mara , Jarrossay David , Lanzavecchia Antonio , Sallusto Federica , Geginat Jens
Published: September 2004

We previously reported that central–memory T cells (TCM cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector–memory T cells (TEM cells) (i.e., CCR7− T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4+ TCM cell pool. TCM cells expressing CXCR3 secreted low amounts of interferon γ, whereas CCR4+ TCM cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3+ TCM and CCR4+ TCM cells invariably generated fully differentiated CCR7− Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5+ TCM cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3+ TCM and TEM cells. We conclude that antigen-specific memory T cells are distributed between TEM cells and different subsets of TCM cells. Our results also explain how the quality of primary T cell responses could be maintained by TCM cells in the absence of antigen.
CCL28 Controls Immunoglobulin (Ig)A Plasma Cell Accumulation in the Lactating Mammary Gland and IgA Antibody Transfer to the Neonate
Authors: Wilson Eric , Butcher Eugene C.
Published: September 2004

The accumulation of immunoglobulin (Ig)A antibody-secreting cells (ASCs) in the lactating mammary gland leads to secretion of antibodies into milk and their passive transfer to the suckling newborn. This transfer of IgA from mother to infant provides transient immune protection against a variety of gastrointestinal pathogens. Here we show that the mucosal epithelial chemokine CCL28 is up-regulated in the mammary gland during lactation and that IgA ASCs from this tissue express CCR10 and migrate to CCL28. In vivo treatment with anti-CCL28 antibody blocks IgA ASC accumulation in the mammary gland, inhibiting IgA antibody secretion into milk and the subsequent appearance of antibody in the gastrointestinal tract of nursing neonates. We propose that CCL28 is a key regulator of IgA ASC accumulation in the mammary gland and thus controls the passive transfer of IgA antibodies from mother to infant.
Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
Authors: Turk Mary Jo , Guevara-Patiño José A. , Rizzuto Gabrielle A. , Engelhorn Manuel E. , Houghton Alan N.
Published: September 2004

Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4+ T cells in tumor-bearing mice resulted in CD8+ T cell–mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8+ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I–restricted epitopes of two melanocyte differentiation antigens. RAG1−/− mice adoptively transferred with CD8+ and CD4+ T cells lacking the CD4+CD25+ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4+CD25+ cells. Naturally occurring CD4+CD25+ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8+ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.
Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells
Authors: Lichterfeld Mathias , Kaufmann Daniel E. , Yu Xu G. , Mui Stanley K. , Addo Marylyn M. , Johnston Mary N. , Cohen Daniel , Robbins Gregory K. , Pae Eunice , Alter Galit , Wurcel Alysse , Stone David , Rosenberg Eric S. , Walker Bruce D. , Altfeld Marcus
Published: September 2004

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon γ assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.
Getting to the Guts of HIV Pathogenesis
Authors: Veazey Ronald S. , Lackner Andrew A.
Published: September 2004

Two groups have shown that, as in macaques infected with simian immunodeficiency virus (SIV), intestinal CD4+ T cells are selectively and rapidly depleted in the intestine of HIV-infected patients. Depletion of intestinal CD4+ T cells occurred at all stages of infection regardless of highly active antiretroviral therapy (HAART). Here we discuss the important implications of these papers for our understanding of HIV pathogenesis, treatment, and vaccine design.
On a certain class of modular functions
Authors: Kohnen Winfried
Published: September 2004

We give a characterization of those meromorphic modular functions on a subgroup of finite index of the full modular group whose divisors are supported at the cusps, in terms of the growth of the exponents of their infinite product expansions.
The vanishing of 𝑇𝑜𝑟₁^{𝑅}(𝑅⁺,𝑘) implies that 𝑅 is regular
Authors: Aberbach Ian
Published: September 2004

Let

(
R
,
m
,
k
)

(R,m,k)

be an excellent local ring of positive prime characteristic. We show that if

Tor
1
R

⁡
(

R
+

,
k
)
=
0

\operatorname {Tor}_1^R(R^+,k) = 0

, then

R
R

is regular. This improves a result of Schoutens, in which the additional hypothesis that

R
R

was an isolated singularity was required for the proof.
Convolution operators induced by approximate identities and pointwise convergence in 𝐿_{𝑝}(ℝ) spaces
Authors: Avramidou Parthena
Published: September 2004

Given a sequence of kernels

ϕ
n

\phi _n

for which the operators

T
n

f
=

ϕ
n

∗
f

T_nf=\phi _n\ast f

converge a.e. in all

L
p

(

R

)

L_p(\mathbb {R})

spaces,

p
≥
1

p\geq 1

, a perturbation method is provided with the property that the modified convolution operators converge pointwise only in selective spaces.
Majorization, range inclusion, and factorization for bounded linear operators
Authors: Barnes Bruce
Published: September 2004

In this paper, relationships among the concepts, majorization, range inclusion, and factorization, are studied in a general setting for bounded linear operators. Some applications of these concepts are given.
On smoothness of symmetric mappings II
Authors: Cantón A.
Published: September 2004

If the dilatation of a quasiconformal selfmap of the upper half-plane vanishes near the real line as a power of the height, the induced quasisymmetric mapping is Lipschitz with the same exponent. In this note, it is shown that the converse does not hold for any positive exponent. In addition, a sufficient condition is found to have locally a quasiconformal extension with the desired growth in the dilatation.
Algebraic polynomials with non-identical random coefficients
Authors: Farahmand K. , Nezakati A.
Published: September 2004

There are many known asymptotic estimates for the expected number of real zeros of a random algebraic polynomial

a
0

+

a
1

x
+

a
2

x
2

+
⋯
+

a

n
−
1

x

n
−
1

.

a_0 +a_1 x+ a_2 x^2+ \cdots +a_{n-1}x^{n-1}.

The coefficients

a
j

a_j

(
j
=
0
,
1
,
2
,
…
,
n
−
1
)

(j=0, 1, 2, \dotsc , n-1)

are mostly assumed to be independent identical normal random variables with mean zero and variance unity. In this case, for all

n
n

sufficiently large, the above expected value is shown to be

O
(
log
⁡
n
)

O(\log n)

. Also, it is known that if the

a
j

a_j

have non-identical variance

(

n
−
1

j

)

\binom {n-1}{j}

, then the expected number of real zeros increases to

O
(

n

)

O(\sqrt {n})

. It is, therefore, natural to assume that for other classes of distributions of the coefficients in which the variance of the coefficients is picked at the middle term, we would also expect a greater number of zeros than

O
(
log
⁡
n
)

O(\log n)

. In this work for two different choices of variance for the coefficients we show that this is not the case. Although we show asymptotically that there is some increase in the number of real zeros, they still remain

O
(
log
⁡
n
)

O(\log n)

. In fact, so far the case of

var

(

a
j

)
=

(

n
−
1

j

)

\mbox {var}(a_j)={\binom {n-1}{j}}

is the only case that can significantly increase the expected number of real zeros.
On a generalized corona problem on the unit disc
Authors: Pau Jordi
Published: September 2004

Let

g
,

f
1

,
…
,

f
n

∈

H

∞

g,f_ 1,\dots ,f_ n\in H^{\infty }

. We give a sufficient condition on the size of a function

g
g

in order for it to be in the ideal generated by

f
1

,
…
,

f
n

f_ 1,\dots ,f_ n

. In particular, this improves Cegrell’s result on this problem.
Projective surfaces with many skew lines
Authors: Rams Sławomir
Published: September 2004

We give an example of a smooth surface

S

d

⊂

P

3

(

C

)

\mathrm {S}_{d}\subset \mathbb {P}_{3}(\mathbb {C})

of degree

d
d

that contains

d
⋅
(
d
−
2
)
+
2

d \cdot (d-2) + 2

pairwise disjoint lines. In particular, our example shows that the degree in Miyaoka’s bound is sharp.
Fourier transforms of stationary processes
Authors: Wu Wei
Published: September 2004

We consider the asymptotic behavior of Fourier transforms of stationary and ergodic sequences. Under sufficiently mild conditions, central limit theorems are established for almost all frequencies as well as for a given frequency. Applications to the widely used linear processes and iterated random functions are discussed. Our results shed new light on the foundation of spectral analysis in that the asymptotic distribution of the periodogram, the fundamental quantity in the frequency-domain analysis, is obtained.
The Valentiner group as Galois group
Authors: Crespo Teresa , Hajto Zbigniew
Published: September 2004

We obtain the complete set of solutions to the Galois embedding problem given by the Valentiner group as a triple cover of the alternating group 

A
6

A_6

.
Convergence in almost periodic cooperative systems with a first integral
Authors: Shen Wenxian , Zhao Xiao-Qiang
Published: September 2004

This paper is to investigate the asymptotic dynamics in almost periodic cooperative systems with a first integral. By appealing to the theory of skew-product semiflows we establish the asymptotic almost periodicity of bounded solutions to such systems, which extends the existing convergence results for time independent and periodic cooperative systems with a first integral and proves a conjecture of B. Tang, Y. Kuang and H. Smith in SIAM J. Math. Anal., 24 (1993), 1331-1339.
Betti numbers of some monomial ideals
Authors: Valla Giuseppe
Published: September 2004

In this paper we compute the graded Betti numbers of certain monomial ideals that are not stable. As a consequence we prove a conjecture, stated by G. Fatabbi, on the graded Betti numbers of two general fat points in

P

3

.

\mathbf {P}^3.
Compact operators on Hilbert modules
Authors: Anoussis M. , Todorov I.
Published: September 2004

We prove that an adjointable contraction acting on a countably generated Hilbert module over a separable unital C*-algebra is compact if and only if the set of its second contractive perturbations is separable.
Circular averages and Falconer/Erdös distance conjecture in the plane for random metrics
Authors: Hofmann S. , Iosevich A.
Published: September 2004

We study a variant of the Falconer distance problem for perturbations of the Euclidean and related metrics. We prove that Mattila’s criterion, expressed in terms of circular averages, which would imply the Falconer conjecture, holds on average. We also use a technique involving diophantine approximation to prove that the well-distributed case of the Erdös Distance Conjecture holds for almost every appropriate perturbation of the Euclidean metric.
Hermite-Biehler functions with zeros close to the imaginary axis
Authors: Kaltenbäck Michael , Woracek Harald
Published: September 2004

A Hermite-Biehler function

E
E

gives rise to a de Branges Hilbert space

H

(
E
)

\mathcal {H}(E)

consisting of entire functions. We are going to show that for Hermite-Biehler functions of sufficiently small growth and a certain distribution of zeros every proper de Branges subspace of

H

(
E
)

\mathcal {H}(E)

coincides for some

n
∈

N

n\in \mathbb {N}

with the

(
n
+
1
)

(n+1)

-dimensional linear space of all polynomials of degree at most

n
n

.
Group automorphisms with few and with many periodic points
Authors: Ward Thomas
Published: September 2004

For each

C
∈
[
0
,
∞
]

C\in [0,\infty ]

a compact group automorphism

T
:
X
→
X

T:X\to X

is constructed with the property that
\[

1
n

log
⁡
|
{
x
∈
X
∣

T
n

(
x
)
=
x
}
|
⟶
C
.

\frac {1}{n}\log \vert \{x\in X\mid T^n(x)=x\}\vert \longrightarrow C.

\]
This may be interpreted as a combinatorial analogue of the (still open) problem of whether compact group automorphisms with any given topological entropy exist.
Which singular K3 surfaces cover an Enriques surface
Authors: Sertöz Alı̇
Published: September 2004

We determine the necessary and sufficient conditions on the entries of the intersection matrix of the transcendental lattice of a singular K3 surface for the surface to doubly cover an Enriques surface.
Joins of projective varieties and multisecant spaces
Authors: Ballico E.
Published: September 2004

Let

X
1

,
…
,

X
s

⊂

P

N

X_1,\dots ,X_s \subset {\mathbf {P}}^N

,

s
≥
1

s \ge 1

, be integral varieties. For any integers

k
i

>
0

k_i>0

,

1
≤
i
≤
s

1 \le i \le s

, and

t
≥
0

t \ge 0

set

k
→

:=
(

k
1

,
…
,

k
s

)

\vec {k}:= (k_1,\dots ,k_s)

and

X
→

:=
(

X
1

,
…
,

X
s

)

\vec {X}:= (X_1,\dots ,X_s)

. Let

Sec

(

X
→

;
t
,

k
→

)

\mbox {Sec}(\vec {X} ;t,\vec {k} )

be the set of all linear

t
t

-spaces contained in a linear

(

k
1

+
⋯
+

k
s

−
1
)

(k_1+\cdots +k_s-1)

-space spanned by

k
1

k_1

points of

X
1

X_1

,

k
2

k_2

points of

X
2

X_2

, …,

k
s

k_s

points of

X
s

X_s

. Here we study some cases where

Sec

(

X
→

;
t
,

k
→

)

\mbox {Sec}(\vec {X} ;t,\vec {k} )

has the expected dimension. The case

s
=
1

s=1

was recently considered by Chiantini and Coppens and we follow their ideas. The two main results of the paper consider cases where each

X
i

X_i

is a surface, more particularly:

s
=
3
,

k
1

=

k
2

=

k
3

=
1
 

and

 
t
=
1

\begin{equation*} s=3, k_1=k_2=k_3=1 \ \mbox {and} \ t=1 \end{equation*}

or

s
=
2
,

k
1

=
2
,

k
2

=
1
 

and

 
t
=
1
.

\begin{equation*} s=2, k_1=2, k_2 = 1 \ \mbox {and} \ t=1 . \end{equation*}
Filling analytic sets by the derivatives of 𝐶¹-smooth bumps
Authors: Fabian Marián , Kalenda Ondřej , Kolář Jan
Published: September 2004

If

X
X

is an infinite-dimensional Banach space, with separable dual, and

M
⊂

X
∗

M\subset X^*

is an analytic set such that any point

x
∗

∈
M

x^*\in M

can be reached from 

0
0

by a continuous path contained (except for the point 

x
∗

x^*

) in the interior of 

M
M

, then

M
M

is the range of the derivative of a

C
1

C^1

-smooth function on 

X
X

with bounded nonempty support.
Analysis of array CGH data: from signal ratio to gain and loss of DNA regions
Authors: Hupé Philippe , Stransky Nicolas , Thiery Jean-Paul , Radvanyi François , Barillot Emmanuel
Published: September 2004

Motivation: Genomic DNA regions are frequently lost or gained during tumor progression. Array Comparative Genomic Hybridization (array CGH) technology makes it possible to assess these changes in DNA in cancers, by comparison with a normal reference. The identification of systematically deleted or amplified genomic regions in a set of tumors enables biologists to identify genes involved in cancer progression because tumor suppressor genes are thought to be located in lost genomic regions and oncogenes, in gained regions. Array CGH profiles should also improve the classification of tumors. The achievement of these goals requires a methodology for detecting the breakpoints delimiting altered regions in genomic patterns and assigning a status (normal, gained or lost) to each chromosomal region.

Results: We have developed a methodology for the automatic detection of breakpoints from array CGH profile, and the assignment of a status to each chromosomal region. The breakpoint detection step is based on the Adaptive Weights Smoothing (AWS) procedure and provides highly convincing results: our algorithm detects 97, 100 and 94% of breakpoints in simulated data, karyotyping results and manually analyzed profiles, respectively. The percentage of correctly assigned statuses ranges from 98.9 to 99.8% for simulated data and is 100% for karyotyping results. Our algorithm also outperforms other solutions on a public reference dataset.

Availability: The R package GLAD (Gain and Loss Analysis of DNA) is available upon request
Malignant Hyperthermia in North America
Authors: Sei Yoshitatsu , Sambuughin Nyamkhishig N. , Davis Edward J. , Sachs Daniel , Cuenca Phil B. , Brandom Barbara W. , Tautz Timothy , Rosenberg Henry , Nelson Thomas E. , Muldoon Sheila M.
Published: September 2004

Background

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type I ryanodine receptor 1 is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population.

Methods

The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions.

Results

Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease.

Conclusions

The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.
Teaching Residents Pediatric Fiberoptic Intubation of the Trachea
Authors: Wheeler Melissa , Roth Andrew G. , Dsida Richard M. , Rae Bronwyn , Seshadri Roopa , Sullivan Christine L. , Heffner Corri L. , Coté Charles J.
Published: September 2004

Background

The authors' hypothesis was that a video-assisted technique should speed resident skill acquisition for flexible fiberoptic oral tracheal intubation (FI) of pediatric patients because the attending anesthesiologist can provide targeted instruction when sharing the view of the airway as the resident attempts intubation.

Methods

Twenty Clinical Anesthesia year 2 residents, novices in pediatric FI, were randomly assigned to either the traditional group (traditional eyepiece FI) or the video group (video-assisted FI). One of two attending anesthesiologists supervised each resident during FI of 15 healthy children, aged 1-6 yr. The time from mask removal to confirmation of endotracheal tube placement by end-tidal carbon dioxide detection was recorded. Intubation attempts were limited to 3 min; up to three attempts were allowed. The primary outcome measure, time to success or failure, was compared between groups. Failure rate and number of attempts were also compared between groups.

Results

Three hundred patient intubations were attempted; eight failed. On average, the residents in the video group were faster, were three times more likely to successfully intubate at any given time during an attempt, and required fewer attempts per patient compared to those in the traditional group.

Conclusions

The video system seems to be superior for teaching residents fiberoptic intubation in children.
Apolipoprotein E Genotype and Cognitive Dysfunction after Noncardiac Surgery
Authors: Abildstrom Hanne , Christiansen Michael , Siersma Volkert D. , Rasmussen Lars S.
Published: September 2004

Background

Apolipoprotein E is important in recovery after neuronal damage. The epsilon4 allele of the apolipoprotein E gene has been shown as a risk factor for Alzheimer disease, poor outcome after cerebral injury, and accelerated cognitive decline with normal aging. The authors hypothesized that patients with the epsilon4 allele would have an increased risk of postoperative cognitive dysfunction (POCD) after noncardiac surgery.

Methods

In a multicenter study, a total of 976 patients aged 40 yr and older undergoing noncardiac surgery were tested preoperatively and 1 week and 3 months after surgery with a neuropsychological test battery comprising seven subtests. POCD was defined as a decline in test performance of more than 2 SD from the expected. Apolipoprotein E genotypes were determined by blood sample analysis at a central laboratory. Multivariate logistic regression analysis with POCD as the dependent variable assessed presence of the epsilon4 allele (yes/no) and other possible risk factors.

Results

The epsilon4 allele was found in 272 patients. One week after surgery, the incidence of POCD was 11.7% in patients with the epsilon4 allele and 9.9% in patients without the epsilon4 allele (P = 0.41). Three months later, POCD was found in 10.3% of patients with the epsilon4 allele and in 8.4% of patients without the epsilon4 allele (P = 0.40). Multivariate logistic regression analysis did not identify the epsilon4 allele as a risk factor at 1 week (P = 0.33) or 3 months (P = 0.57).

Conclusions

The authors were unable to show a significant association between apolipoprotein E genotype and POCD, but statistical power was limited because of a lower incidence of POCD than expected.
Effects of Cardiopulmonary Bypass on Sufentanil Pharmacokinetics in Patients Undergoing Coronary Artery Bypass Surgery
Authors: Hudson Robert J. , Thomson Ian R. , Jassal Rajive
Published: September 2004

Background

Complete pharmacokinetic modeling, including assessment of the effect of cardiopulmonary bypass (CPB) on sufentanil disposition, has not been reported. The aims of this investigation were to define a model that accurately predicted sufentanil concentrations during and after cardiac surgery and to determine if CPB had a clinically significant impact on sufentanil pharmacokinetics.

Methods

Population pharmacokinetic modeling was applied to data from 21 patients undergoing coronary artery bypass grafting. The predictive ability of models was assessed by calculating bias, accuracy, and measured:predicted concentration ratios versus time. A simple three-compartment model, without covariates, was initially compared with models having weight or gender as covariates and was subsequently used as the foundation for multiple CPB-adjusted models (allowing step-changes of parameters at the start or end of CPB). The primary criterion for choosing more complex models was a significant improvement in log-likelihood; secondary criteria were significant improvement in bias or accuracy.

Results

Neither covariate (weight or gender) models improved bias or accuracy compared with the simple three-compartment model. A final CPB-adjusted model with V2 and Cl3 changing at the start of CPB and V1, Cl2, and Cl3 changing at the end of CPB had significantly greater log-likelihood values when compared with the simple three-compartment model and with less elaborate CPB-adjusted models. However, bias and accuracy for this final model were not significantly different from the simple three-compartment model.

Conclusions

When sufentanil is infused at a constant rate, with initiation of CPB, a pharmacokinetic model adjusted for CPB predicts that the sufentanil concentration will decrease approximately 17% and that it will begin to return to the prebypass concentration 12 min after initiation of CPB. At the end of CPB, this model also predicts a brief spike of the sufentanil concentration. These predictions reflect changes in the measured sufentanil concentrations. However, compared with a simple, three-compartment model, incorporating step-changes of pharmacokinetic parameters at the start or end of cardiopulmonary bypass (or both) did not significantly improve overall perioperative prediction of measured sufentanil concentrations. This suggests that CPB has clinically insignificant effects on sufentanil kinetics in adults.
A Brief Regional Ischemic-reperfusion Enhances Propofol-induced Depression in Left Ventricular Function of in situ Rat Hearts
Authors: Kuzumoto Naoya , Kitagawa Yutaka , Uemura Koichi , Ueyama Takashi , Yoshida Ken-ichi , Furuya Hitoshi , Takaki Miyako
Published: September 2004

Background

Propofol is short-acting intravenous general anesthetics that reduces cardiovascular hemodynamics. The effects of propofol on intrinsic myocardial contractility, however, remain debatable. The aim of the current study was to test the hypothesis that inhibitory effects of propofol on left ventricular (LV) contractility and mechanical work capability of in situ ejecting rat hearts are attenuated after a brief regional ischemia and reperfusion.

Methods

The authors obtained steady-state LV pressure-volume loops and intermittently obtained LV end-systolic pressure-volume relation and evaluated effects of propofol on LV function by end-systolic pressure (ESPmLVV), systolic pressure-volume area (PVAmLVV) at midrange LV volume (mLVV).

Results

Propofol (5.2 +/- 0.3 approximately 11.1 +/- 3.7 microg.ml) significantly decreased ESP0.08 to 78 +/- 12% approximately 64 +/- 13% of prepropofol and PVA0.08 to 76 +/- 13%approximately 63 +/- 16% of prepropofol in normal hearts, whereas propofol at a lower concentration (4.1 +/- 1.0 microg/ml) did not. Although brief ischemic-reperfusion per se did not affect LV function, propofol after that, even at a lower concentration (4.1 +/- 1.0 microg/ml), significantly decreased ESP0.08 to 70 +/- 27% of prepropofol and PVA0.08 to 68 +/- 33% of prepropofol. Pretreatment with a protein kinase C (PKC) inhibitor, bisindolylmaleimide reduced the propofol (4.1 +/- 1.0 microg/ml)-induced greater decreases in ESP0.08 and PVA0.08 after brief ischemic-reperfusion to 94 +/- 33% and 92 +/- 39% of prepropofol. In the propofol-infused hearts after brief ischemic-reperfusion, protein kinase C-epsilon translocation to the nucleus-myofibril fraction was found.

Conclusion

In contrast to the study hypothesis, brief ischemic-reperfusion enhanced the inhibitory effects of propofol on LV systolic function; this enhancement is attributable to activation of protein kinase C.
Isoflurane Reduces the Carbachol-evoked Ca2+Influx in Neuronal Cells
Authors: Corrales Alexandra , Xu Fang , Garavito-Aguilar Zayra V. , Blanck Thomas J. J. , Recio-Pinto Esperanza
Published: September 2004

Background

The authors previously reported that the isoflurane-caused reduction of the carbachol-evoked cytoplasmic Ca transient increase ([Ca]cyt) was eliminated by K or caffeine-pretreatment. In this study the authors investigated whether the isoflurane-sensitive component of the carbachol-evoked [Ca]cyt transient involved Ca influx through the plasma membrane.

Methods

Perfused attached human neuroblastoma SH-SY5Y cells were exposed to carbachol (1 mm, 2 min) in the absence and presence of isoflurane (1 mm) and in the absence and presence of extracellular Ca (1.5 mm). The authors studied the effect of the nonspecific cationic channel blocker La (100 microm), of the L-type Ca channel blocker nitrendipine (10 microm), and of the N-type Ca channel blocker omega-conotoxin GVIA (0.1 microm) on isoflurane modulation of the carbachol-evoked [Ca]cyt transient. [Ca]cyt was detected with fura-2 and experiments were carried out at 37 degrees C.

Results

Isoflurane reduced the peak and area of the carbachol-evoked [Ca]cyt transient in the presence but not in the absence of extracellular Ca. La had a similar effect as the removal of extracellular Ca. Omega-conotoxin GVIA and nitrendipine did not affect the isoflurane sensitivity of the carbachol response although nitrendipine reduced the magnitude of the carbachol response.

Conclusions

The current data are consistent with previous observations in that the carbachol-evoked [Ca]cyt transient involves both Ca release from intracellular Ca stores and Ca entry through the plasma membrane. It was found that isoflurane attenuates the carbachol-evoked Ca entry. The isoflurane sensitive Ca entry involves a cationic channel different from the L- or N- type voltage-dependent Ca channels. These results indicate that isoflurane attenuates the carbachol-evoked [Ca]cyt transient at a site at the plasma membrane that is distal to the muscarinic receptor.
Influence of Propofol on Neuronal Damage and Apoptotic Factors after Incomplete Cerebral Ischemia and Reperfusion in Rats
Authors: Engelhard Kristin , Werner Christian , Eberspächer Eva , Pape Monika , Stegemann Uta , Kellermann Kristine , Hollweck Regina , Hutzler Peter , Kochs Eberhard
Published: September 2004

Background

Propofol reduces neuronal damage from cerebral ischemia when investigated for less than 8 postischemic days. This study investigates the long-term effects of propofol on neuronal damage and apoptosis-related proteins after cerebral ischemia and reperfusion.

Methods

Male Sprague-Dawley rats were randomly assigned as follows: group 1 (n = 32, control): fentanyl and nitrous oxide-oxygen; group 2 (n = 32, propofol): propofol and oxygen-air. Ischemia (45 min) was induced by carotid artery occlusion and hemorrhagic hypotension. Pericranial temperature and arterial blood gases were maintained constant. After 1, 3, 7, and 28 postischemic days, brains were removed, frozen, and sliced. Hippocampal eosinophilic cells were counted. The amount of apoptosis-related proteins Bax, p53, Bcl-2, and Mdm-2 and neurons positive for activated caspase-3 were analyzed.

Results

In propofol-anesthetized rats, no eosinophilic neurons were detected, whereas in control animals, 16-54% of hippocampal neurons were eosinophilic (days 1-28). In control animals, the concentration of Bax was 70-200% higher after cerebral ischemia compared with that in animals receiving propofol over time. Bcl-2 was 50% lower in control animals compared with propofol-anesthetized rats during the first 3 days. In both groups, a maximal 3% of the hippocampal neurons were positive for activated caspase-3.

Conclusions

These data show sustained neuroprotection with propofol. This relates to reduced eosinophilic and apoptotic injury. Activated caspase-3-dependent apoptotic pathways were not affected by propofol. This suggests the presence of activated caspase-3-independent apoptotic pathways.
Remifentanil Preconditioning Protects against Ischemic Injury in the Intact Rat Heart
Authors: Zhang Ye , Irwin Michael G. , Wong Tak Ming
Published: September 2004

Background

Opioid receptors mediate cardiac ischemic preconditioning. Remifentanil is a new, potent ultra-short-acting phenylpiperidine opioid used in high doses for anesthesia. The authors hypothesize that pretreatment with this drug confers cardioprotection.

Methods

Male Sprague-Dawley rats were anesthetized and the chest was opened. All animals were subjected to 30 min of occlusion of the left coronary artery and 2 h of reperfusion. Before the 30-min occlusion, rats received either preconditioning by ischemia (ischemic preconditioning, 5-min occlusion, 5-min reperfusion x 3) or pretreatment with remifentanil, performed with the same regime (3 x 5-min infusions) using 0.2, 0.6, 2, 6, or 20 microg.kg.min intravenously. The experiment was repeated with naltrindole (a selective Delta-opioid receptor antagonist, 5 mg/kg), norbinaltorphimine (a selective kappa-OR antagonist, 5 mg/kg), or CTOP (a selective mu-opioid receptor antagonist, 1 mg/kg) administered before remifentanil-induced preconditioning or ischemic preconditioning, respectively. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining.

Results

There was a dose-related reduction in infarct size/area at risk after treatment with remifentanil that was similar to that seen with ischemic preconditioning. This effect was prevented or significantly attenuated by coadministration of a mu, kappa, or Delta-opioid antagonist. The infarct-sparing effect of ischemic preconditioning was abolished by blockade of kappa-opioid receptors or Delta-opioid receptors but not by mu-opioid receptors.

Conclusion

Remifentanil mimics cardioprotection via all three opioid receptors. This differs from ischemic preconditioning, which confers cardioprotection via kappa- and Delta-, but not mu-opioid receptors. Part of the protective effect of remifentanil may be produced by mu-agonist activity outside the heart.
Influence of GABAAReceptor γ2Splice Variants on Receptor Kinetics and Isoflurane Modulation
Authors: Benkwitz Claudia , Banks Matthew I. , Pearce Robert A.
Published: September 2004

Background

Gamma-aminobutyric acid type A (GABAA) receptors, the major inhibitory receptors in the brain, are important targets of many drugs, including general anesthetics. These compounds exert multiple effects on GABAA receptors, including direct activation, prolongation of deactivation kinetics, and reduction of inhibitory postsynaptic current amplitudes. However, the degree to which these actions occur differs for different agents and synapses, possibly because of subunit-specific effects on postsynaptic receptors. In contrast to benzodiazepines and intravenous anesthetics, there is little information available about the subunit dependency of actions of volatile anesthetics. Therefore, the authors studied in detail the effects of isoflurane on recombinant GABAA receptors composed of several different subunit combinations.

Methods

Human embryonic kidney 293 cells were transiently transfected with rat complementary DNAs of alpha1beta2, alpha1beta2gamma2L, alpha1beta2gamma2S, alpha5beta3, or alpha5beta3gamma2S subunits. Using rapid application and whole cell patch clamp techniques, cells were exposed to 10- and 2,000-ms pulses of gamma-aminobutyric acid (1 mm) in the presence or absence of isoflurane (0.25, 0.5, 1.0 mm). Anesthetic effects on decay kinetics, peak amplitude, net charge transfer and rise time were measured. Statistical significance was assessed using the Student t test or one-way analysis of variance followed by the Tukey post hoc test.

Results

Under control conditions, incorporation of a gamma2 subunit conferred faster deactivation kinetics and reduced desensitization. Isoflurane slowed deactivation, enhanced desensitization, and reduced peak current amplitude in alphabeta receptors. Coexpression with a gamma2 subunit caused these effects of isoflurane to be substantially reduced or abolished. Although the two gamma2 splice variants imparted qualitatively similar macroscopic kinetic properties, there were significant quantitative differences between effects of isoflurane on deactivation and peak current amplitude in gamma2S- versus gamma2L-containing receptors. The net charge transfer resulting from brief pulses of gamma-aminobutyric acid was decreased by isoflurane in alphabeta but increased in alphabetagamma receptors.

Conclusions

The results indicate that subunit composition does substantially influence modulation of GABAA receptors by isoflurane. Specifically, the presence of a gamma2 subunit and the identity of its splice variant are important factors in determining physiologic and pharmacologic properties. These results may have functional implications in understanding how anesthetic effects on specific types of GABAA receptors in the brain contribute to changes in brain function and behavior.
Topical Humidified Carbon Dioxide to Keep the Open Surgical Wound Warm
Authors: Persson Mikael , Elmqvist Håkan , van der Linden Jan
Published: September 2004

Background

Perioperative hypothermia is common in open surgery and is associated with increased rates of wound infection. This is a result of decreased wound tissue oxygenation, which can be normalized by local warming. Recently, a technique has been developed to establish a carbon dioxide atmosphere in an open surgical wound. Therefore, the authors studied the possible "greenhouse effect" of carbon dioxide insufflation and operation lamps on wound temperature.

Methods

In a fully ventilated operating room surface temperature was measured at steady state in a model of an open surgical wound containing blood agar. The wound model was randomized to either no insufflation or insufflation of dry and humidified carbon dioxide or air, respectively, at a flow of 5 l/min via a gas diffuser. The surface temperature was measured with operation lamps switched on and off, respectively. Evaporation rates were also measured.

Results

With the operation light off, the surface temperature in the control was 31.8 degrees C, and with the operation light on, the temperature increased by 1.5 degrees C (P < 0.001). Additional insufflation of dry carbon dioxide increased the surface temperature another 1.9 degrees C (P < 0.001). When the carbon dioxide was humidified, the evaporation rate was lowest and the surface temperature increased further to 35.6 degrees C (P = 0.002). In contrast, insufflation of dry and humidified air did not have a significant effect on the evaporation rate and only marginally increased the wound temperature in comparison with the control.

Conclusions

Insufflation of humidified carbon dioxide in combination with light from the operation lamps may help to keep the open wound warm during surgery.
Severe Neurological Complications after Central Neuraxial Blockades in Sweden 1990–1999
Authors: Moen Vibeke , Dahlgren Nils , Irestedt Lars
Published: September 2004

Background

Central neuraxial blockades find widespread applications. Severe complications are believed to be extremely rare, but the incidence is probably underestimated.

Methods

A retrospective study of severe neurologic complications after central neuraxial blockades in Sweden 1990-1999 was performed. Information was obtained from a postal survey and administrative files in the health care system. During the study period approximately 1,260,000 spinal blockades and 450,000 epidural blockades were administered, including 200,000 epidural blockades for pain relief in labor.

Results

: The 127 complications found included spinal hematoma (33), cauda equina syndrome (32), meningitis (29), epidural abscess (13), and miscellaneous (20). Permanent neurologic damage was observed in 85 patients. Incidence of complications after spinal blockade was within 1:20-30,000 in all patient groups. Incidence after obstetric epidural blockade was 1:25,000; in the remaining patients it was 1:3600 (P < 0.0001). Spinal hematoma after obstetric epidural blockade carried the incidence 1:200,000, significantly lower than the incidence 1:3,600 females subject to knee arthroplasty (P < 0.0001).

Conclusions

: More complications than expected were found, probably as a result of the comprehensive study design. Half of the complications were retrieved exclusively from administrative files. Complications occur significantly more often after epidural blockade than after spinal blockade, and the complications are different. Obstetric patients carry significantly lower incidence of complications. Osteoporosis is proposed as a previously neglected risk factor. Close surveillance after central neuraxial blockade is mandatory for safe practice.