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Morphogen-induced nerve regeneration and repair
United States Patent: 7,557,078
Issued: July 7, 2009
Inventors: Rueger; David C.
(Hopkinton, MA), Kuberasampath; Thangavel (Medway, MA), Oppermann; Hermann
(Medway, MA), Ozkaynak; Engin (Milford, MA), Pang; Roy H. L. (Etna, NH),
Cohen; Charles M. (Medway, MA)
Assignee: Stryker
Corporation (Kalamazoo, MI)
Appl. No.: 08/937,756
Filed: September 25, 1997
Pharm/Biotech Jobs
Disclosed are therapeutic treatment
methods, compositions and devices for maintaining neural pathways in a
mammal, including enhancing survival of neurons at risk of dying, inducing
cellular repair of damaged neurons and neural pathways, and stimulating
neurons to maintain their differentiated phenotype. In one embodiment, the
invention provides means for stimulating CAM expression in neurons. The
invention also provides means for evaluating the status of nerve tissue,
including means for detecting and monitoring neuropathies in a mammal. The
methods, devices and compositions include a morphogen or morphogen-stimulating
agent provided to the mammal in a therapeutically effective concentration.
Description of the
The present invention provides methods and compositions for maintaining
neural pathways in a mammal in vivo, including methods for enhancing the
survival of neural cells.
In one aspect, the invention features compositions and therapeutic treatment
methods that comprise the step of administering to a mammal a
therapeutically effective amount of a morphogenic protein ("morphogen"), as
defined herein, upon injury to a neural pathway, or in anticipation of such
injury, for a time and at a concentration sufficient to maintain the neural
pathway, including repairing damaged pathways, or inhibiting additional
damage thereto.
In another aspect, the invention features compositions and therapeutic
treatment methods for maintaining neural pathways in a mammal in vivo which
include administering to the mammal, upon injury to a neural pathway or in
anticipation of such injury, a compound that stimulates in vivo a
therapeutically effective concentration of an endogenous morphogen within
the body of the mammal sufficient to maintain the neural pathway, including
repairing damaged pathways or inhibiting additional damage thereto. These
compounds are referred to herein as morphogen-stimulating agents, and are
understood to include substances which, when administered to a mammal, act
on tissue(s) or organ(s) that normally are responsible for, or capable of,
producing a morphogen and/or secreting a morphogen, and which cause the
endogenous level of the morphogen to be altered. The agent may act, for
example, by stimulating expression and/or secretion of an endogenous
In particular, the invention provides methods for enhancing the survival of
neurons at risk of dying, including protecting neurons from the tissue
destructive effects associated with the body's immune/inflammatory response
to a nerve injury. The invention also provides methods for stimulating
neurons to maintain their differentiated phenotype, including inducing the
redifferentiation of transformed cells of neuronal origin to a morphology
characteristic of untransformed neurons. In one embodiment, the invention
provides means for stimulating production of cell adhesion molecules in
cells, particularly nerve cell adhesion molecules (N-CAM) in neurons. The
invention also provides methods, compositions and devices for stimulating
cellular repair of damaged neurons and neural pathways, including
regenerating damaged axons of the peripheral and central nervous systems. In
addition, the invention also provides means for evaluating the status of
nerve tissue, and for detecting and monitoring neuropathies in a mammal by
monitoring fluctuations in the morphogen levels or endogenous morphogen
antibody levels present in a mammal's serum or cerebrospinal fluid.
As used herein, a "neural pathway" describes a nerve circuit for the passage
of electric signals from a source to a target cell site. The pathway
includes the neurons through which the electric impulse is transported,
including groups of interconnecting neurons, the nerve fibers formed by
bundled neuronal axons, and the glial cells surrounding and associated with
the neurons.
In one aspect of the invention, the morphogens described herein are useful
in repairing damaged neural pathways of the peripheral nervous system. In
particular, the morphogens are useful for repairing damaged pathways,
including transected or otherwise damaged nerve fibers (nerves) requiring
regeneration of neuronal processes, particularly axons, over extended
distances to bridge a gap in the nerve itself, or between the nerve and a
post-synaptic cell. Specifically, the morphogens described herein are
capable of stimulating complete axonal nerve regeneration, including
vascularization and reformation of the protective myelin sheath. The
morphogen preferably is provided to the site of injury dispersed in a
biocompatible, bioresorbable carrier material capable of maintaining the
morphogen at the site and, where necessary, means for directing axonal
growth from the proximal to the distal ends of a severed neuron or nerve.
For example, means for directing axonal growth may be required where nerve
regeneration is to be induced over an extended distance, such as greater
than 10 mm. Many carriers capable of providing these functions are
envisioned. For example, useful carriers include substantially insoluble
materials or viscous solutions prepared as disclosed herein comprising
laminin, hyaluronic acid or collagen, or other suitable synthetic,
biocompatible polymeric materials such as polylactic, polyglycolic or
polybutyric acids and/or copolymers thereof. The currently preferred carrier
comprises an extracellular matrix composition, such as one described herein
derived, for example, from mouse sarcoma cells. Also envisioned as
especially useful are brain tissue-derived extracellular matrices.
In a particularly preferred embodiment, the morphogen is provided to the
site as part of a device wherein the morphogen is disposed in a nerve
guidance channel which spans the distance of the damaged pathway. The
channel acts both as a protective covering and a physical means for guiding
growth of a neuronal process such as an axon. Useful channels comprise a
biocompatible membrane or casing, which may be tubular in structure, having
a dimension sufficient to span the gap or break in the nerve to be repaired,
and having openings adapted to receive severed nerve ends. The casing or
membrane may be made of any biocompatible, nonirritating material, such as
silicone or a biocompatible polymer such as polyethylene or polyethylene
vinyl acetate. The casing also may be composed of biocompatible,
bioresorbable polymers, including, for example, collagen, hyaluronic acid,
polylactic, polybutyric and polyglycolic acids. In a currently preferred
embodiment, the outer surface of the channel is substantially impermeable.
The morphogen may be disposed in the channel in association with a
biocompatible carrier material, or it may be adsorbed to or otherwise
associated with the inner surface of the casing, such as is described in
U.S. Pat. No. 5,011,486, provided that the morphogen is accessible to the
severed nerve ends. Additionally, although the nerve guidance channels
described herein generally are tubular in shape, it should be evident to
those skilled in the art that various alternative shapes may be employed.
The lumen of the guidance channels may, for example, be oval or even square
in cross section. Moreover the guidance channels may be constructed of two
or more parts which may be clamped together to secure the nerve stumps.
Nerve endings may be secured to the nerve guidance channels by means of
sutures, biocompatible adhesives such as fibrin glue, or other means known
in the medical art.
The morphogens described herein also are envisioned to be useful in
autologous peripheral nerve segment implants to bypass damaged neural
pathways in the central nervous system, such as in the repair of damaged or
detached retinas, or other damage to the optic nerve. Here the morphogen is
provided to the site of attachment to stimulate axonal growth at the graft
site, particularly where the damaged axonal segment to be bypassed occurs
far from the neuronal cell body.
The morphogens described herein also are useful for enhancing survival of
neuronal cells at risk of dying, thereby preventing, limiting or otherwise
inhibiting damage to neural pathways. Non-mitotic neurons are at risk of
dying as a result of a neuropathy or other cellular dysfunction of a neuron
or glial cell inducing cell death, or following a chemical or mechanical
lesion to the cell or its surrounding tissue. The chemical lesions may
result from known toxic agents, including lead, ethanol, ammonia,
formaldehyde and many other organic solvents, as well as the toxins in
cigarette smoke and opiates. Excitatory amino acids, such as glutamate also
may play a role in the pathogenesis of neuronal cell death (see Freese et
al. (1990) Brain Res. 521:254-264). Neuronal cell death also is thought to
be a significant contributing factor in a number of neurodegenerative
diseases, including Alzheimer's disease, Huntington's chorea, and
Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis.
The etiology of these neuropathies may be metabolic, as results in hepatic
encephalopathy, infectious, toxic, autoimmune, nutritional or ischemic. In
addition, ethanol and a number of other toxins also have been identified as
significant contributing factors in neurodegenerative diseases. The
morphogens described herein may be provided to cells at risk of dying to
enhance their survival and thereby protect the integrity of the neural
pathway. The morphogens may be provided directly to the site, or they may be
provided systemically. Alternatively, as described above, an agent capable
of stimulating endogenous morphogen expression and/or secretion, preferably
in cells associated with the nerve tissue of interest, may be administered
to the mammal.
In another aspect of the invention, the method disclosed is useful for
redifferentiating transformed cells, particularly transformed cells of
neuronal or glial origin, such that the morphogen-treated cells are induced
to display a morphology characteristic of untransformed cells. Where the
transformed cells are cells of neuronal origin, morphogen treatment
preferably induces cell rounding and cell aggregation (clumping), cell-cell
adhesion, neurite outgrowth formation and elongation, and N-CAM production.
The methods described herein are anticipated to substantially inhibit or
reduce neural cell tumor formation and/or proliferation in nerve tissue. It
is anticipated that the methods of this invention will be useful in
substantially reducing the effects of various carcinomas of nerve tissue
origin such as retinoblastomas, neuroblastomas, and gliomas or glioblastomas.
In addition, the method also is anticipated to aid in inhibiting neoplastic
lesions caused by metastatic tissue. Metastatic tumors are one of the most
common neoplasms of the CNS, as they can reach the intracranial compartment
through the bloodstream. Metastatic tumors may damage neural pathways for
example, by distorting normal nerve tissue structure, compressing nerves,
blocking flow of cerebrospinal fluid or the blood supply nourishing brain
tissue, and/or by stimulating the body's immune response.
In another aspect of the invention, the morphogens described herein are
useful for providing neuroprotective effects to alleviate neural pathway
damage associated with the body's immune/inflammatory response to an initial
injury to nerve tissue. Such a response may follow trauma to nerve tissue,
caused, for example, by an autoimmune dysfunction, neoplastic lesion,
infection, chemical or mechanical trauma, disease, by interruption of blood
flow to the neurons or glial cells, for example following ischemia or
hypoxia, or by other trauma to the nerve or surrounding material. For
example, the primary damage resulting from hypoxia or ischemia-reperfusion
following occlusion of a neural blood supply, as in an embolic stroke, is
believed to be immunologically associated. In addition, at least part of the
damage associated with a number of primary brain tumors also appears to be
immunologically related. Application of the morphogen directly to the cells
to be treated, or providing the morphogen to the mammal systemically, for
example, intravenously or indirectly by oral administration, may be used to
alleviate and/or inhibit the immunologically related response to a neural
injury. Alternatively, administration of an agent capable of stimulating
morphogen expression and/or secretion in vivo, preferably at the site of
injury, also may be used. Where the injury is to be induced, as during
surgery or other aggressive clinical treatment, the morphogen or agent may
be provided prior to induction of the injury to provide a neuroprotective
effect to the nerve tissue at risk.
In still another aspect, the invention described herein provides methods for
supporting the growth and maintenance of differentiated neurons, including
inducing neurons to continue expressing their phenotype. It is anticipated
that this activity will be particularly useful in the treatment of nerve
tissue disorders where loss of function is caused by reduced or lost
cellular metabolic function and cells become senescent or quiescent, such as
is thought to occur in aging cells and to be manifested in Alzheimer's
disease. Application of the morphogen directly to cells to be treated, or
providing it systemically by parenteral or oral administration stimulates
these cells to continue expressing their phenotype, significantly inhibiting
and/or reversing the effects of the cellular metabolic dysfunction, thereby
maintaining the neural pathway at risk. Alternatively, administration of an
agent capable of stimulating endogenous morphogen expression and/or
secretion in vivo may be used.
In still another aspect, the invention provides methods for stimulating CAM
expression levels in a cell, particularly N-CAM expression in neurons. CAMs
are molecules defined as carrying out cell-cell interactions necessary for
tissue formation. CAMs are believed to play a fundamental regulatory role in
tissue development, including tissue boundary formation, embryonic induction
and migration, and tissue stabilization and regeneration. Altered CAM levels
have been implicated in a number of tissue disorders, including congenital
defects, neoplasias, and degenerative diseases.
In particular, N-CAM expression is associated with normal neuronal cell
development and differentiation, including retinal formation, synaptogenesis,
and nerve-muscle tissue adhesion. Inhibition of one or more of the N-CAM
isoforms is known to prevent proper tissue development. Altered N-CAM
expression levels also are associated with neoplasias, including
neuroblastomas (see infra), as well as with a number of neuropathies,
including normal pressure hydrocephalous and type II schizophrenia.
Application of the morphogen directly to the cells to be treated, or
providing the morphogen to the mammal systemically, for example,
parenterally, or indirectly by oral administration, may be used to induce
cellular expression of one or more CAMs, particularly N-CAMs. Alternatively,
administration of an agent capable of stimulating morphogen expression
and/or secretion in vivo, preferably at the site of injury, also may be used
to induce CAM production.
CAMs also have been postulated as part of a morphoregulatory pathway whose
activity is induced by a to date unidentified molecule (See, for example,
Edelman, G. M. (1986) Ann. Rev. Cell Biol. 2:81-116). Without being limited
to any given theory, the morphogens described herein may act as the inducer
of this pathway.
Finally, modulations of endogenous morphogen levels may be monitored as part
of a method of detecting nerve tissue dysfunction. Specifically, modulations
in endogenous morphogen levels are anticipated to reflect changes in nerve
tissue status. Morphogen expression may be monitored directly in biopsied
cell samples, in cerebrospinal fluid, or serum. Alternatively, morphogen
levels may be assessed by detecting changes in the levels of endogenous
antibodies to the morphogen. For example, one may obtain serum samples from
a mammal, and then detect the concentration of morphogen or antibody present
in the fluid by standard protein detection means known to those skilled in
the art. As an example, binding protein capable of interacting specifically
with the morphogen of interest such as an anti-morphogen antibody may be
used to detect a morphogen in a standard immunoassay. The morphogen levels
detected then may be compared to a previously determined standard or
reference level, with changes in the detected levels being indicative of the
status of the tissue.
In one preferred embodiment of the invention, the morphogen or morphogen-stimulating
agent is administered systemically to the individual, e.g., orally or
parenterally. In another embodiment of the invention, the morphogen may be
provided directly to the nerve tissue, e.g., by injection to the cerebral
spinal fluid or to a nerve tissue locus.
In any treatment method of the invention, "administration of morphogen"
refers to the administration of the morphogen, either alone or in
combination with other molecules. For example, the mature form of the
morphogen may be provided in association with its precursor "pro" domain,
which is known to enhance the solubility of the protein. Other useful
molecules known to enhance protein solubility include casein and other milk
components, as well as various serum proteins. Additional useful molecules
which may be associated with the morphogen or morphogen-stimulating agent
include tissue targeting molecules capable of directing the morphogen or
morphogen-stimulating agent to nerve tissue. Tissue targeting molecules
envisioned to be useful in the treatment protocols of this invention include
antibodies, antibody fragments or other binding proteins which interact
specifically with surface molecules on nerve tissue cells.
Still another useful tissue targeting molecule is part or all of the
morphogen precursor "pro" domain, particularly that of OP-1 or GDF-1. These
proteins are found naturally associated with nerve tissue but also may be
synthesized in other tissues and targeted to nerve tissue after secretion
from the synthesizing tissue. For example, while the protein has been shown
to be active in bone tissue, the primary source of OP-1 synthesis appears to
be the tissue of the urogenic system (e.g., renal and bladder tissue), with
secondary expression levels occurring in the brain, heart and lungs (see
below.) Moreover, the protein has been identified in serum, saliva and
various milk forms. In addition, the secreted form of the protein comprises
the mature dimer in association with the pro domain of the intact morphogen
sequence. Accordingly, the associated morphogen pro domains may act to
target specific morphogens to different tissues in vivo.
Associated tissue targeting or solubility-enhancing molecules also may be
covalently linked to the morphogen using standard chemical means, including
acid-labile linkages, which likely will be preferentially cleaved in the
acidic environment of bone remodeling sites.
Finally, the morphogens or morphogen-stimulating agents provided herein also
may be administered in combination with other molecules known to be
beneficial in maintaining neural pathways, including, for example, nerve
growth factors and anti-inflammatory agents.
Where the morphogen is intended for use as a therapeutic for disorders of
the CNS, an additional problem must be addressed: overcoming the so-called
"blood-brain barrier", the brain capillary wall structure that effectively
screens out all but selected categories of molecules present in the blood,
preventing their passage into the brain. The blood-brain barrier may be
bypassed effectively by direct infusion of the morphogen or morphogen-stimulating
agent into the brain. Alternatively, the morphogen or morphogen-stimulating
agent may be modified to enhance its transport across the blood-brain
barrier. For example, truncated forms of the morphogen or a morphogen-stimulating
agent may be most successful. Alternatively, the morphogen or morphogen-stimulating
agent may be modified to render it more lipophilic, or it may be conjugated
to another molecule which is naturally transported across the barrier, using
standard means known to those skilled in the art, as, for example, described
in Pardridge, Endocrine Reviews 7:314-330 (1986) and U.S. Pat. No.
Accordingly, as used herein, a functional "analog" of a morphogen refers to
a protein having morphogenic biological activity but possessing additional
structural differences compared to a morphogen as defined herein, e.g.,
having additional chemical moieties not normally a part of a morphogen. Such
moieties (introduced, for example, by acylation, alkylation, cationization,
or glycosylation reactions, or other means for conjugating the moiety to the
morphogen) may improve the molecule's solubility, absorption, biological
half-life, or transport, e.g., across the blood-brain barrier.
Among the morphogens useful in this invention are proteins originally
identified as osteogenic proteins, such as the OP-1, OP-2 and CBMP2
proteins, as well as amino acid sequence-related proteins such as DPP (from
Drosophila), Vgl (from Xenopus), Vgr-1 (from mouse, see U.S. Pat. No.
5,011,691 to Oppermann et al.), GDF-1 (from mouse, see Lee (1991) PNAS
88:4250-4254), all of which are presented in Table II (see Original Patent)
and Seq. ID Nos.5-14), and the recently identified 60A protein (from
Drosophila, Seq. ID No. 24, see Wharton et al. (1991) PNAS 88:9214-9218.)
The members of this family, which include members of the TGF-.beta.
super-family of proteins, share substantial amino acid sequence homology in
their C-terminal regions. The proteins are translated as a precursor, having
an N-terminal signal peptide sequence, typically less than about 30
residues, followed by a "pro" domain that is cleaved to yield the mature
sequence. The signal peptide is cleaved rapidly upon translation, at a
cleavage site that can be predicted in a given sequence using the method of
Von Heijne ((1986) Nucleic Acids Research 14:4683-4691.) Table I (see Original Patent)
describes the various morphogens identified to date, including their
nomenclature as used herein, their Seq. ID references, and publication
sources for the amino acid sequences for the full length proteins not
included in the Seq. Listing. The disclosure of these publications is
incorporated herein by reference.
In one preferred aspect, the morphogens of this invention comprise one of
two species of generic amino acid sequences: Generic Sequence 1 (Seq. ID No.
1) or Generic Sequence 2 (Seq. ID No. 2); where each Xaa indicates one of
the 20 naturally-occurring L-isomer, .alpha.-amino acids or a derivative
thereof. Generic Sequence 1 comprises the conserved six cysteine skeleton
and Generic Sequence 2 comprises the conserved six cysteine skeleton plus
the additional cysteine identified in OP-2 (see residue 36, Seq. ID No. 2).
In another preferred aspect, these sequences further comprise the following
additional sequence at their N-terminus -- see Original Patent.
Preferred amino acid sequences within the foregoing generic sequences
include: Generic Sequence 3 (Seq. ID No. 3), Generic Sequence 4 (Seq. ID No.
4), Generic Sequence 5 (Seq. ID No. 30) and Generic Sequence 6 (Seq. ID No.
31), listed below. These Generic Sequences accommodate the homologies shared
among the various preferred members of this morphogen family identified in
Table II, as well as the amino acid sequence variation among them.
Specifically, Generic Sequences 3 and 4 are composite amino acid sequences
of the following proteins presented in Table II and identified in Seq. ID
Nos. 5-14: human OP-1 (hOP-1, Seq. ID Nos. 5 and 16-17), mouse OP-1 (mOP-1,
Seq. ID Nos. 6 and 18-19), human and mouse OP-2 (Seq. ID Nos. 7, 8, and
20-22), CBMP2A (Seq. ID No. 9), CBMP2B (Seq. ID No. 10), DPP (from
Drosophila, Seq. ID No. 11), Vgl, (from Xenopus, Seq. ID No. 12), Vgr-1
(from mouse, Seq. ID No. 13), and GDF-1 (from mouse, Seq. ID No. 14.) The
generic sequences include both the amino acid identity shared by the
sequences in Table II, as well as alternative residues for the variable
positions within the sequence. Note that these generic sequences allow for
an additional cysteine at position 41 or 46 in Generic Sequences 3 or 4,
respectively, providing an appropriate cysteine skeleton where inter- or
intramolecular disulfide bonds can form, and contain certain-critical amino
acids which influence the tertiary structure of the proteins.
Similarly, Generic Sequence 5 (Seq. ID No. 30) and Generic Sequence 6 (Seq.
ID No. 31) accommodate the homologies shared among all the morphogen protein
family members identified in Table II. Specifically, Generic Sequences 5 and
6 are composite amino acid sequences of human OP-1 (hOP-1, Seq. ID Nos. 5
and 16-17), mouse OP-1 (mOP-1, Seq. ID Nos. 6 and 18-19), human and mouse
OP-2 (Seq. ID Nos. 7, 8, and 20-22), CBMP2A (Seq. ID No. 9), CBMP2B (Seq. ID
No. 10), DPP (from Drosophila, Seq. ID No. 11), Vgl, (from Xenopus, Seq. ID
No. 12), Vgr-1 (from mouse, Seq. ID No. 13), and GDF-1 (from mouse, Seq. ID
No. 14), human BMP3 (Seq. ID No. 26), human BMP5 (Seq. ID No. 27), human
BMP6 (Seq. ID No. 28) and 60(A) (from Drosophila, Seq. ID Nos. 24-25). The
generic sequences include both the amino acid identity shared by these
sequences in the C-terminal domain, defined by the six and seven cysteine
skeletons (Generic Sequences 5 and 6, respectively), as well as alternative
residues for the variable positions within the sequence. As for Generic
Sequences 3 and 4, Generic Sequences 5 and 6 allow for an additional
cysteine at position 41 (Generic Sequence 5) or position 46 (Generic
Sequence 6), providing an appropriate cysteine skeleton where inter- or
intramolecular disulfide bonds can form, and containing certain critical
amino acids which influence the tertiary structure of the proteins.
Particularly useful sequences for use as morphogens in this invention
include the C-terminal domains, e.g., the C-terminal 96-102 amino acid
residues of Vgl, Vgr-1, DPP, OP-1, OP-2, CBMP-2A, CBMP-2B, GDF-1 (see Table
II (see Original Patent) and Seq. ID Nos. 5-14), as well as proteins
comprising the C-terminal domains of 60A, BMP3, BMP5 and BMP6 (see Seq. ID
Nos. 24-28), all of which include at least the conserved six or seven
cysteine skeleton. In addition, biosynthetic constructs designed from the
generic sequences, such as COP-1, 3-5, 7, 16, disclosed in U.S. Pat. No.
5,011,691, also are useful. Other sequences include the inhibins/activin
proteins (see, for example, U.S. Pat. Nos. 4,968,590 and 5,011,691).
Accordingly, other useful sequences are those sharing at least 70% amino
acid sequence homology or "similarity", and preferably 80% homology or
similarity with any of the sequences above. These are anticipated to include
allelic and species variants and mutants, and biosynthetic muteins, as well
as novel members of this morphogenic family of proteins. Particularly
envisioned in the family of related proteins are those proteins exhibiting
morphogenic activity and wherein the amino acid changes from the preferred
sequences include conservative changes, e.g., those as defined by Dayoff et
al., Atlas of Protein Sequence and Structure; vol. 5, Suppl. 3, pp. 345-362,
(M. O. Dayoff, ed., Nat'l BioMed. Research Fdn., Washington, D.C. 1979). As
used herein, potentially useful sequences are aligned with a known morphogen
sequence using the method of Needleman et al. ((1970) J. Mol. Biol.
48:443-453) and identities calculated by the Align program (DNAstar, Inc.).
"Homology" or "similarity" as used herein includes allowed conservative
changes as defined by Dayoff et al.
The currently most preferred protein sequences useful as morphogens in this
invention include those having greater than 60% identity, preferably greater
than 65% identity, with the amino acid sequence defining the conserved six
cysteine skeleton of hOP1 (e.g., residues 43-139 of Seq. ID No. 5). These
most preferred sequences include both allelic and species variants of the
OP-1 and OP-2 proteins, including the Drosophila 60A protein. Accordingly,
in another preferred aspect of the invention, useful morphogens include
active proteins comprising species of polypeptide chains having the generic
amino acid sequence herein referred to as "OPX", which accommodates the
homologies between the various identified species of OP1 and OP2 (Seq. ID
No. 29).
The morphogens useful in the methods, composition and devices of this
invention include proteins comprising any of the polypeptide chains
described above, whether isolated from naturally-occurring sources, or
produced by recombinant DNA or other synthetic techniques, and includes
allelic and species variants of these proteins, naturally-occurring or
biosynthetic mutants thereof, as well as various truncated and fusion
constructs. Deletion or addition mutants also are envisioned to be active,
including those which may alter the conserved C-terminal cysteine skeleton,
provided that the alteration does not functionally disrupt the relationship
of these cysteines in the folded structure. Accordingly, such active forms
are considered the equivalent of the specifically described constructs
disclosed herein. The proteins may include forms having varying
glycosylation patterns, varying N-termini, a family of related proteins
having regions of amino acid sequence homology, and active truncated or
mutated forms of native or biosynthetic proteins, produced by expression of
recombinant DNA in host cells.
The morphogenic proteins can be expressed from intact or truncated cDNA or
from synthetic DNAs in procaryotic or eucaryotic host cells, and purified,
cleaved, refolded, and dimerized to form morphogenically active
compositions. Currently preferred host cells include E. coli or mammalian
cells, such as CHO, COS or BSC cells. A detailed description of the
morphogens useful in the methods, compositions and devices of this invention
is disclosed in copending U.S. patent application Ser. Nos. 07/752,764,
filed Aug. 30, 1991, and 07/667,274, filed Mar. 11, 1991, the disclosure of
which are incorporated herein by reference.
Thus, in view of this disclosure, skilled genetic engineers can isolate
genes from cDNA or genomic libraries of various different species which
encode appropriate amino acid sequences, or construct DNAs from
oligonucleotides, and then can express them in various types of host cells,
including both procaryotes and eucaryotes, to produce large quantities of
active proteins capable of maintaining neural pathways in a mammal,
including enhancing the survival of neurons at risk of dying and stimulating
nerve regeneration and repair in a variety of mammals, including humans.
Claim 1 of 18 Claims
1. A method for decreasing neuronal cell
death associated with a neuropathy, wherein neuronal cell survival is
mediated by expression of N-CAM or L1, comprising: administering to a
subject afflicted with said neuropathy a morphogen comprising a dimeric
protein, the dimeric protein having one or more of the following: (1) a
conserved C-terminal six-cysteine skeleton at least 60% identical to
residues 43-139 of SEQ ID NO: 5; (2) a conserved C-terminal seven-cysteine
skeleton at least 70% homologous to residues 38-139 of SEQ ID NO: 5; (3) a
conserved C-terminal six-cysteine skeleton at least 70% homologous to
residues 43-139 of SEQ ID NO: 5; or (4) an amino acid sequence of human
OP-1, mouse OP-1, human OP-2, mouse OP-2, 60A, GDF-1, BMP2A, BMP2B, DPP,
Vgl, Vgr-1, BMP3, BMP5, or BMP6; wherein the morphogen (i) stimulates the
production of said N-CAM or L1 in said neuronal cell, and (ii) decreases
neuronal cell death associated with said neuropathy.
If you want to learn more
about this patent, please go directly to the U.S.
Patent and Trademark Office Web site to access the full


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Wedding Band of Gold Dated 1899
Suitable for man or woman, this smashing solid 18k yellow gold wedding band is octagonal in configuration. Each of the eight sides is deeply worked with patterning and a foliate motif. Full English hallmarks add a touch of historical interest and exact dating.
Date: 1899.
Measurements: 1/4 of an inch (0.8 cm) in length north to south on the hand. Weight of 3.8 grams (2.5 dwt).
Ring Size: US 8-1/2 (UK Q-1/2; Euro or Int. Circum. 58.2 mm; Int. Dia. 18.5 mm; Japan 17). This ring and can be sized down with a bit of pattern loss but cannot be sized up. Ring sizing information.
Hallmarks: Full set of English hallmarks for 18k, Chester (England), a date letter for 1899; mostly worn maker's mark with a V.
Condition: Excellent.
Origin: English.
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(MB: t. 21; l. 60'11"; b. 11'7"; dph. 5'7"; dr. 1'11" (forward); s. 14¼ k.; cpl. 5; a. 2 1-pdrs.)
Wyandance (SP-359)—a motorboat built in 1905 at Bayonne, N.J., by the Electric Boat Co.—was acquired from Mr. M. S. Burrill of Jericho, Long Island, N.Y., on 19 June 1917 and was commissioned on 24 August 1917 at New York. She served the Navy only briefly— a little more than five months—as a patrol boat with the section patrol in the 3d Naval District. Wyandance was decommissioned early in 1918; and her name was struck from the Navy list on 2 February 1918, the day on which she was returned to her owner


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Do you need some volunteer hours for school? Do you want to help cute littlies learn how to read? You can do that at the Library!
We need:
Reading Buddies volunteers for Bowness Library
Reading Buddies volunteers for Forest Lawn Library
Interested? Fill out the Youth Volunteer Application here, or contact us. Talk to Samuel (403-260-2709) or Tammy (403-221-2062).
And for the tech-savvy, try Computer Buddies. In this program, you will help students in Grades 1 to 6 learn to safely navigate the Internet and get creative with Microsoft Office.
Computer Buddies volunteers for Bowness Library
Computer Buddies volunteers for Forest Lawn Library
To volunteer for Computer Buddies, contact Jessica Hagel at 403-221-2036, or at email@example.com.
If you're 15 or younger, you can enter the Children's Fiction Writing Awards - and get published!
Winning stories will be published in an anthology. Your biography and photo will be in there too, so start practicing your Top Model smile. But hurry - the deadline is October 10th.
In the 12-15 year old category, stories need to be at least 3000 words (about 6 pages).
The stories must fall within one of the following genres: Science Fiction, Fantasy, or Mystery. So if your story has vampires, spaceships, or secrets, you're good.
Check out the Calgary Book Fair site for details.
Writer's block? Check out these collections to get some ideas:
Lay-Ups and Long Shots: an Anthology of Short Stories
Angry Management by Chris Crutcher
The Starry Rift: Tales of New Tomorrows (includes stories by Scott Westerfeld and Neil Gaiman)
Firebirds Rising (includes stories from Tamora Pierce and Diana Wyne Jones)
Prom Nights from Hell (includes stories by Stephenie Meyer and Meg Cabot)
The media is, was, might be, will be, has been blamed for, has been praised for, can do, can't do, provides, causes and influences a lot of things. We are exposed to it in one form or another every day, if not every minute. Sometimes we choose to participate (like when you read this awesome blog) and sometimes a bus just happens to go by (how did it know I needed more mayonnaise in my life?!).
Yet, whether you choose to be exposed to commercials / films / sitcoms / news / books (have you ever read a book by accident?) / websites / posters, or not, odds are it's going to happen. The only choice you have is what you do with this information.
I'm sure your teachers have stressed the importance of using reliable, authentic sources when writing reports and essays in school, and the information you use in your day-to-day life is no different. Although I'm sure many of us aren't fooled by the purported pros of solar powered broom racks (they're environmentally friendly!), things aren't always so obvious.
Can a picture lie?
Can you determine the difference between fact and opinion?
Who publishes websites?
Do you decide what is attractive to you? Is it biological, or is it something you learn?
There are many great resources dedicated to media awareness. Media-Awareness.ca is a non-profit organization with a great website which covers everything from surfing the web (should you fill out that online survey???) to the portrayal of men and women in the media. Did you know that the average model weights 20% less than the average woman? If you fit the dimensions of a Barbie doll, you would have to remove half of your liver and most of your bowels. Gross.
Although the "media" comes in many forms, the common factor is information. Make sure you know who put that information there and why, especially if it is information that you are basing your decisions or opinions on. For reliable online sources you can check out our E-Library collection of magazine articles, encyclopedias, business directories and other databases. You can also browse our catalogue online to search for books, movies, magazines, music… media.
There is a wealth of truly wonderful / awful / informative / ridiculous / strange / and fascinating information out there, but remember to use your ?'s as often as possible.


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Minnesota Vikings Tickets
The Purple People Eaters have been living up to their fearsome nickname as the deafening crowds at the Hubert H. Humphrey Metrodome will testify. Minnesota Vikings tickets are always likely to sell out. So don't miss out, whether you want to sit on the 50 or in the end zone you can get your Minnesota Vikings tickets here, now.
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Jackson, Tennessee
I went to this restaurant back in October 2013 and it was great! I had the scallops and my dad had the shrimp and the deviled crab. My mom had the shrimp. Food overall was good. We were there on an off time and there weren't any people there. I highly recommend this restaurant to anyone going to Myrtle Beach!
ref: 27230
Kenna, West Virginia
This was our 2nd time here, my husband ordered stuffed flounder, and I had ordered sauteed scallops, which both were delicious, our waitress was excellent, the atmosphere was great, staff very helpful.
ref: 27076
Burlington, North Carolina
We have wanted to try a seafood restaurant in Calabash for many years and decided to ride down from Myrtle Beach and find one. We didn't have a clue as to which one to try but wanted to have a view of the water. When we came to Captain John's - it fit our needs exactly. We immediately found the senior menu and picked out what we wanted. My husband got shrimp and deviled crab and I got flounder and deviled crab. Everything was delicious! We paid about the same here for a great seafood meal as we would have back home in Burlington, North Carolina. We now have our Calabash restaurant when we visit Myrtle Beach each year.
ref: 27069
Dunbar, West Virginia
My family ate here last summer and we were so happy with it. My nephew has a form of autism so it's very hard to go places with him. Captain johns staff was very understanding and so nice. It made my made nephews day and he's already asking if we can eat "at that place on the water"!!! We never go out while on vacation because of the issues and responses we get from other people around us. Thank you so much"!!!
ref: 26647
Greensboro, N
Have been going to eat at Capt. Tom's for about 25 years. Best food at the beach and consistently good. Great wait service and friendly management.
ref: 25927
Charleston, West Virginia
My wife and I traveled here from WV. We liked the surroundings and the food was great.We had the seniors dinner and was well leased with the price too. The man who took our order was very good, and took good care of us. Some the reviews on here were bad, but would probably complain about their mother. To Capt. John's management keep up the good work! The review by an employee downgrading peoples review, only makes the company look bad.
\R. G. Charleston wv
ref: 25829
Charleston, West Virginia
This is a fantastic restaurant. The food and atmosphere were both great. I will go again and again. Anyone that would say otherwise is pathetic and I would not want them to be in the same restaurant with my family. Cannot wait to go again. Keep up the good work.
ref: 25740
Hayesville, North Carolina
We were quickly seated, which was a nice surprise, since the restaurant up the road had a 75 minute wait! Of course, this also made us wary of what to expect. We were quicky greeted by a wonderful waiter, Erwin, who was very friendly and knowledgable. We ordered the chowder, it was very good. I had the flounder and my husband had the scallops. We both thought the food was excellent and our service was above average. Will definitely go back, I would certainly recommend. The restaurant had a nice atmosphere and water view, although we opted for a booth, which was further from the windows. Thank you Capt. John's for a nice dinner!
ref: 25662
Greensboro, North Carolina
Had 9 reviewers in my group today. Hush puppies were perfect and plentiful. I did have one voicing the opinion that the flounder was a little dry, and 2 that said it was only soso. The other 6 including myself gave them 5 stars across the board. Hot, fresh, and plentiful.
ref: 25605
Telford, Tennessee
There were three of us from Tennessee for supper July 7 about 6pm. As we came into Calabash most of the restaurants had lines out the door. No line at Captain John's and we were seated right away. I had a Fuzzy Navel that didn't seem to have any alcohol. I had the senior fried oysters that were good. We all liked the hush puppies. My husband had fried shrimp and our daughter had a small lobster tail.
Two hours later I threw up the Fuzzy Navel three times and lost all my supper. Was a horrible night. Evidently the oysters were bad.
Our server was nice and tried to keep up but he had too many tables and too many people to serve.
ref: 25603
Lake Waccamaw, NO
I've been to cap't johns many,many,many times out of the last 20 years.they have a beautiful view of the calabash river with docks that constantly have shrimp boats coming in to dock with their fresh catch for the day.they also have large fishing boats at their docks that you can either go out for 1/2 day or go to the gulf stream for a whole day.when you get back to the dock after your wonderful day of fishing,you can get your catch cleaned right there on the dock before ever leaving......wonderful! now as for the food everything i've ever had to eat there was absolutely excellent! once in a long while the hushpuppies aren't scalding hot, but if you will say something right then to your server they will straighten that out asap for you.....i read a review from someone that says 6 mins tops in a hot fryer......sir you have no clue as to what you are saying.....everything at cap't johns is cooked to order and that includes the hushpuppies! what most of us need to realize is that is a very large resturant,and our little table isn't the only one in there.....but never the less we are always treated as though we are just as important as all the rest and taken care of in that fashion!remember calabash style means lightly breaded,lightly fried and yes the small shrimp....i don't eat seafood in calabash anywhere but cap't johns and it might be to your advantage to return and try it again,you might be very surprised!.
ref: 25231
Nmb, South Carolina
The batter used in which to fry the fish did not taste greasy. Everything we ate tasted fresh and home made. Our waitress, Jean, was really good. I was impressed with she remembered items we needed and the way she picked up on what we liked and we would need before we even asked.
ref: 25229
Winchester, Virginia
Have always had excellent service, food and atmosphere.
The owner and staff have always been pleasant and courteous. My husband and I always make a trip from Winchester VA he always wants to eat there.
ref: 25112
Princeton, West Virginia
Our family stops at Captain John's every time we go to the beach. The atmosphere was great, and was also before the remodeling. We ate the seafood platter and the sauteed shrimp. Sandra was the best. She brought our food promptly and kept the tea coming.
ref: 24852
Florence, South Carolina
The fish fried so crisp it could hardly be pulled apart.
The shrimp over breaded and soaked in grease.
The deviled crab so small it was funny.
The baked potatoes small and tasted like it was baked three days before and let in the oven.
The clam soup tasted like water with a couple of over cooked chewy clams in it.
ref: 24410
Washington, Virginia
Our service started off a little rocky as whoever was to serve us forgot us. A nice fellow stopped to ask if anyone was taking care of us and he said he would take care of us. He was great. He had our meal fast and it was the best seafood I think I ever had. I had the fried seafood platter. I will return again next year for sure. It is as good as Capt. George's if not better. Everyone should try it at Capt. John's.
ref: 24028
Stephens City, Virginia
The family and myself travel to Calabash from Stephens City, Virginia abt. every year to every other year.
Upon arriving in Calabash,my wife insists that our first stop be to Capt. Johns to wind down from the long drive and having dinner.
My adult children and their significant others always enjoy going as a family on trips to Calabash.
We all enjoy the quality and quantity of service at Capt. Johns.
Delicious food, confortable atmosphere and great prices.
Their staff have always treated us very wonderfully.
Ok Captain Johns, We'll see you in July!!!
ref: 22221
Nashville, Tennessee
Awseome experience! Food was great but service was amazing! You've got to ask for ben! Southern hospitality at it's finest! He will keep you laughing! You're made to feel like family from the time of arrival!
ref: 21586
St. Louis, Missouri
The scallops were the best I ever had. A heaping portion on a large platter made it a real value. My companion had other seafood and was happy with it...maybe not as happy as I was with my scallops but we both recommend it. Oh the hush puppies are different and excellent.
ref: 21583
Hickory, North Carolina
I have eaten at Capt. Johns 3 times. The first time I went, it was just a new restaurant, so EVERYONE was there. My parents didn't want to go to Captain Nances because their food is just disgusting. The first time, we had to wait a while but their crab legs were DELICIOUS. The second time we went, we had to wait a little, probably about 10 minutes. Crab legs were still good. But this year we went around my birthday, 3 days before my birthday actually. The food was not that good, but it was fun to play with it because it was my mother, my sister, and my sister and i had 3 friends altogether there. It was hilarious, but I don't think the person who had to clean it up had fun :p And we didn't have to wait at all, and there were probably 5 people in that restaurant besides us. The first and second time we went it was PACKED. Eat here if you enjoy crab legs though.
ref: 21500
Sunset Beach, North Carolina
Mobbed with families during the summer, this place is your typical tourist trap where they throw mountains of bland deep-fried food at you. Don't believe they could stay in business if they didn't have the hordes of beachgoers looking for shrimp platters.
ref: 20841
Belmont/oib, North Carolina
For 25 years may family and friends have frequented Calabash seafood houses at least 20 times a year. A competitor had most of our business for many of those years and not one time did the family owners ever walk over to our table to say thank you for your patronage or recognize us as we paid our check. After spending on average $2000 per year I would have expected them to at least say "nice to see you again". This past year we have been eating at all the dfferent Calabash restaurants and have now adopted Captain John's as our restaurant of choice. Having eaten there over 8 times this summer, we have found the atmosphere inviting, the food well prepared, the host and wait staff to be cordial and attentive, and the food quality better than the competition. I had some fish one evening that didn't meet my expectations and told the server. He immediately took the plate and replaced it within 5 minutes with hot portions and apologized. We have dined on weeknights, weekends, early, and late. Though sometimes having to wait longer than I like to wait, I get the attention once seated and realize this restaurant seats and serves its customers as quickly as they can and the wait is always worth it. The management seems to appreciate business patronage and even though not yet familiar with my name, recognize me and family as repeat customers.
ref: 20757
Mason, Ohio
Seafood had no flavor or seasoning. It was overcooked as well. This was to be my last great meal during my vacation and it was a dissapointment. I wouldn't recommend eating there unless you get the "Hush Puppy Buffet".
ref: 20105
Liberty Township, Ohio
I vacation in Calabash every single year with my extended family. There are in total, 11 of us. We always go to Captain Johns. I don't understand these negative reviews. We had a plethora of hushpuppies and the flounder was right on par. The service was great. I don't remember every having to even ask for a refill. I also had the french silk pie. It was DELICIOUS. I highly recommend this restaurant to anyone I know who is coming to Sunset Beach.
ref: 19344
Martinsville, Virginia
Myself and three friends had dinner at Captain John's. When we received our orders we all had a large portion of uneatable food. The oysters were small and burnt and I think the oil was bad. I am not exaggerating when I say every member of my party threw up their food as soon as we returned to our rooms. Stay away!!! After we paid, we told the manager, Mr. Frank, we thought this was our worst seafood experience ever and he said we are the only complaint he has received tonight. We must be the only people that have eaten there today. For the record, our waitress was excellent.
ref: 19230
Seymour, Tennessee
We ate at Captain John's and the food was very good. Not excessively greasy. The service was excellent. I would highly recommend.
ref: 18862
Procidence, Kentucky
Was wonderful!!!!! When ask to speak to the cook.... he came to my table and was very delighful. I told him how wonderful the food was and thank him for making my trip more wonderful. Dale, I believe was his name. I did miss Captian John. It is not the same with out him and you could tell the difference.
I hope the son's of Captian John know what a jewel they have in Dale. Thanks you guys.
ref: 18860
Orlando, Florida
I recently dined at Capt John's with my husband and I must say that it was a genuine treat!! We were seated overlooking the water where we could watch the boats. The server arrived at our table with fresh, hot hush puppies within 2 minutes of us being seated. I ordered the deluxe seafood platter and it was cooked to perfection. The fish was tender and tasty as was the oysters and shrimp. The food was on the table within 10 minutes of ordering and our server was attentive and anticipated our needs well. I would recommend Capt John's to anyone who wants a truly delightful dining experience!
ref: 18855
Medina, Ohio
This has been a regular stop for us each year and it is usually very good. We decided to go on our last night in MB so we could have seafood one last time. I have to say that the food, this time, was not that great. They gave a bowl the size of a shot-glass for the salad bar (which was less than desirable). The entrees came out and most of them were cold and some had to be sent back for a little more heat. I had the crab legs which were very good, but were ice cold. They give you drawn butter which is served in a cold dish (doesn't work very well) with no burner. They don't put anything over the crab legs to keep them hot (like a cloth napkin with boiling water on it) and with the butter getting cold....you get the idea... I will say the service was outstanding, but with cold food, it still wasn't a great experience. Hopefully this was just an off-night.
ref: 17576
Seaford, New York
My FH and I walked in and were seated right away, however we sat there for 20 minutes and a waitress STILL failed to greet us. The place reminded me of a dirty, noisy, cafeteria. Needless to say, we left.
ref: 16651
Atlanta, Georgia
I guess this is like most places...just a matter of your server and time you were in the restaurant. We were there on Saturday the 1st of August. It was HORRIBLE. The hushpuppies were soggy and we asked for a new basket. We were told it would be 15 minutes. WTF...a deep fryer 4-6 minutes maximum. The flounder tasted frozen and the waitress was incompetent. Will not be back, but I doubt they care.
ref: 16522
Kingsport, Tennessee
Ate there tonight. Food was great. I had the Small Seafood Platter ($11.95) which came with one large piece of flounder, shrimp and a devaled crab as well as a baked potato and cole slaw. The fish was moist and fried in a nice cornmeal, the shrimp was lightly battered and succulent as for the develed crab it was to die for. My 8 year old daughter had the flounder and shrimp, fries and cole slaw (seniors menu $7.95) and thought the flounder was the "best fish she has ever eaten" she even swapped most half of her shrimp to me for the last half of my flounder. My 5 year old had shrimp an fries off my 8 year olds plate. The only bad thing I can say is the fries was from a bag so order the baked potato. Oh yeah dont let the words small and senior fool you. we all left stuffed and I am a big eater. My wife was with us and doesn't like seafood so she ate off the salad bar ($5.50) which was fresh and well kept (she is a salad nut anyway).
ref: 16506
Daytona Beach, Florida
Nightmare...In one word that should describe this place. Stay away from Captain John's. This place was horrible. The experience in this place left a sour taste (in more ways than one) on our entre beach trip!
ref: 16194
Raleigh, North Carolina
We went to Capt John's on Sunday night at 6:30pm on June 28, 2009. Walked right in and were seated immediately as the place was less than half full. We were waited on within 10 minutes. There were seven in our party. I ordered the Whiting special. The Whiting was only one piece and it was bony and skinny. It wouldn't have fed a cat. Two others ordered the rib eye steak which was not done according to the order and had to be sent back. The rib eyes were tasty but the price was expensive. Another ordered a shrimp plate and it was very small and expensive for the amount. Another ordered a large seafood platter which was small and expensive. Another ordered the two item seafood platter and it was adequate. It took 30 minutes to receive our food from the time it was ordered.
I talked to the waiter about my Whiting and he said he could bring me a flounder for $6 more. I asked to see the manager. The manager said I got exactly what I ordered and I should be satisfied. Well I wasn't. There are plenty of good restaurants in Calabash and I would avoid Capt John's.
ref: 15767
Jackson, Tennessee
This is the best place to be if you want some good shrimp that's not overpriced.
If you go there, do the sunset cruise.(It's fun!)
ref: 15090
Winston-salem, North Carolina
Overall it was a classic North Carolina fish resturant. They had a good selection of shrimp, flounder, oyster, ect.. And everything, for the most part, can be prepared anyway you like (broiled, fried, grilled, ect..). The price is reasonable, and they have several steaks in case you have a non-seafood lover in your life. The food itself tasted fresh, came in a reasonable time, and I would recommend it to others. However, my only draw back is lack of creativity. Like many seafood resturants at the beach they do the basics well or better. But they have nothing that really sets them apart. Don't expect something fancy like pecan crusted flounder, or a rosemary/dill rubbed tilipa... If you want good seafood at a good price this place isn't bad.
ref: 12969
Bahamanc, North Carolina
After years of not coming to Capt.Johns I was excited to be there. NOT what I expected. They should look at themselves and find that 20 years ago, this was the place to be. So upset. I had told my daughter that this was the best. It was the worse. They even started cutting lights off before we finished. Menu a mess. Food cold. So upset. $85 for junk food I could have gotten on a strip mall. Will not go there again.
ref: 11703
Kings Mountain, North Carolina
This is the best place for there green shrimp me and mother has eaten shrimp there at least four or five times.
ref: 11619
Youngsville, North Carolina
This was our first time visiting Calabash. We were very happy with Capt John's. Our server was excellent, the food was delicious, the salad bar was delicious too. The view of the water was beautiful. We were so happy with our decision to eat here.
Our bill was $46.00 for 2 dinners + 2 salad bars + 2 beers + 1 soda & a bowl of soup. That did not include the tip.
I ordered the Fantail Shrimp with baked potato & salad bar. My husband ordered the Steak (filet) it was cooked perfectly & also delicious.
With so many seafood restaruants to pick from in Calabash - you can not go wrong with this place.
The interior decor could use a little updating - but it was still very clean & nice.
ref: 11433
Kingsport, Tennessee
My Dad took me here when I was a little girl. I go every year, sometimes 2 or 3 times, whenever I go to Myrtle Beach I take the short drive up. It is a family tradition to eat there and then go to Callahan's and get christmas ornaments. Love it, would recommend it to anyone who loves good, fresh seafood. My Mom dreams about the crab cakes!
ref: 11195
Greeneville, Tennessee
I persuaded our group of four to try this place after checking the reviews here, surprisingly, it wasn't as good as I had hoped for. I guess the waiter sort of set the tone for the evening when he noticed my University of Tennessee shirt and exclaimed, "I hate Tennesee fans!" (He was from Alabama). All that aside, the hushpuppies were far from the best that we have had, my garlic basted shrimp was just "OK", another in the party couldn't eat his salad because the lettuce wasn't cold, and his fried shrimp didn't have much taste. Another in the party did say that his flounder was good, so I guess it wasn't a total loss. The waiter did attend to our drinks, etc., so even with the remarks he had made earlier, he didn't ignor us. We had previously tried two of the other waterfront restaurants at the same area, and will undoubtedly revisit one of those on our return next year.
ref: 11101
Candler, North Carolina
The food was delicious, the service was excellent and the hush puppies are to die for!!! We went there about 29 years ago and loved it. Should have been back before now. I surely will go again next year.
ref: 8538
Belmont, N.
We travel to North Myrtle Beach at least 4 times a year, and we always include Captain John's in our plans. We always order the sea food platter,(blackened), and we have never been disapointed. The food is great, and our grandkids love the hushpuppies. The service is outstanding as well as the atmosphere. We will be back in November for an anniversary trip, so we will see you then.
ref: 8489
Akron, Ohio
We went to Capt. John's in search of good seafood, but what we received was far from that. We thought that eating at a seafood house would guarantee fresh seafood prepared properly. What we actually received was overcooked, bland, and right out of a can. The seafood platters were cooked so long that everything was dry and mushy. The shrimp were the biggest disappointment though. We were expecting nice sized, fresh shrimp, but we received popcorn sized, right out of a can shrimp.
We do not recommend going here if you are looking for seafood. The only thing the food is good for is fishing bait. You would have a better meal at Long John Silver's
ref: 7633
Johnsonville, South Carolina
We have been customers of this seafood house for years and have always been delighted by the service, atmosphere, and the food. We ate there on 8-8-07 and had our first bad experience. First I ordered a bowl of oyster soup as an appetizer and didn't get it until the main course was served. Also the fried oysters were overcooked and cold. Had one scallop that tasted awful. Guess after all these years we were bound to have a bad visit, but were totally surprised to have it at capt. John's. Don't know if we'll make that long trip again soon.
ref: 7520
Lancaster, Ohio
Went there for the first time and had a good meal and I liked the atmosphere of the restaurant.
ref: 6757
Myrtle Beach, South Carolina
I've eaten here with my family the last two times I've eaten in Calabash. The food is good and plentiful, and the service is alright. I had scallops and oysters, and the scallops were exceptional. They serve a delicious honey-butter with their hush puppies and it's hard not to fill up on them before your food arrives. I enjoyed looking out over the water while I ate.
ref: 6513
Akron, Ohio
We have been going to Capt John's for 20 yrs or so. This is "the" place for seafood. It is always one of the highlights of vacation. We talked to the owner on this visit, and he was so nice and friendly. The service is always excellent. The hush puppies are the best we have ever eaten. We cannot wait for vacation next year and dinner at Capt. John's.
ref: 6363
Rockville, Maryland
Worst restaurant experience of my life. Four of the five people at our table could not eat their food... I just turned mine back after 2 bites. You would think that a restaurant on the water water would have fresh seafood not frozen! even frozen it was the worst meal ever placed before me. Never once did the owner or manager come to the table to see why the food was returned or not eaten. The waitress was an order taker that's it... The bill came un-itemized for a total of $100. The whole experience was so bad that we just let it go and left. This is your worst kind of tourist trap. Save you money... Go to wendys..
ref: 6072
Chicago, Illinois
Captain John's is the highlight of our annual trips to Myrtle Beach. The seafood platter is a fish lover's dream come true! We've been coming here for the past 18 years and have never been disappointed. Our kids can't get enough of the hush puppies and would love to make a meal out of them alone!!! As the winter snows pile up here in Chicago, I close my eyes and dream of my next visit to Captain Johns!
ref: 5087
Raleigh, North Carolina
My wife and I were down in October 06, celebrating our Anniversary. We stopped by late one afternoon, had a great meal, and really enjoyed the place. The Owner's were in and they were exteremely nice and helpful. Would recommend it highly.
ref: 5065
Newport, North Carolina
My husband & I planned to eat lunch at Capt Johns , Nov. 17th, 2006.
Imagine our disappointment when we found it closed.
We're not sure for how long....
ref: 4351
N. Myrtle Beach, South Carolina
My husband and I went to Captain Johns on July 29th with my best friend and her 2 adult children. First time there, won't be last! Best of the best in Calabash area. Been to 4 others and not as impressive as this one! Much cleaner, friendlier, and food was AWESOME. Waiter was top notch even in the HEAT, which was the only drawback. Need more ceiling fans in all areas of dining area. Other than that nothing needs improving upon. Had Seafood platter, best ever, especially the shrimp --- very fresh and great. Others had flounder and equally as good.
S. Sands, N. Myrtle Beach, SC
ref: 3393
Kure Beach, North Carolina
Great service and the food was delicious. Heard a lot about the Calabash style of food and it was wonderful!
ref: 3206
Rochester Hills, Michigan
Great service and the food was delicious.
ref: 3205
Mebane, North Carolina
We picked Capt. John's because it had the most cars in the parking lot (always a good sign) and we were not disappointed. We got seated immediately and the service was excellent throughout the entire meal. Our server brought us more hush puppies and iced tea without us ever having to ask. The grilled shrimp and tuna were some of the best we
have ever had. And the crab legs and fried calabash shrimp were also exceptional. Everything was tasty and fresh! My husband was impressed by the slaw and ate 3 bowls of it. And the kids loved the hush puppies with the honey butter dip. We'll most certainly go back there again next time we come to North Myrtle Beach.
ref: 2715
Creedmoor, North Carolina
We just made our first visit to Capt. Johns and found it to be very nice on the inside with a great water view and the smoking area was in a room to itself. The calabash shrimp was some of the best I've had but the fried flounder left alot to be desired. My daughter had the lemon-pepper fish and said it was good. The wait there was not as long as some other places and they also have a salad bar.
ref: 1018
Morganton, North Carolina
My family has been coming to Capt. John's for over 20 years and we have tried all the Resturants around Capt. John's and none has ever compared to this favorite hot spot. We used to love to come to Capt. John's then ride the Mary B cruise boat. Thank you for Great Food and a good time. Christie Buckland..
ref: 779


text:
Olia Womens Gold Jess Tassle Necklace
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How to fix the Comcast lag problem?
|Soliouss | 09/04/2009 19:31:36
I've been getting terrible ms for a good 2-3 weeks now. Instant spells have been taking anywhere from half of a GCD to cast to PAST an entire GCD to cast. I've never had this problem last this long before in my entire life. If there were ever Comcast problems, the problem usually only happened for a day or so, maybe a few days, never a week. It has been going on for a good 3 weeks now and I'm really hating this game ATM.
Naturally everything else works at proper speed. Any other online game, internet sites, XBL, anything else besides World of freaking Warcraft.
HOW DO I FIX THIS PROBLEM? I tried waiting it out but it DOES NOT SEEM TO BE GOING AWAY.
|Charlesps | 09/04/2009 19:43:16
Hello Soliouss,Technical support needs your feedback. Please take the time to fill out a survey using the link below and tell me how I am doing:
We should consider tracing to your realm rather than the logon server for this issue using the netstat command.
1) Click Start and then Run
2) Type "command" and press Enter
1) Click Start and in the "Start Search" field type "command" or "cmd"
2) Right click on the CMD icon and select Run as - Administrator to start the Command window
Running Netstat
Creating the Traceroute
|Charlesps | 09/04/2009 22:36:05
This is a diagnostic to see if we can find an issue on the route. If there is one you can take that information to the ISP and ask them to look into and resolve the issue.Technical support needs your feedback. Please take the time to fill out a survey using the link below and tell me how I am doing:


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The Volcker Rule is a requirement in the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010 that is sometimes referred to as a "mini-Glass-Steagall." It is based on the same principle...December 9, 2013 | Explainer |
The City of Detroit's bankruptcy was driven by a severe decline in revenues (and, importantly, not an increase in obligations to fund pensions). Depopulation and long-term unemployment caused Detroit...November 20, 2013 | Report |
Three years have passed since David (the American public) defeated Goliath (the big banks) and the Dodd-Frank Act became law. Implementation staggers forward and there have been some recent...July 21, 2013 | Policy Brief |
This is the third of several papers examining the underlying validity of the assertion that regulation of the financial markets is unduly burdensome. These papers assert that the value of the...June 13, 2013 | Report |
On March 15, 2013, the Senate's Permanent Subcommittee on Investigations held hearings on the London Whale scandal. The indomitable and indefatigable Chairman Carl Levin, ably supported by the...March 19, 2013 | Report |
My name is Wallace Turbeville. I am a Senior Fellow at Demos, a national public policy organization working to reduce political and economic inequality, advancing a vision of a country where we all...March 14, 2013 | Testimony |
Demos Strongly Urges the Senate to Confirm Richard Cordray as Director of the Consumer Financial Protection Bureau
Demos strongly urges the members of the U.S. Senate Banking Committee to vote in favor of confirming Richard Cordray to direct the Consumer Financial Protection Bureau for a full term. Director...March 11, 2013 | Advocacy Letter |
This is the second of a series of articles, entitled "The Financial Pipeline Series", examining the underlying validity of the assertion that regulation of the financial markets reduces their...March 8, 2013 | Report |
This is the first article in the "Financial Pipeline Series," which will examine the underlying validity of the assertion that regulation of the financial markets reduces their efficiency. These...December 5, 2012 | Report |
What does the acronym, "LIBOR," stand for? The "London Inter-bank Offered Rate." What does LIBOR represent? LIBOR is promoted as representing the average interest rate that large banks can borrow...July 17, 2012 | Policy Brief |


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» News
The Inertia and Drive For Power
If you asked Obama right now he would say he is doing a great job.
ht/ dsm_cal
» 11 Comments
And he would be wrong+5
Very powerful message.
So whats wrong with his message about big government and power mr Wrong?+1
Obama would be wrong
If you asked Obama right now he would say he is doing a great job.+3
My Apologies, thought you were responding to Friedmans comments.+2
And to think that Mr. Friedman taught for 30 years at the University of Chicago!! Wasn't anyone in Chicago listening?!+9
Boo really wants to get rid of our Constitution and our way of life, to him and everyone around him everything is outworn. We know better than to believe his lies. The link is from the UK reporting of his coronation with pictures, the quote is him on 1-21-13. None of this you will see in our press.
."We understand that outworn programs are inadequate to the needs of our time. We must harness new ideas and technology to remake our government, revamp our tax code, reform our schools, and empower our citizens with the skills they need to work harder, learn more, and reach higher".
Read more: http://www.dailymail.co.uk/news/article-2266156/Obama-inauguration-2013-Barack-Michelle-attend-inaugural-ball-Washington-Convention-Center.html#ixzz2IlhRZqMl
Follow us: @MailOnline on Twitter | DailyMail on Facebook+3
Nobody listened to Milton. Now there are more people in the cart being pulled, than pulling the cart. Dinesh D'Souza.
America is in deep shit.+4
Speaking of not listening to warnings…
Here's a must-read book coming out in May.
Aside from focusing on my failed Administration, which was riddled with Communists, it warns of an unfortunate parallel of today.
The book warns of a traitor in the White House, whose Administration is riddled with Islamists, determined to destroy America from within.
So, Franklin, how many such books on those two topics are already in print? ..15 ..20?
Most of America is oblivious to the obvious.
Books are like poison to the low information voters. It requires some interest and effort to read a book. The L/I/V's prefer to get their "facts' from
the talking heads on Tee Vee.
Mr. Friedman is ignored by the socialists in government because path is too complicated to grasp.
The socialist path is simple: if you WANT something,$500 sneakers, a boat,a fur coat, buy it. If you NEED something, food, shelter, medical care,
the government will provide it.+2
Keep paying your taxes fools.+1


text:
Our Saber Collection from Gascho is an excellent example of solid maple furniture. The drop leaf table is made from select solid maple, ensuring that your furniture investment is heirloom quality. Add the two 12-inch leaves and the table extends to 42" x 72". The table and side chairs are handcrafted to the highest quality standards, giving you a first-rate maple dining room set at a remarkable value.
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Cupcake Favor Boxes (set of 12)
So you've picked out your favorite cupcake flavors and matching frosting for the special event, but still searching for the perfect way to present them.. Well look no further! Our adorable Cupcake Favor Boxes are the perfect way to package your much-loved goodies and say thank you to all your friends and family for sharing your special day. These containers perfectly envelope your scrumptious cupcakes and are sealed with a satin ribbon, fashioning a touch of elegance to your delicious favor. These gifts are the perfect accessory for any table setting, and make desserts on the go easier than ever!
Included with the boxes are color coordinated blank labels that you can use to handwrite your guests' names. Or you can even add personalized labels to these precious Cupcake Favor Boxes to make truly custom favors that allow you to personally say "thank you" to each and every guest.
Each set of 12 contains: 12 Clear Boxes, 12 Scallop Edge Cupcake Holders (Holds the cupcakes in place), 12 pre-cut Satin Ribbons, 12 Blank Labels.
Matching personalized labels are available for $0.25 per label when ordering 2 or more sets of this item.
When ordering personalized labels, please note that they will arrive separate from the cupcake boxes, some assembly required (attaching them to cupcake box).
Size: 3" x 3" x 3"Note: White has been discontinued.
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Personalized Playing Cards - Cupcake Party
Complete your cupcake themed bridal or baby shower with something your guests can take home and play! These Cupcake Themed Personalized Playing Cards are a novel gift to give your guests at your fancy cupcake soiree. Personalized labels for the outside of the box are un-attached. Some assembly required.
NOTE: Only outside personalized label color can be changed, the actual playing cards cannot be personalized and will stay the same design regardless.
Due to the personalization for this product the minimum order is 24.
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Women's Brooks® Infiniti Capri III :: When you want everyday looks with more than everyday performance, the Infiniti Capri III features moisture-wicking compression fabric that supports your every move on the run, and around the town.
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The Secret Lives of Words
Harcourt, 2000 - Language Arts & Disciplines - 296 pages
Word enthusiasts will find trivia and treasure" (Kirkus Reviews) in this collection of unusual etymologies authored by an unmatched prose stylist and fabulous wordsmith.
Over the centuries, thousands of our words have been so twisted, tangled, misused, and muddled that their original meanings have been obscured. You'll be surprised to learn that table napkins were once made of and referred to as asbestos, a cloud was once a hill, and lasagna could be
literally translated as chamberpot pasta. In The Secret Lives of Words, acclaimed author and stylist Paul West fulfills a personal odyssey to seek out the elusive roots of these and a few hundred other of his favorite words, from abracadabra to zoot suit. Derived from handwritten notebooks, West chronicles the tortuous travels of words across continents and through cultures in this Antiques Road Show approach to etymology. A delight in both form and content, West's collection will capture the attention of word enthusiasts, speakers, writers, thinkers, and readers around the globe.
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What people are saying - Write a review
LibraryThing ReviewUser Review - raizel - LibraryThing
I've skimmed this book and it looks interesting. It is a list of words with comments about their origins and use. And in his explanations of the first and last words (abacus and zymurgist), he goes from dust to dust. Read full review
Review: The Secret Lives of WordsUser Review - Marianna Monaco - Goodreads
An interesting exploration the the mind of Paul West, and the words he chooses to write about, and the histories (personal and otherwise) and meanings he gives them. Read full review
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actually akin American ancient Anglo-Saxon Arabic ball became become blurb bread British called Cockney rhyming slang coined comes course cricket denote deriving dialect Diane Ackerman dictionaries diminutive doubt Dutch etymology famous fiction gerund gluons Greek haps heard human idea idiom Indo-European invented Italian language late Latin live look meaning meant metaphor Middle Dutch Middle English military mind modern Nazi never nineteenth century noun novel nowadays oddly Odysseus Old English Old French Old Norse once origin Paul West perhaps person phrase piropo plural poet prehistoric Germanic PREMARIN pudding quarks reference Rhesus Romans Samuel Beckett SCREW THE POOCH scuzz seems sense seventeenth century sixteenth century slang someone sometimes sound speech spin sure Syphilis teenth century term thing thought tion trying verb verbal Vulgar Latin whereas woman wonder word word's write


text: EAT BREAKFAST WITH THE DOLPHINS!Soaring ceilings top this architecturally unique home; large spacious rooms (and closets)overlooking our sparkling bay. Wrap decks, landscaping and a totally private, secluded estate. This will take your breath away. The home has been extremely well maintained and in 2009/2010 all new ductwork and hvac's replaced along with other remodelling. Pier and Plinth approx 10' beneath slab begins the excellent construction of this home and is carried throughout.(Rm sizes approx)


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Cranford, where everything changes and all remains the same, and Miss Matty's house is full of bustle when her maid Martha gives birth to a daughter. Elsewhere the shadow of the new railway still looms. Miss Matty is concerned about a young girl who lives in an isolated cottage with her mother and domineering brother. Her worries open a Pandora's box and fears that Cranford will never recover.
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- I graduated from Murray State University with a Bachelor's Degree in Learning and Behavior Disorders in December 2003.
- I began teaching in Hopkins County, KY in January of 2004.
- I finished my Master's Degree in 2008 from the University of Louisville. My degree is in Special Education with an emphasis in Assistive Technology.
- My family and I moved from our small town to the heart of the Bluegrass in 2010 where I started teaching at my second school.
- I teach resource and collaboration/coteaching in grades 3, 4, & 5.
- I love my jobs and love my kids. Teaching allows me to make a difference in the lives of children.
Mrs. Hinton
6 comments:
I am happy to have found your blog from a link on Extra Special Teaching! I, too, am a KY girl (from Hopkins County). As a parent of a special ed student, I've turned to the blogging world to find a little incite into the special ed classroom. I've already subscribed by email so I won't miss anything! Thank you for taking the time to create your blog! --mdbc77ReplyDelete
Thanks so much for following!! I taught in Hopkins County for six and half years before moving to Central Kentucky!! What a small world! I hope you can find something useful that will help you!! :)ReplyDelete
- EHANFORDAugust 5, 2012 at 9:02 PM
I would love to receive a copy of your data collection for xcel. I think this might be just what I am looking for. Thanks Again! I am subscribing by email. Look for Hanford to find the correct address. With Gratitude! E. HanfordReplyDeleteReplies
Awesome! Sent!!Delete
Glad to have found your blog! I am also a Murray St. graduate and a resource teacher in Paducah. Thanks for sharing all of your great ideas!! GO CATS!!!ReplyDeleteReplies
Glad to have another KY girl following me!! Let me know if you ever have any questions!Delete