'Why are we not doing more for them?': genocide prevention lessons from the Kindertransport.

OBJECTIVES: Genocide remains one of the most widespread forms of preventable mortality and morbidity for children today. Despite the creation of multiple human rights treaties, genocide has not been eliminated and its effects disproportionally impact children. The Kindertransport was a series of rescue efforts that brought thousands of refugee children to the United Kingdom from Nazi Germany between 1938 and 1940. This qualitative study asks what public health professionals can learn from the prevention efforts of the Kindertransport by examining the experiences and reflections of individuals rescued as children. The specific aims of the study were (1) to analyze qualitatively the impact of the rescue on rescued children; (2) to evaluate the strengths and limitations of the Kindertransport as a prevention effort; and (3) to draw implications for contemporary public health responses to global genocide. STUDY DESIGN: Qualitative research study. METHODS: In-depth interviews, using a semi-structured interview guide, were conducted with 27 survivors of the rescue. The data were thematically coded, and excerpts exported and interpreted in reflection of patterns and themes using Dedoose. RESULTS: Five inductive themes emerged from the data related to the broad spectrum of antisemitic persecution: the breakup of families; integration in the UK via the Kindertransport; the challenges of adapting to a new environment; and the implications for global rescue efforts. CONCLUSIONS: The results suggest that the public health community should act to prevent genocide through rapid intervention and rescue; at the same time, the effects of persecution must be addressed and sustained social, emotional, and psychological support must be provided to those rescued.

'Between Combat boots and Birkenstocks'-Lessons from HIV/AIDS, SARS, H1N1 and Ebola.

OBJECTIVES: In late 2013, an Ebola outbreak quickly grew into an epidemic of extraordinary magnitude, killing more people than all previous Ebola outbreaks combined. Although the epidemic was unprecedented, the world had previously experienced several acute public health emergencies requiring global coordination. HIV/AIDS, SARS and H1N1 tested global response, and in each case coordination proved problematic, making the 2013-2015 Ebola epidemic no exception. The purpose of this project was to identify persistent vulnerabilities within global public health emergency response and to identify areas for future research and improvement. STUDY DESIGN: Non-systematic review and qualitative interview study. METHODS: Using PubMed and Google, a comprehensive search of articles connected to the HIV/AIDS, SARS, H1N1 and Ebola responses was conducted. Then, 21 key responders involved in those emergencies, primarily from the US Centers for Disease Control and Prevention, participated in in-depth interviews. The content analysis and in-depth interview data were analysed using MAXQDA analysis software. RESULTS: A number of issues emerged, including cultural and political clashes within relevant agencies and a lack of confidence in those agencies, policy barriers that hinder long-term international response, a shortage of personnel and resources, itemized funding streams that limit flexibility to direct resources, and challenges to deploying responders internationally. CONCLUSIONS: The data suggest that the world remains ill prepared to handle sustained responses and global pandemics. The study identified major vulnerabilities persistent within US-led global public health response and offers recommendations for further focused research to fully understand why these challenges persist.

CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans.

Galectin-1 induces death of immature thymocytes and activated T cells. Galectin-1 binds to T cell-surface glycoproteins CD45, CD43, and CD7, although the precise roles of each receptor in cell death are unknown. We have determined that CD45 can positively and negatively regulate galectin-1-induced T cell death, depending on the glycosylation status of the cells. CD45(+) BW5147 T cells lacking the core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) were resistant to galectin-1 death. The inhibitory effect of CD45 in C2GnT(-) cells appeared to require the CD45 cytoplasmic domain, because Rev1.1 cells expressing only CD45 transmembrane and extracellular domains were susceptible to galectin-1 death. Moreover, treatment with the phosphotyrosine-phosphatase inhibitor potassium bisperoxo(1,10-phenanthroline)oxovanadate(V) enhanced galectin-1 susceptibility of CD45(+) T cell lines, but had no effect on the death of CD45(-) T cells, indicating that the CD45 inhibitory effect involved the phosphatase domain. Expression of the C2GnT in CD45(+) T cell lines rendered the cells susceptible to galectin-1, while expression of the C2GnT in CD45(-) cells had no effect on galectin-1 susceptibility. When CD45(+) T cells bound to galectin-1 on murine thymic stromal cells, only C2GnT(+) T cells underwent death. On C2GnT(+) cells, CD45 and galectin-1 co-localized in patches on membrane blebs while no segregation of CD45 was seen on C2GnT(-) T cells, suggesting that oligosaccharide-mediated clustering of CD45 facilitated galectin-1-induced cell death.

Effects of calcium buffering on the synthesis of the 26-kDa heat-shock protein family.

We have reported on the effect of heat in C127 cells having various basal levels of the Ca(2+)-binding proteins calmodulin (CaM) or parvalbumin [Evans, Simonette, Rasmussen, Means, and Tomasovic, J. Cell. Physiol. 142, 615-627 (1990)]. These studies suggested that induction of the synthesis of 26-kDa heat-shock protein (hsp-26) depended on increased intracellular free Ca2+ [Ca2+]i and that induction was abrogated by increased Ca(2+)-binding capacity. To evaluate further the role of [Ca2+]i in mediating the response to hyperthermia and the potential for Ca(2+)-buffering to affect these processes, we loaded C127 parental cells with the Ca2+ chelators BAPTA or quin-2 (5 microM for 60 min) and then immediately heated the cells (30 min at 43 degrees C) and labeled them (3 h at 37 degrees C) with [3H]leucine. Measurements of [Ca2+]i with quin-2 and fura-2 showed that an increase in [Ca2+]i occurred with this heat dose, but that the quin-2 buffered that increase. Two-dimensional gels showed that cells loaded with BAPTA and quin-2 had a reduced rate of synthesis of the most basic (nonphosphorylated) hsp-26a isoform. The apparent synthesis of the more acidic isoforms (hsp-26b, hsp-26c) was less affected, but labeling studies with 32P showed this reflected continued accumulation of these phosphorylated isoforms, especially the most highly phosphorylated hsp-26c. Although it reduced hsp-26a synthesis, the temporary buffering of [Ca2+]i did not alter the subsequent expression of heat killing or the extent of thermotolerance significantly, possibly because phosphorylated hsp-26 was still generated. These data support the hypothesis that perturbations of [Ca2+]i directly modulate induction of hsp-26a synthesis.

Affinity isolation of heat-shock and other calmodulin-binding proteins following hyperthermia.

The interaction of calmodulin (CaM) with heat-shock and other binding proteins was studied in rat adenocarcinoma cells. Cells were equilibrium-labeled for 48 h prior to heating for 1 h at 43 degrees C, or pulse-labeled for 2 h at 37 degrees C after heating, to monitor the effect of heat on the affinity of CaM-binding proteins synthesized under these conditions. A CaM antagonist shown to sensitize to heat killing, W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], was used in competition assays to help monitor any changes in affinity. We found that heating tended to reduce the CaM-binding of proteins synthesized before heating relative to their 37 degrees C controls and proteins synthesized after heating tended to have increased binding relative to their respective controls. Members of the heat-shock protein (hsp) 90-, 70-, and 26-kDa families were among the proteins that bound to CaM and were eluted by W-7. The peak elution fractions for the hsp's and other cellular proteins varied, but hsp-70 eluted in the early fractions. The hsp-70 family was also found to be among a number of W-7-binding proteins. We conclude that the assumption that CaM antagonists potentiate killing of heated cells solely by competing nonspecifically for CaM-binding protein sites on CaM does not explain the process completely. These antagonists could also act by competing for CaM-binding sites with specific proteins whose interaction with CaM is important for survival following heating, or by directly binding to other proteins whose function is important for survival and inhibiting their activity. We do not have sufficient data to discern the predominant mechanism among these possibilities, but we believe all are likely to occur in heated cells and speculate that inhibition of the functions of the hsp-70 family is important in several of these antagonist actions.

Altered synthesis of the 26-kDa heat stress protein family and thermotolerance in cell lines with elevated levels of calcium-binding proteins.

Using a bovine papilloma virus-based vector, mouse mammary adenocarcinoma cells have been transformed to express elevated amounts of functional calmodulin (CaM) (Rasmussen and Means, 1987) and another Ca2(+)-binding protein, parvalbumin (PV) (Rasmussen and Means, 1989) that is not normally synthesized in these cells. Parental cells (C127) and cells transformed by the vector alone (BPV-1), the vector containing a CaM gene (CM-1), or the vector containing parvalbumin (PV-1) were used to study the effect of increased synthesis of Ca2(+)-binding proteins on heat-stress protein (HSP) synthesis and cell survival following heating at 43 degrees C. The induction, stability, and repression of the synthesis of most HSPs after 43 degrees C heating was not significantly affected by increased amounts of Ca2(+)-binding proteins, but the rate of synthesis of all three isoforms of the 26-kDa HSP (HSP26) was greatly reduced. C127 cells, which have about one half as much CaM as do BPV-1 cells, synthesized the most HSP26. CM-1 cells, which have more than fourfold higher levels of CaM than do BPV-1 cells, had a rate of synthesis of HSP26 approaching that of unheated cells. BPV-1 cells, with a two-fold increase in CaM, were intermediate in HSP26 synthesis. This effect on HSP26 synthesis may be largely related to the Ca2(+)-binding capacity of CaM rather than to a specific CaM-regulated function, since PV-1 cells also showed reduced rates of HSP26 synthesis. Survival experiments showed that reduced HSP26 synthesis in cells with increased amounts of Ca2(+)-binding proteins did not significantly alter intrinsic resistance to continuous 43 degrees C heating. Thermotolerance was not reduced and appeared to develop more rapidly in CM-1 and PV-1 cells. These results suggest that (1) the signal for HSP26 synthesis can be largely abrogated by elevated Ca2+ binding protein levels, and (2) if these HSPs are involved in thermotolerance development, that function may be associated with intracellular Ca2+ homeostasis.

The effect of calmodulin antagonists on hyperthermic cell killing and the development of thermotolerance.

The role of calmodulin (CaM) in hyperthermic cell killing, and the development of thermotolerance in rat 13762NF mammary adenocarcinoma cells, was investigated by using the CaM antagonists W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide] and W-13 [N-(4-aminobutyl)-2-chloro-naphthalenesulphonamide] and their less active analogues W-5 [N-(6-aminohexyl)-1-naphthalenesulphonamide] and W-12 [N-(4-aminobutyl)-2-naphthalenesulphonamide]. The CaM antagonists W-7 and W-13 potentiated 43 degrees C cell killing (and the less active analogues did not) at a concentration compatible with CaM inhibition, thus hyperthermic perturbation of CaM-regulated processes may contribute to cellular lethality. The potentiation of hyperthermic killing by antagonists appeared to be temperature-dependent, sensitizing much more effectively to 43 degrees C than to 42 degrees C killing. The effect may be related to differing primary mechanisms of hyperthermic killing activated at the two temperatures, or simply to differences in incorporation or localization of the antagonists. The presence of the CaM antagonists throughout fractionated 42 degrees C or 43 degrees C heating, or during continuous 42 degrees C heating, did not significantly inhibit or potentiate the triggering and development of thermotolerance or alter the rates of heat stress protein (HSP) synthesis. Studies using CaM-agarose isolation of CaM-binding proteins indicated that binding of some HSP to CaM-agarose occurred and was Ca2+-dependent. The specificity and physiological relevance of these HSP binding to CaM was not clear, since their affinity was not high in these cells. Presumably W-7 would perturb any physiologically relevant CaM-protein interactions in cells but W-7 concentrations that reduced HSP and other protein binding to CaM-agarose columns by 50 per cent or more, had no effect on thermotolerance development in cells. These observations, combined with the studies that showed little effect of CaM antagonists on HSP synthesis at concentrations which potentiated cell killing, suggested that events leading to triggering or developing thermotolerance were not strongly dependent on any putative HSP binding to CaM. These studies also suggest some targets of hyperthermic cell killing at 43 degrees C are different from those that lead to the triggering and development of thermotolerance.

Survival of rat mammary tumor cell clones and DNA strand damage following adriamycin treatment.

Tumor cell subpopulations have been shown to be heterogeneous in a number of phenotypic characteristics, including responses to cytotoxic drugs. This phenotypic heterogeneity has been used here to study mechanisms associated with Adriamycin (doxorubicin HCl)-induced cytotoxicity. Clonogenic survival and alkaline elution methods were employed to examine the response of two tumor cell subpopulations to Adriamycin. The cells were derived from a primary 13762NF rat mammary adenocarcinoma (clone MTC) and a lung metastasis in the same animal (clone MTLn3). The MTC cells were significantly more resistant to Adriamycin than were the MTLn3 cells; the dose effective in reducing cell survival by 50% was 10-fold higher. Protein-associated DNA strand breakage assayed by alkaline elution was dose-dependent in both clones, and MTC cells were again more resistant to break induction than were MTLn3. These results showed that clonal tumor subpopulations isolated from a primary tumor and its metastases possessed different intrinsic survival responses to Adriamycin treatment in vitro and that this survival response correlated with Adriamycin-induced production of protein-associated DNA single-strand breaks.

European double-blind multicenter study comparing isoxicam and indomethacin in treatment of degenerative joint disease.

A three-month, double-blind, indomethacin-controlled, European multicenter study of isoxicam (Maxicam), a nonsteroidal anti-inflammatory drug, was conducted in 365 patients who had degenerative joint disease of the knee or hip. Patients were randomly assigned to receive one of two treatments: isoxicam, 133 mg per day (Week 1), 166 mg per day (Week 2), and 200 mg per day (Weeks 3 to 12); or indomethacin, 100 mg per day (Week 1), 125 mg per day (Week 2), and 150 mg per day (Weeks 3 to 12). Efficacy measurements included, for patients with knee or hip involvement, intensity of starting pain on motion, pain on walking, night pain, overall assessment by physician and patient, and global assessment at the end of treatment; maximal extension and flexion (knee); extent of pain-free abduction and maximal abduction (hip). The results of the efficacy measurements favor isoxicam over indomethacin, although the differences are not statistically significant. The isoxicam group had significantly fewer adverse reactions than the indomethacin group.

Multiple phenotypic divergence of mammary adenocarcinoma cell clones. II. Sensitivity to radiation, hyperthermia and FUdR.

We have shown that, with in vitro passage, subclones derived from clonal cell populations of 13762NF mammary adenocarcinoma undergo phenotypic drift and diversification in their cellular properties. Here we examine whether phenotypic divergence of 13762NF cell clones extends to therapeutic treatments used in eliminating mammary tumors and whether the apparent rates of phenotypic divergence vary for different treatments. Six subclones isolated from low passage clone MTF7 (T11; tissue culture passage 11) cells were compared to a similar number of subclones isolated from high passage clone MTF7 (T35; tissue culture passage 35) cells. Subclones derived from clone MTF7 (T11) were relatively homogeneous (not significantly different) in their inherent sensitivities to ionizing radiation, extrapolation coefficients and quasithreshold dose values (Do = 1.61-1.99 Gy; n = 0.89-3.42; Dq = 0-2.34). When the MTF7 (T11) subclones were examined for their sensitivities to 45 degrees C hyperthermic treatment, the inherent sensitivities and dose-response curve parameters (Do = 5.24-10.05 min; n = 1.08-10.47; Dq = 0.78-12.31) were heterogeneous (significantly different). In addition, the MTF7 (T11) subclones were heterogeneous (significantly different) in their sensitivities and dose-response curve parameters to 5-fluoro-2'-deoxyuridine (FUdR) treatment (slope = -0.70 to -1.59; y-intercept = 1.31 X 10(2) to 47.80 X 10(2]. The LD50 values for FUdR ranged from 14-150 nM for the MTF7 (T11) subclones. At high passage MTF7 (T35) subclones were heterogeneous in their dose-response parameters to ionizing radiation (Do = 1.17-2.05 Gy; n = 0.80-41.18; Dq = 1.79-4.94), hyperthermia (Do = 3.57-6.32 min; n = 2.08-13.54; Dq = 3.68-9.30) and FUdR (slope = -0.77 to -0.93; y-intercept = 4.64 X 10(2) to 8.83 X 10(2); LD50 = 50-160 nM). The results indicate that clonal cells diverge for distinct phenotypic properties at differing rates to form heterogeneous cell populations with unique sensitivities to various therapeutic treatments.

A model of reflex tracheal constriction in the dog.

1 A tracheal pouch with its nerve and blood supply intact has been prepared in situ in dogs. 2 Mechanical stimulation of the upper airways in dogs anaesthetized with chloralose induced a consistent increase in pouch pressure which was abolished by bilateral vagal section. 3 The response of the pouch following mechanical stimulation of the airways was abolished by intravenous pentobarbitone, atropine, administered systemically or when present in the pouch, and tetracaine, applied to the stimulus area or when present in the pouch. 4 Salbutamol had no inhibitory effects on the response regardless of its route of administration. 5 These results suggest that the increase in pouch pressure following mechanical stimulation of the upper airways is mediated by a vagal reflex arc. 6 The technique may distinguish between drugs the site of action of which is at the afferent or efferent end of this reflex arc.

Medicines of choice in low back pain.

The marketed formulations of 6 analgesic preparations were compared in the treatment of patients suffering from acute exacerbations of low back pain using a crossover trial of balanced incomplete block design. Sixty out-patients with symptoms resulting from a mechanical or degenerative condition were each prescribed 3 drugs which were administered consecutively for 1 week each. The medications (and daily dosages) were coded as A --aspirin (3600 mg), B --dextropropoxyphene plus paracetamol (260 mg plus 2600 mg), C --indomethacin (150 mg), D --mefenamic acid (1500 mg), E --paracetamol (4000 mg), and F --phenylbutazone (300 mg). Daily pain scores were significantly lower (p less than 0.05) during treatment D than during treatments E and B, and significantly lower (p less than 0.05) during treatment A than during treatment B. There were large and significant differences between treatments in the percentages of recommended doses acceptable to the patients and in the number of defaults from the prescribed regimens. The patients chose F and D significantly more (p less than 0.05) often than A. Overall, there were consistently superior performances by mefenamic acid and phenylbutazone with little to choose between the two.

A model of irritant-induced bronchoconstriction in the spontaneously breathing guinea-pig.

1 Inhalation of an aqueous aerosol of citric acid caused bronchoconstriction in anaesthetized guinea-pigs which was abolished by bilateral vagal section. 2 Conscious guinea-pigs developed slow, laboured breathing within 90 s of exposure to citric acid aerosol. The onset of this pattern of breathing was delayed by prior aerosol administration of atropine, ipratropium bromide, isoprenaline and tetracaine. 3 The data suggest that exposure of guinea-pigs to citric acid may be a useful model of reflex bronchoconstriction.

Lumbar spinal manipulation on trial. Part I--clinical assessment.

Thirty-two patients with chronic low back pain were treated three times at weekly intervals with rotational manipulation. Patients with femoral or sciatic root pain were included provided they did not exhibit root compression signs. Background therapy of codeine phosphate was administered throughout. There was a significant increase in spinal flexion measured clinically during the three-week period of manipulation followed by a significant decrease in the three-week period after manipulation. The first week of manipulative treatment was more painful than the corresponding week in the control group but in the second and third weeks there was less pain in the manipulated group. Pain scores were reduced to a significant degree within four weeks of starting treatment only in the group manipulated in the first treatment period. Patients benefitting subjectively from manipulation were more likely to be older and to have had symptoms for a shorter period than those not deriving benefit. The age of onset of symptoms was significantly later in the responders.

Lumbar spinal manipulation on trial. Part II--radiological assessment.

In a trial of manipulation for chronic low back pain, radiographs of the lumbar spine and radiographic assessment of spinal motion were of no value in predicting or assessing the response of the patients to manipulation. Although radiography of the lumbar spine is a commonly requested investigation, it contributes little to the management of such patients except to exclude serious spinal pathology before any form of physical treatment is commenced.

Studies on the role of histamine and 5-hydroxytryptamine in immunity against the nematode Trichostrongylus colubriformis. IV. Inhibition of the expulsion of worms transplanted into the duodenum of immune guinea pigs.

Significant numbers of fourth larval stage Trichostrongylus colubriformis from sheep donors are expelled from the small intestine of T. colubriformis-immune guinea pigs within 8 h of transplantation into this organ. This model system for the immune expulsion of gastrointestinal nematode parasites was used in the current experiments to examine the effect of drugs recently shown to modify the release of histamine. The experiments showed that worm expulsion was inhibited by the beta-adrenergic agonists salbutamol and isoprenaline, the phosphodiesterase inhibitors aminophylline and ICI 63,197, the antiallergic drug ICI 74,917 and the antihistamine mepyramine. The beta-blocker propranolol prevented inhibition of worm expulsion following salbutamol treatment and there was some evidence of synergistic action between salbutamol and ICI 63,197. The results support previous findings suggesting an important role for histamine release in the effector mechanism of the immune response of guinea pigs against the parasitic nematode T.colubriformis.

Human eosinophils, acidic tetrapeptides (ECF-A) and histamine. Interactions in vitro and in vivo.

The ECF-A acidic tetrapeptides Val-Gly-Ser-Glu, Ala-Gly-Ser-Glu and the analogue Val-Gly-Asp-Glu were selectively chemotactic for human eosinophils over a narrow dose range although eosinophils from different individuals varied in their dose-response pattern. Histamine abrogated the chemotactic properties of the individual tetrapeptides. When Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu were combined in various concentrations the resultant chemotaxis was either negligible or no greater than that produced when each peptide was tested separately. Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu both promoted eosinophil accumulation when applied to the abraded skin of man or i.d. to the marmoset. Biopsies of marmoset skin revealed that peptide-induced eosinophilia was not associated with mast-cell degranulation. Histamine, which was chemotactic in vitro, did not lead to appreciable eosinophil accumulation in vivo, and combinations of histamine and the acidic tetrapeptides evoked little or no cutaneous eosinophil infiltration either in man or the marmoset. These studies suggest that there is a complex interaction between histamine and the ECF-A tetrapeptides; however, the tetrapeptides alone can promote the recruitment and localization of eosinophils by a mechanism apparently independent of mast-cell degranulation.