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Hospital ship doctrine in the United States Navy: the Halsey effect on scoop- and-sail tactics.

Although hospital ships have a long history, naval strategists have paid little attention to their tactical employment in naval and amphibious warfare. Often employed as floating ambulances, operational doctrine for hospital ships did not permit their use as floating combat surgical hospitals until the final amphibious campaigns of World War II. Based on operational archives-ships' logs, war diaries, battle plans, and other official records-this essay traces the evolution of tactical doctrine on hospital ships from Guadalcanal to Inchon. Early in World War II, there were insufficient hospital ships to permit much flexibility in their employment. By the Philippine campaign in 1944, the increased availability of afloat medical assets prompted Third Fleet Commander Vice Admiral William F. Halsey to propose that the ships be used as acute surgical hospitals at the amphibious landing sites rather than as sea-going ambulances. Facing the prospect of a growing number of casualties for the major assaults being planned, Halsey needed to maximize medical and surgical efficacy and return-to-duty rates to conserve the fighting strength of his invasion forces. Admiral Chester A. Nimitz approved Halsey's proposal, and the battle plan at Iwo Jima combined the careful triage of casualties at the waterfront with early, forward employment of hospital ships. Despite more than 21,000 casualties at Iwo Jima, they were handled better than at any previous operation in the Pacific theater. The tactical doctrine for hospital ships suggested by Halsey has since been employed in every major amphibious operation, including Okinawa and Inchon, and has also been used in modern-era contingency and humanitarian missions.

Altruism↗

Cloning of the genomic locus of mouse SH2 containing inositol 5-phosphatase (SHIP) and a novel 110-kDa splice isoform, SHIPdelta.

The SH2 domain containing inositol 5'-phosphatase (SHIP) was initially described as a 145-kDa protein phosphorylated on tyrosines upon growth factor and cytokine stimulation. It was shown to be phosphorylated after Fc and B cell receptor activation and plays a role in negative signaling. Different isoforms of the SHIP protein result from alternative mRNA splicing, proteolysis, or a combination of both. The expression of discrete SHIP isoforms changes with the potential developmental-dependent maturation state of myeloid cells, suggesting mechanisms for the regulation of SHIP interactions with other signaling molecules. A p135 (SHIPbeta) spliced isoform is known to be expressed in developing myeloid cells. Now we have identified a new SHIP isoform, SHIPdelta, which is the product of an out-of-frame splice with a deletion of 167 nucleotides in the C-terminal region, resulting in an approximately 110-kDa protein. Biochemically, SHIPdelta differs from SHIPalpha by exhibiting little or no tyrosine phosphorylation or association with the signaling protein Shc after M-CSF activation of FD-Fms cells. In addition, we have characterized the structure of the entire SHIP genomic locus, which provides a basis for understanding the alternative splicing events. SHIP is expressed in hematopoiesis and spermatogenesis, and we also describe the promoter for the SHIP gene, which has potential for explaining the tissue-specific expression pattern.

3T3 Cells↗

The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading.

Recently, evidence has been accumulating that inositol and phosphatidylinositol polyphosphate play important roles in a variety of signal transduction systems including membrane traffic, actin cytoskeleton rearrangement and cell motility. In this paper, we show for the first time that the SH2-domain-containing inositol 5-phosphatase (SHIP)-2 binds directly to the hepatocyte growth factor (HGF/SF) receptor, c-Met, via phosphotyrosine 1356. HGF induces the breakdown of cell junctions and the dispersion of colonies of epithelial cells including MDCK cells. Whereas only few lamellipodia are observed in MDCK cells 2 min after stimulation with HGF, both SHIP-2- and SHIP-1-overexpressing cells form large, broad lamellipodia. The number of lamellipodia is 2-4-fold greater than that of mock-transfected MDCK cells in the same time period and SHIP is found to colocalize with actin at the leading edge. Furthermore, overexpression of a catalytic inactive mutant of SHIP-2 suppresses HGF-potentiated cell scattering and cell spreading, although these mutant-expressing cells form enhanced number of lamellipodia 2 min after HGF stimulation. Interestingly, cells expressing a mutant lacking the proline-rich domain of SHIP-2 at the C-terminal form few lamellipodia, but still spread and scatter upon stimulation with HGF at a reduced rate. These data suggest that phosphatase activity is required for HGF-mediated cell spreading and scattering but not for alteration of lamellipodium formation, while the proline-rich region influences lamellipodium formation. Furthermore, treatment with 10 microM of phosphatidylinositol 3 (PI3) kinase inhibitor, LY294002, abrogates HGF-induced cell scattering of SHIP-2-overexpressing cells but not parental HEK293 cells, suggesting that a balance between PI3 kinase and SHIP is important for cell motility.

Animals↗

Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow.

The Src homology (SH)2-containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP(-/-) animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP(-/-) mice. Lineage-negative marrow (Lin(-)) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP(-/-) mice. Furthermore, culture supernatants of SHIP(-/-) Lin(-) cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP(-/-) Lin(-) cells contained more IL-6 transcripts than wild-type Lin(-) cells, and neutralizing anti-IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP(-/-) Lin(-) cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin(-) bone marrow cells reproduced the phenotype of SHIP(-/-) bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow.

Animals↗

Up-regulation of the T cell quiescence factor KLF2 in a leukaemic T-cell line after expression of the inositol 5'-phosphatase SHIP-1.

Inositol 5'-phosphatase SHIP-1 (SHIP) is a negative regulator of signal transduction in haematopoietic cells. SHIP inactivation may be involved in the pathogenesis of leukaemia. An inducible expression system was combined with microarray analysis to identify target genes regulated by SHIP in the human T-cell leukaemia cell line Jurkat. One gene identified was Krüppel-like factor 2 (KLF2), which was up-regulated two to threefold at the RNA and protein level after the induced expression of SHIP. KLF2, a negative regulator of T cell proliferation, has been implicated in T cell quiescence. KLF2 or SHIP expression in Jurkat cells caused 45% or 60% reduction of proliferation, respectively. SHIP can up-regulate KLF2 expression, implicating KLF2 in the SHIP-mediated growth inhibition of a human leukaemic T-cell line.

Cell Proliferation↗

An ensemble source spectra model for merchant ship-radiated noise.

This paper presents an evaluation of the classical model for determining an ensemble of the broadband source spectra of the sound generated by individual ships and proposes an alternate model to overcome the deficiencies in the classical model. The classical model, proposed by Ross [Mechanics of Underwater Noise (Pergamon, New York, 1976)] postulates that the source spectrum for an individual ship is proportional to a baseline spectrum with the constant of proportionality determined by a power-law relationship on the ship speed and length. The model evaluation, conducted on an ensemble of 54 source spectra over a 30-1200-Hz to 1200-Hz frequency band, shows that this assumption yields large rms errors in the broadband source level for the individual ships and significantly overestimates the variability in the source level across the ensemble of source spectra. These deficiencies are a consequence of the negligible correlation between the source level and the ship speed and the source level and the ship length. The alternate model proposed here represents the individual ship spectra by a modified rational spectrum where the poles and zeros are restricted to the real axis and the exponents of the terms are not restricted to integer values. An evaluation of this model on the source spectra ensemble indicates that the rms errors are significantly less than those obtained with any model where the frequency dependence is represented by a single baseline spectrum. Furthermore, at high frequencies (400 to 1200 Hz), a single-term rational spectrum model is sufficient to describe the frequency dependence and, at the low frequencies (30 to 400 Hz), there is only a modest reduction in the rms error for a higher order model. Finally, a joint probability density on the two parameters of the single term model based on the measured histograms of these parameters is proposed. This probability density provides a mechanism for generating an ensemble of ship spectra.

Journal Article↗

Inhibition of the Jun N-terminal protein kinase pathway by SHIP-1, a lipid phosphatase that interacts with the adaptor molecule Dok-3.

Dok-3 is a Dok-related adaptor expressed in B cells and macrophages. Previously, we reported that Dok-3 is an inhibitor of B-cell activation in A20 B cells and that it associates with SHIP-1, a 5' inositol-specific lipid phosphatase, as well as Csk, a negative regulator of Src kinases. Here, we demonstrate that Dok-3 suppresses B-cell activation by way of its interaction with SHIP-1, rather than Csk. Our biochemical analyses showed that the Dok-3-SHIP-1 complex acts by selectively inhibiting the B-cell receptor (BCR)-evoked activation of the Jun N-terminal protein kinase (JNK) cascade without affecting overall protein tyrosine phosphorylation or activation of previously described SHIP-1 targets like Btk and Akt/PKB. Studies of B cells derived from SHIP-1-deficient mice showed that BCR-triggered activation of JNK is enhanced in the absence of SHIP-1, implying that the Dok-3-SHIP-1 complex (or a related mechanism) is a physiological negative regulator of the JNK cascade in normal B cells. Together, these data elucidate the mechanism by which Dok-3 inhibits B-cell activation. Furthermore, they provide evidence that SHIP-1 can be a negative regulator of JNK signaling in B cells.

Adaptor Proteins, Signal Transducing↗

Altered responsiveness to chemokines due to targeted disruption of SHIP.

SHIP has been implicated in negative signaling in a number of hematopoietic cell types and is postulated to downregulate phosphatidylinositol-3-kinase- (PI-3K-) initiated events in diverse receptor signaling pathways. Because PI-3K is implicated in chemokine signaling, we investigated whether SHIP plays any role in cellular responses to chemokines. We found that a number of immature and mature hematopoietic cells from SHIP-deficient mice manifested enhanced directional migration (chemotaxis) in response to the chemokines stromal cell-derived factor-1 (SDF-1) and B-lymphocyte chemoattractant (BLC). SHIP(-/-) cells were also more active in calcium influx and actin polymerization in response to SDF-1. However, colony formation by SHIP-deficient hematopoietic progenitor cell (HPCs) was not inhibited by 13 myelosuppressive chemokines that normally inhibit proliferation of HPCs. These altered biologic activities of chemokines on SHIP-deficient cells are not caused by simple modulation of chemokine receptor expression in SHIP-deficient mice, implicating SHIP in the modulation of chemokine-induced signaling and downstream effects.

Actins↗

Consideration of percentage of milk shipped for calculation of total lactation yields from various morning and evening plans of milk sampling.

Milk yield recorded on DHI test day was compared with data on milk shipped from Texas and Minnesota herds for an innovative DHI test plan referred to as alternate a.m.-p.m. without a timer. Controls were yields for test day and for milk shipped from official DHI herds in Texas, Illinois, Minnesota, and several northeastern US states. Herd milk yield for a test day as a percentage of milk shipped was considered to be an indicator of the accuracy of the DHI recording plans. Mean percentage of milk shipped was 103 for all plans and regions. When herd test days with missing values were excluded, the percentage of herd test days within 96 to 110% of milk shipped were 77 for Texas and 82 for Minnesota innovative plans and 82 for Texas, 82 for Minnesota, 79 for Illinois, and 81 for northeastern official plans. Analysis indicated that the percentage of milk shipped was consistent across herd sizes, data source, and milk yield. Eight hypothetical testing plans were examined with or without adjustment of lactation yields for percentage of milk shipped. Estimates of variance components of lactation milk yields were computed and compared using a multitrait animal model. Adjustment of records for percentage of milk shipped would decrease mean milk yields by 3%, could result in better estimates of actual milk produced, but would have little effect on accuracy of genetic evaluations.

Animals↗

Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors.

The leukemic T cell line Jurkat is deficient in protein expression of the lipid phosphatases Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and phosphatase and tensin homolog deleted on chromosome ten (PTEN). We examined whether the lack of expression of SHIP-1 and PTEN is shared by other leukemic T cell lines and PBLs. Analysis of a range of cell lines and PBLs revealed that unlike Jurkat cells, two other well-characterized T cell lines, namely CEM and MOLT-4 cells, expressed the 5'-phosphatase SHIP at the protein level. However, the 3-phosphatase PTEN was not expressed by CEM or MOLT-4 cells or Jurkat cells. The HUT78 cell line and PBLs expressed both SHIP and PTEN. Jurkat cells exhibited high basal levels of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P(3); the lipid substrate for both SHIP and PTEN) as well as saturated protein kinase B (PKB) phosphorylation. Lower levels of PI(3,4,5)P(3) and higher levels of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) as well as unsaturated constitutive phosphorylation of PKB were observed in CEM and MOLT-4 cells compared with Jurkat cells. In PBLs and HUT78 cells which express both PTEN and SHIP-1, there was no constitutive PI(3,4,5)P(3) or PKB phosphorylation, and receptor stimuli were able to elicit robust phosphorylation of PKB. Expression of a constitutively active SHIP-1 protein in Jurkat cells was sufficient to reduce both constitutive PKB membrane localization and PKB phosphorylation. Together, these data indicate important differences between T leukemic cells as well as PBLs, regarding expression of key lipid phosphatases. This study provides the first evidence that SHIP-1 can influence the constitutive levels of PI(3,4,5)P(3) and the activity of downstream phosphoinositide 3-kinase effectors in T lymphocytes.

Animals↗

Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses.

Previously we demonstrated that SHIP(-/-) mice accept allogeneic bone marrow transplants (BMT) without significant acute graft-vs-host disease (GvHD). In this study we show that SHIP(-/-) splenocytes and lymph node cells are poor stimulators of allogeneic T cell responses that cause GvHD. Intriguingly, SHIP(-/-) splenocytes prime naive T cell responses to peptide epitopes, but, conversely, are partially impaired for priming T cell responses to whole Ag. However, dendritic cells (DC) purified from SHIP(-/-) splenocytes prime T cell responses to allogeneic targets, peptide epitopes, and whole Ag as effectively as SHIP(+/+) DC. These findings point to an extrinsic effect on SHIP(-/-) DC that impairs priming of allogeneic T cell responses. Consistent with this extrinsic effect, we found that a dramatic expansion of myeloid suppressor cells in SHIP(-/-) mice impairs priming of allogeneic T cells. These findings suggest that SHIP expression or its activity could be targeted to selectively compromise T cell responses that mediate GvHD and graft rejection.

Animals↗

Mutation analysis of SHIP gene in acute leukemia.

The SH2 domain containing inositol 5'-phosphatase (SHIP) was initially described as a 145 kD protein phosphorylated on tyrosines upon growth factor and cytokine stimulation. SHIP is predominately expressed in hematopoietic cells, and is a crucial negative regulator in the development of hematopoietic cells. To evaluate the role of the SHIP gene in human leukemogenesis, expression and mutation of SHIP gene in bone marrow and/or peripheral blood from 32 patients with acute myeloid leukemia (AML), 9 patients with acute lymphoblastic leukemia (ALL), as well as human hematopoietic cell lines were analyzed by reverse transcription-polymerase chain reaction (RT-PCR), single strand conformational polymorphism (SSCP) and sequencing. The RT-PCR showed that all samples expressed SHIP gene. Mutations of SHIP gene were detected in 7 out of 32 AML patients (22%) and one out of 9 ALL patients (12%). Interestingly, two missense mutations that had been observed in one AML patient at diagnosis disappeared after complete remission (CR). In addition, Akt phosphorylation was prolonged and increased following IL-3 stimulation in this patient sample. In conclusion, data of this study demonstrate the mutation of the SHIP gene in acute leukemia for the first time and suggest a possible role of the mutation of this gene in the development of acute leukemia. SHIP serves as a tumor suppressor by negatively regulating the PI3K/Akt signaling pathway in hematopoietic cells.

Cell Line↗

Multiple forms of the SH2-containing inositol phosphatase, SHIP, are generated by C-terminal truncation.

The SH2-containing inositol phosphatase, SHIP, often appears as multiple bands in anti-SHIP immunoblots. To characterize these bands, antisera were generated against the N-terminal (anti-N), mid-region (anti-M), and C-terminal (anti-C) portions of SHIP. Immunoprecipitation and immunoblotting studies showed that 145-, 135-, 125-, and 110-kD bands were detected in lysates from the murine hematopoietic cell line, DA-ER, with either anti-N or anti-M antisera, whereas only the 145- and 135-kD bands were recognized by the anti-C antiserum. This finding suggested that the smaller proteins might be C-terminal truncations of the full-length SHIP. To confirm this and determine if these proteins arose through alternate splicing or posttranslational cleavage, a 5'-hemagglutin (HA)-tagged full-length SHIP cDNA was expressed in these cells. We observed, via Western analysis with anti-HA antibodies, the same 4 bands with either anti-N or anti-M and only the 145- and 135-kD bands with anti-C immunoprecipitation. After interleukin-3 stimulation of HA-SHIP-expressing DA-ER cells, only the 145-kD form coprecipitated with Shc, raising the possibility that different forms of SHIP may have distinct intracellular sites. This was confirmed by subcellular fractionation, which showed that only the 110-kD form is present in the cytoskeleton of DA-ER cells. This 110-kD form possesses the same PIP3 5-ptase activity as the 145-kD form and can be generated from the latter in vitro by digestion with calpain. It is therefore possible that the different forms of SHIP are generated in vivo by calpain-mediated C-terminal truncations and perform distinct functions within hematopoietic cells.

Adaptor Proteins, Signal Transducing↗

Role of the inositol phosphatase SHIP in B cell receptor-induced Ca2+ oscillatory response.

Src homology-2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP) is a recently identified protein that has been implicated as an important signaling molecule. Although SHIP has been shown to participate in the FcgammaRIIB-mediated inhibitory signal, the functional role of SHIP in activation responses by immunoreceptor tyrosine-based activation motif-bearing receptors such as B cell receptor (BCR) remains unclear. Indeed, it has been proposed that SHIP serves as a linking molecule for the regulation of the extracellular signal-regulated kinase pathway in BCR signaling, because SHIP associates with Shc. We now report that SHIP-deficient DT40 B cells display enhanced Ca2+ mobilization in response to BCR ligation, whereas extracellular signal-regulated kinase activation is unaffected. This Ca2+ enhancement is due to a sustained intracellular Ca2+ increase or to long-lasting Ca2+ oscillations by loss of SHIP, as revealed by single-cell Ca2+ imaging analysis. These results demonstrate the importance of SHIP in B cell activation by the modulation of Ca2+ mobilization.

Animals↗

Skin disorders in ship's engineers exposed to oils and solvents.

Ship's engineers are exposed to mineral oil and solvents in their work. This study was intended to investigate if the ship's engineers had an increased prevalence of skin disorders and whether any such increased risk could be linked to exposure to mineral oils and solvents. A self-administered questionnaire was sent to 700 male seamen from 3 Norwegian ferry countries. Of the 492 respondents, 169 were currently working as ship's engineers and 295 had never worked as ship's engineers. The outcomes eczema, acne, dry skin, and dermatitis and hand dermatitis were defined from the questionnaire. Prevalences of these skin disorders were compared between the groups. Logistic regression was used to elucidate explanatory variables further. When comparing current ship's engineers with those who had never worked as ship's engineers, the crude prevalence ratios were 1.7 (95% CI 1.1-2.7) for dry skin, 1.7 (95% CI 1.1-2.5) for any dermatitis, 1.3 (95% CI 0.66-2.67) for acne and 1.2 (CI 0.61-2.27) for eczema. The risk of these symptoms increased for the engineers in the regression analysis, after controlling for age, self-reported use of Stoddard solvent, and the use of fuel oil as hand cleansing agent. The increased prevalence of skin disorders found among ship's engineers in this investigation may be explained by direct contact with mineral oils and solvents.

Adult↗

Gastrointestinal illness on passenger cruise ships, 1975-1978.

Following investigations in 1972-1973 of outbreaks of enteric disease on cruise ships using American ports, a surveillance system was established which required that 24 hours before arrival in port, each ship report the number of persons with diarrheal illness seen by the ship's physician during the cruise. The reported data were found to be reliable; they established a baseline incidence for diarrhea on cruise ships. A significantly high portion of enteric disease outbreaks occurred on vessels that did not pass routine annual or semiannual sanitation inspections. The cruise ship sanitation program, developed with the cooperation of the cruise ship industry and the Centers for Disease Control, appears to have been successful in reducing the overall rate of cruise ship associated outbreaks of enteric illness.

Diarrhea↗

Passenger mortalities aboard cruise ships.

OBJECTIVES: to study the epidemiology of passenger mortalities on cruise ships. METHODS, MATERIAL AND RESULTS: during six years (April 1995 to April 2001) deaths aboard two similar cruise ships (A & B) were registered and studied. Each ship had an average of approximately 800 passengers with median age about 65 years. Twenty five passengers died: 9 men and 3 women on ship A and 10 men and 3 women on ship B. There was an average of one death every six months per ship. More men than women died, although there were more female passengers on both ships (P<0.05). Eleven passengers were found dead in their cabins. Five deaths outside the medical centers were witnessed; four of them had asystole and one ventricular fibrillation when medical staff arrived. Nine patients died after 1/2 to 52 hours of intensive care in the medical centers aboard.

Age Factors↗

Work-related mortality among British seafarers employed in flags of convenience shipping, 1976-95.

OBJECTIVE: To establish and analyse the causes and circumstances of all deaths among British seafarers who were working in flags of convenience merchant shipping between 1976 and 1995, to compare mortality with British seafarers employed in British merchant shipping, and to discuss implications for health and safety. METHODS: A retrospective longitudinal study of occupational mortality, based on official mortality files. RESULTS: Out of a total of 200 deaths in flags of convenience shipping, illnesses caused 68 deaths, accidents 91, homicide 3, suicide 7, drug and alcohol intoxication 4, and disappearances at sea and other unknown causes 27. Deaths from non-natural causes and, in particular, maritime disasters accounted for a significantly higher proportion of all deaths in flags of convenience than in British shipping. The maritime disasters largely involved small cargo ships foundering or disappearing in bad weather. CONCLUSIONS: Although mortality rates could not be calculated, because of the unavailability of population information, British seafarers who work for flags of convenience registries appear to be at increased risk of mortality through maritime disasters, as well as through occupational accidents and suicide. Many of the occupational accidents, such as asphyxiation in cargo holds, were caused by hazardous working practices, and the disappearances of small cargo ships raises questions about their seaworthiness. Future efforts should focus on investigating the mortality and health of seafarers working in flags of convenience ships, and on improving mortality and population information systems for these registries.

Accidents, Occupational↗