Comparative distribution of substance P (SP) and cholecystokinin (CCK) binding sites and immunoreactivity in the brain of the sea bass (Dicentrarchus labrax).

Specific binding sites for cholecystokinin (CCK) and substance P (SP) were detected in the brain of a marine teleost fish, the sea bass, after in vitro incubation of tissue sections with the tritiated peptides and light microscopic autoradiography. Specific binding sites for [3H]-CCK were detected in the dorsal and ventral telencephalon, in the preoptic, tuberal and posterior hypothalamus, in the optic tectum, in the valvulla cerebelli, in the vagal lobe and further in a dorsal location in the medulla oblongata. Areas rich in [3H]-SP binding were located in the ventral telencephalon, in the entire hypothalamic and thalamic region, in the midbrain tegmentum, in the optic tectum, in the valvulla cerebelli and in the medulla oblongata. The distribution of these binding sites seemed to match fairly well with the location of the corresponding immunoreactive elements, although some minor mismatches could be observed. These autoradiographic findings provide the first anatomical evidence for the presence of CCK-like and SP-like binding sites in the brain of a teleost fish.     

Big flies, small repeats: the "Thr-Gly" region of the period gene in Diptera

The region of the clock gene period (per) that encodes a repetitive tract of threonine-glycine (Thr-Gly) pairs has been compared between Dipteran species both within and outside the Drosophilidae. All the non- Drosophilidae sequences in this region are short and present a remarkably stable picture compared to the Drosophilidae, in which the region is much larger and extremely variable, both in size and composition. The accelerated evolution in the repetitive region of the Drosophilidae appears to be mainly due to an expansion of two ancestral repeats, one encoding a Thr-Gly dipeptide and the other a pentapeptide rich in serine, glycine, and asparagine or threonine. In some drosophilids the expansion involves a duplication of the pentapeptide sequence, but in Drosophila pseudoobscura both the dipeptide and the pentapeptide repeats are present in larger numbers. In the nondrosophilids, however, the pentapeptide sequence is represented by one copy and the dipeptide by two copies. These observations fulfill some of the predictions of recent theoretical models that have simulated the evolution of repetitive sequences.      

A PKS/NRPS/FAS Hybrid Gene Cluster from Serratia plymuthica RVH1 Encoding the Biosynthesis of Three Broad Spectrum,Zeamine-Related Antibiotics

Serratia plymuthica strain RVH1, initially isolated from an industrial food processing environment, displays potent antimicrobial activity towards a broad spectrum of Gram-positive and Gram-negative bacterial pathogens. Isolation and subsequent structure determination of bioactive molecules led to the identification of two polyamino antibiotics with the same molecular structure as zeamine and zeamine II as well as a third, closely related analogue, designated zeamine I. The gene cluster encoding the biosynthesis of the zeamine antibiotics was cloned and sequenced and shown to encode FAS, PKS as well as NRPS related enzymes in addition to putative tailoring and export enzymes. Interestingly, several genes show strong homology to the pfa cluster of genes involved in the biosynthesis of long chain polyunsaturated fatty acids in marine bacteria. We postulate that a mixed FAS/PKS and a hybrid NRPS/PKS assembly line each synthesize parts of the backbone that are linked together post-assembly in the case of zeamine and zeamine I. This interaction reflects a unique interplay between secondary lipid and secondary metabolite biosynthesis. Most likely, the zeamine antibiotics are produced as prodrugs that undergo activation in which a nonribosomal peptide sequence is cleaved off.     

Hospital Standardized Mortality Ratio: Consequences of Adjusting Hospital Mortality with Indirect Standardization

Background

The hospital standardized mortality ratio (HSMR) is developed to evaluate and improve hospital quality. Different methods can be used to standardize the hospital mortality ratio. Our aim was to assess the validity and applicability of directly and indirectly standardized hospital mortality ratios.

Methods

Retrospective scenario analysis using routinely collected hospital data to compare deaths predicted by the indirectly standardized case-mix adjustment method with observed deaths. Discharges from Dutch hospitals in the period 2003–2009 were used to estimate the underlying prediction models. We analysed variation in indirectly standardized hospital mortality ratios (HSMRs) when changing the case-mix distributions using different scenarios. Sixty-one Dutch hospitals were included in our scenario analysis.

Results

A numerical example showed that when interaction between hospital and case-mix is present and case-mix differs between hospitals, indirectly standardized HSMRs vary between hospitals providing the same quality of care. In empirical data analysis, the differences between directly and indirectly standardized HSMRs for individual hospitals were limited.

Conclusion

Direct standardization is not affected by the presence of interaction between hospital and case-mix and is therefore theoretically preferable over indirect standardization. Since direct standardization is practically impossible when multiple predictors are included in the case-mix adjustment model, indirect standardization is the only available method to compute the HSMR. Before interpreting such indirectly standardized HSMRs the case-mix distributions of individual hospitals and the presence of interactions between hospital and case-mix should be assessed.     

The age factor in optic nerve regeneration: Intrinsic and extrinsic barriers hinder successful recovery in the short‐living killifish

As the mammalian central nervous system matures, its regenerative ability decreases, leading to incomplete or non‐recovery from the neurodegenerative diseases and central nervous system insults that we are increasingly facing in our aging world population. Current neuroregenerative research is largely directed toward identifying the molecular and cellular players that underlie central nervous system repair, yet it repeatedly ignores the aging context in which many of these diseases appear. Using an optic nerve crush model in a novel biogerontology model, that is, the short‐living African turquoise killifish, the impact of aging on injury‐induced optic nerve repair was investigated. This work reveals an age‐related decline in axonal regeneration in female killifish, with different phases of the repair process being affected depending on the age. Interestingly, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of this impairment. Overall, we introduce the killifish visual system and its age‐dependent regenerative ability as a model to identify new targets for neurorepair in non‐regenerating individuals, thereby also considering the effects of aging on neurorepair.     

Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels

Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and mechanisms of alphaPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. alphaPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF(R)Is), and enhanced the efficacy of chemotherapy and VEGF(R)Is. alphaPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF(R)Is, alphaPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF(R)Is. Moreover, it did not cause or enhance VEGF(R)I-related side effects. The efficacy and safety of alphaPlGF, its pleiotropic and complementary mechanism to VEGF(R)Is, and the negligible induction of an angiogenic rescue program suggest that alphaPlGF may constitute a novel approach for cancer treatment.