A facile synthesis and anti-avian influenza virus (H5N1) screening of some novel pyrazolopyrimidine nucleoside derivatives

Treatment of 5-amino-1-(9-methyl-5,6-dihydronaphtho[1',2':4,5]thieno[2,3-d]pyrimidin-11-yl)-1H-pyrazole-4-carbonitrile (1) with formic acid afforded pyrazolo[3,4-d]pyrimidin-4-one derivative 2. The sodium salt of the latter compound (generated in situ) was treated with some alkyl halides to afford the corresponding N-substituted compounds 3-7. The siloxy derivative 8 (generated also in situ from 2) was ribosylated and glycosylated to yield compounds 9 and 11, respectively. Deprotection of compounds 9 and 11 in methanolic ammonia produced the free nucleosides 10 and 12, respectively. Moreover, the prepared compounds were tested for antiviral activity against H5N1 virus [A/chicken/Egypt/1/2006] and some of them revealed moderate results compared with the other tested compounds.     

Structural basis for specific inhibition of the highly sensitive ShHTL7 receptor

Striga hermonthica is a root parasitic plant that infests cereals, decimating yields, particularly in sub‐Saharan Africa. For germination, Striga seeds require host‐released strigolactones that are perceived by the family of HYPOSENSITIVE to LIGHT (ShHTL) receptors. Inhibiting seed germination would thus be a promising approach for combating Striga. However, there are currently no strigolactone antagonists that specifically block ShHTLs and do not bind to DWARF14, the homologous strigolactone receptor of the host. Here, we show that the octyl phenol ethoxylate Triton X‐100 inhibits S. hermonthica seed germination without affecting host plants. High‐resolution X‐ray structures reveal that Triton X‐100 specifically plugs the catalytic pocket of ShHTL7. ShHTL7‐specific inhibition by Triton X‐100 demonstrates the dominant role of this particular ShHTL receptor for Striga germination. Our structural analysis provides a rationale for the broad specificity and high sensitivity of ShHTL7, and reveals that strigolactones trigger structural changes in ShHTL7 that are required for downstream signaling. Our findings identify Triton and the related 2‐[4‐(2,4,4‐trimethylpentan‐2‐yl)phenoxy]acetic acid as promising lead compounds for the rational design of efficient Striga‐specific herbicides.     

Biochemical Changes Observed After PUVA Versus PUVA Plus Methotrexate Therapy in Mycosis Fungoides Using Synchrotron Infrared Microspectroscopy

Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma in which the distinction between early stage MF and other inflammatory dermatosis remains difficult. Twenty patients of early stage MF and nine patients with psoriasis and lichen planus were included in this study. Ten MF patients were treated with psoralen plus UVA (PUVA) and the other 10 MF patients were treated with PUVA plus methotrexate (MTX) until complete clinical remission. Synchrotron infrared microspectroscopy (SIRM) found that MF lesions were biochemically different compared to inflammatory diseases. After treating MF with either therapeutic modality, the lymphocytic count decreased significantly in both the epidermis and dermis (P < 0.001) but no biochemical changes were observed in the remaining lymphocytes after treatment, indicating the disease process was slowed by treatment but not eradicated. In conclusion SIRM is a promising method for distinguishing MF from other inflammatory diseases such as psoriasis and lichen planus. A significant reduction in lymphocyte count indicated that PUVA therapy is an effective treatment for early stage MF, and MTX could be reserved for more advanced cases that are not PUVA responsive. However, SIRM evidence of persistent disease suggests that maintenance therapy is recommended after clinical remission.     

Merosin deficient congenital muscular dystrophy: Clinical,neuroimaging and immunohistochemical study of 8 Egyptian pediatric patients

Congenital muscular dystrophies (CMD) are a group of heterogeneous inherited autosomal recessive disorders characterized by muscular weakness, hypotonia and contractures. The Merosin Negative CMD (MNCMD) is considered to be the most severe form and is usually associated with white matter abnormalities as seen with brain imaging. Merosin is also expressed in the nervous system and its deficiency could affect its development. This article describes the clinical picture, muscle biopsy findings and neuroimaging abnormalities of eight Egyptian Pediatric patients with the clinical presentation of merosin negative congenital muscular dystrophy. The leading clinical presentation in almost all patients was severe hypotonia, muscular weakness and failure to achieve motor developmental milestones, only Case 2 walked at 2 years of age. Mentality was normal in most patients with exception of Case 2 in whom scholastic achievement was poor and was associated with behavior abnormality. Serum Creatine kinase ranged from moderate to severe elevation, 536–3563 U/L, Electromyography demonstrated a myopathic pattern in all patients. Brain MRI showed extensive demyelination of the cerebral white matter in 6/8 patients with extension to cerebellar demyelination in Case 5. 5/8 patients underwent muscle biopsy for which immunofluorescence staining for merosin demonstrated complete deficiency of laminin α2 in Case 5 & partial deficiency of laminin α2 in Case 2.This report demonstrates the utility of Immunofluorescence staining as a guide to confirm the diagnosis of MDCMD especially when molecular diagnosis is not available.     

A Systematic Review of Instruments to Assess Organizational Readiness for Knowledge Translation in Health Care

Background

The translation of research into practices has been incomplete. Organizational readiness for change (ORC) is a potential facilitator of effective knowledge translation (KT). However we know little about the best way to assess ORC. Therefore, we sought to systematically review ORC measurement instruments.

Methods

We searched for published studies in bibliographic databases (Pubmed, Embase, CINAHL, PsychINFO, Web of Science, etc.) up to November 1^st, 2012. We included publications that developed ORC measures and/or empirically assessed ORC using an instrument at the organizational level in the health care context. We excluded articles if they did not refer specifically to ORC, did not concern the health care domain or were limited to individual-level change readiness. We focused on identifying the psychometric properties of instruments that were developed to assess readiness in an organization prior to implementing KT interventions in health care. We used the Standards for Educational and Psychological Testing to assess the psychometric properties of identified ORC measurement instruments.

Findings

We found 26 eligible instruments described in 39 publications. According to the Standards for Educational and Psychological Testing, 18 (69%) of a total of 26 measurement instruments presented both validity and reliability criteria. The Texas Christian University –ORC (TCU-ORC) scale reported the highest instrument validity with a score of 4 out of 4. Only one instrument, namely the Modified Texas Christian University – Director version (TCU-ORC-D), reported a reliability score of 2 out of 3. No information was provided regarding the reliability and validity of five (19%) instruments.

Conclusion

Our findings indicate that there are few valid and reliable ORC measurement instruments that could be applied to KT in the health care sector. The TCU-ORC instrument presents the best evidence in terms of validity testing. Future studies using this instrument could provide more knowledge on its relevance to diverse clinical contexts.     

Primary ciliogenesis is a crucial step for multiciliated cell determinism in the respiratory epithelium

The alteration of the mucociliary clearance is a major hallmark of respiratory diseases related to structural and functional cilia abnormalities such as chronic obstructive pulmonary diseases (COPD), asthma and cystic fibrosis. Primary cilia and motile cilia are the two principal organelles involved in the control of cell fate in the airways. We tested the effect of primary cilia removal in the establishment of a fully differentiated respiratory epithelium. Epithelial barrier integrity was not altered while multiciliated cells were decreased and mucous-secreting cells were increased. Primary cilia homeostasis is therefore paramount for airway epithelial cell differentiation. Primary cilia-associated pathophysiologic implications require further investigations in the context of respiratory diseases.     

Physiological and structural changes of the lung tissue in male albino rat exposed to immobilization stress

In case of a life-threatening, stressful event, the body prepares for an emergency. Indeed, the lung is unique in which alveolar cells are constantly exposed to physical and chemical stresses. This study aimed to study the impact of immobilization stress on the blood–air barrier and how it initiate and maintain an inflammatory response, plus determining the resolution of lung inflammation and repair. There was a significant increase in the plasma levels of stress markers “corticosterone and catecholamines” with a decrease in surfactant protein A (a lung-injury marker). Chronic stress produced a significant increase in the pulmonary oxidative and inflammatory markers malondialdehyde, tumor necrosis factor α, and induced nitric oxide synthase when compared with that of acute stress. Both stresses provoked marked pulmonary morphological and ultrastructural changes with a significant increase in caspase-3 immunoexpression. There was increasing evidence of lung’s capacity for repair. This process involved edema resolution, cell proliferation, and tissue remodeling in improving the lung-injury, oxidative, and inflammatory markers.     

Effects of Temperature and Salinity on Vibrio vulnificus Population Dynamics as Assessed by Quantitative PCR

The abundance of Vibrio vulnificus in coastal environments has been linked to water temperature, while its relationship to salinity is less clear. We have developed a culture-independent, most-probable-number quantitative PCR approach to examine V. vulnificus population dynamics in Barnegat Bay, N.J. Based on the combined analysis of our results from Barnegat Bay and from the literature, the present data show that (i) V. vulnificus population dynamics are strongly correlated to water temperature and (ii) although the general trend is for V. vulnificus abundance to be inversely correlated with salinity, this relationship depends on salinity levels. Irrespective of temperature, high abundances of V. vulnificus are observed at 5 to 10 ppt, which thus appears to be the optimal salinity regime for their survival. At 20 to 25 ppt, V. vulnificus abundances show a positive correlation to salinity. Unsuccessful attempts to resuscitate V. vulnificus, combined with our inability to detect cells during the winter despite an assay adapted to detect viable but nonculturable (VBNC) cells, suggest that the decline and eventual disappearance of V. vulnificus from the water column during the winter months is due primarily to a significant reduction in population size and is not only the consequence of cells entering the VBNC state. These findings are in line with the hypothesis that the sediment serves as a refuge for a subpopulation of V. vulnificus over the winter and weather-driven mixing events during the spring initiate a summer bloom in the water column.     

Genetic variation among populations of the endangered fan mussel <Emphasis Type="Italic">Pinna nobilis</Emphasis> (Mollusca: Bivalvia) along the Tunisian coastline

The Mediterranean fan mussel Pinna nobilis is an endangered invertebrate due to overexploitation and habitat deterioration. In this species, two distinctive morphs, the “combed” and “straight and wide” forms, have been recorded and it is not known whether this morphometric variability is attributed to genetic or environmental factors. In this study, we used mitochondrial COI sequences to describe the genetic variability of five Pinna nobilis populations sampled along the northern, eastern, and southern Tunisian coastline, and to examine whether there is a genetic differentiation between the two forms of this species. DNA sequences of 675 bp from the mitochondrial COI gene have revealed 10 different haplotypes among 49 examined specimens. Haplotype diversity was high, ranging between 0.40441 and 0.80952, and showed a decreasing North-East gradient, which seems to be explained by the hydrogeography of the study area. The mitochondrial COI marker did not suggest a genetic distinctiveness between the two Pinna nobilis shell forms, “combed” and “straight and wide”. Although the morphometric plasticity of the fan mussel could be due to the influence of environmental factors, further genetic studies using nuclear markers are envisaged to investigate whether this differentiation is associated to gene flow restrictions.