Murine thymocytes proliferate in direct response to interleukin-7

The ability of interleukin-7 (IL-7) to stimulate murine thymocyte proliferation was investigated. IL-7, either alone or in concert with lectin, induced proliferation of adult thymocytes as well as day 13 fetal and adult CD4-/CD8-thymocytes. The IL-7-induced proliferative response of unfractionated thymocytes could not be inhibited by antibodies to IL-2, or IL-4, IL-6, or the IL-2 receptor. In addition, IL-2, IL-4, and IL-6 were not produced by thymocytes activated with IL- 7, as judged by the absence of biologically active cytokine in IL-7- stimulated culture supernatants. IL-7 could act in concert with IL-2 and IL-4 or with IL-4 to enhance the proliferative response of thymocyte cultures. Thus, IL-7 may cause proliferation of thymocytes directly, not indirectly, through production of IL-2, IL-4, or IL-6. IL- 7 may then play a significant role in differentiation of T lymphocytes.     

Platelet-activating factor primes neutrophil responses to agonists: role in promoting neutrophil-mediated endothelial damage

During inflammation polymorphonuclear cells (PMNs) are exposed to agonistic stimuli including activated complement, kallikrein, arachidonic acid metabolites, monokines, and platelet-activating factor (PAF). We report that PAF not only directly activates PMNs but in miniscule quantities (10(-12) mol/L) "primes" them as well, that is, permits PMNs to respond to subsequent stimuli that would be otherwise ineffectual. PAF priming of responses including superoxide generation, elastase release, and aggregation is time dependent and is maximal within five minutes. PAF need not be present during the subsequent exhibition of PMN agonists, but priming is inhibited by cold and is also inhibited by the PAF receptor antagonists BN 52021, L-652, and kadsurenone. An intact PAF molecule is required because lyso-PAF and methoxy-PAF do not prime PMN responses. PAF priming is associated with both enhanced expression of the adhesive glycoprotein identified by OKM- 1 antibody and an enhanced rise in intracellular calcium levels in response to the subsequent addition of agonists such as FMLP. PMNs primed with PAF and stimulated with either F-Met-Leu-Phe or phorbol esters are more effective in lysing and detaching cultured human endothelial cells--damage that can also be inhibited by the PAF antagonists. Because PAF is synthesized and exhibited on surfaces of endothelial cells perturbed by coagulation, we suggest that this lipid may potentiate otherwise trivial activators of marginated PMNs so that they become damaging to the PAF-synthesizing endothelium itself. If so, our studies suggest a possible therapeutic role for PAF inhibitors in excessive inflammatory states.     

Implementation of a multidisciplinary guideline‐driven approach to the care of the extremely premature infant improved hospital outcomes

Aim: To test the hypothesis that implementing guidelines for the standardized care of the extremely premature infant (<27 weeks) in the first week of life would improve patient outcomes in an all referral NICU. Methods: Data were collected on all infants <27 weeks gestational age and <7 days of age on admission cared for using these small baby guidelines (SBG), as well as on all age‐matched infants admitted the year prior (comparison). Results: Thirty‐seven patients were cared for utilizing the SBG and 40 patients were in the comparison group. There were no differences between the groups in gestational age, birthweight or age on admission. There was no difference in survival to discharge (73% SBG, 70% comparison). The mean length of stay for survivors was 112 ± 38 days SBG and 145 ± 76 days (p < 0.05) comparison group. Survival without BPD was greater in the SBG group (24%) than in the comparison group (9%; p < 0.05), and survival without severe IVH was greater in the SBG group (65%) than in the comparison group (38%; p < 0.01). Conclusions: These data demonstrate that applying a unified approach to the care of the extremely premature infant in the first week of life resulted in a decrease in the length of hospitalization and improved patient outcomes.     

Combined targeting of MEK/MAPK and PI3K/Akt signalling in multiple myeloma

So-called RAS-dependent pathways, such as those signalling via mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/Akt, are implicated in proliferation and survival of multiple myeloma (MM) cells. However, the effects of their combined blockade and its potential therapeutic utility for the treatment of RAS-mutated MM have not systematically been analysed. Here, we tested the functional consequences of single versus combined inhibition of the MEK/MAPK and PI3K/Akt pathways in a large series of primary MM samples (n = 55) and MM cell lines (n = 11). Additionally, the anti-myeloma activity of different treatments was analysed with respect to the RAS mutation status. PI3K/Akt blockade was generally more pro-apoptotic than blockade of MEK/MAPK both in cell lines and in primary MM samples. Simultaneous blockade of both pathways led to significantly enhanced anti-myeloma activity in 75% of primary MM samples, whereas the remainder was largely resistant. Resistance to combination blockade was exclusively observed in RAS wildtype cases, whereas sensitivity was noted in RAS wildtype and in RAS mutated MM. These results suggest that oncogenic RAS is a predictor of sensitivity to combination treatment with PI3K/Akt and MEK/MAPK inhibitors and that such an approach might therefore be beneficial for this genetically well-defined subgroup of MM patients.     

Post-traumatic endophthalmitis due to Brevibacterium casei : A case report

Endophthalmitis is a serious post-traumatic ocular complication that can lead to loss of vision. We report a case of acute post-traumatic endophthalmitis following a penetrating injury caused by an unusual organism, Brevibacterium casei . The patient was successfully treated with intravitreal antibiotics like ceftazidime and vancomycin, along with topical cefazolin and tobramycin. Brevibacterium casei can be added to the list of rare bacteria causing endophthalmitis and should be kept in mind by clinicians as a potential source of pathology.     

Erratum

Hahm J-O, Cramer KS, Sur M. 1999. Pattern formation by retinal afferents in the ferret lateral geniculate nucleus: developmental segregation and the role of N-methyl-D-aspartate receptors. J Comp Neurol 411:327–345. Due to a printer's error, Figures 6 and 12 were transposed after the proofs of the article had been approved by the author. The correct figures and legends are reprinted on the following pages. The publisher regrets the error.