Assessment of correlation between knee notch width index and the three-dimensional notch volume

This study was done to determine whether there is a correlation between the notch volume and the notch width index (NWI) as measured on the three most frequently used radiographic views: the Holmblad 45°, Holmblad 70°, and Rosenberg view. The notch volume of 20 cadaveric knees was measured using Computed Tomography (CT). The Holmblad 45°, Holmblad 70°, and Rosenberg notch view radiographs were digitally re-created from the CT scans for each specimen, and the NWI was measured by two observers. The Pearson correlation coefficient between the NWI and notch volume was calculated, as well as between the three views. An independent t test was performed to determine the difference in NWI and notch volume between male and female specimens. The reliability for each view was also determined. There was no correlation between the NWI as measured on the Holmblad 45°, Holmblad 70°, or Rosenberg view and the notch volume. All three radiographic views proved reliable, but showed only a moderate correlation with each other. Men had larger notch volumes than women, but there was no difference in NWI. A knee with a small intercondylar notch is often considered an increased risk for ACL rupture. The NWI is a frequently used two-dimensional method to determine notch size. However, in the present study, this index was not positively correlated with the overall volume of the notch. Based on the results of the current study, the authors would advice to use caution when using notch view radiographs in a clinical setting to predict risk of ACL rupture

Predictors of Antibiotics Co-prescription with Antimalarials for Patients Presenting with Fever in Rural Tanzania.

Successful implementation of malaria treatment policy depends on the prescription practices for patients with malaria. This paper describes prescription patterns and assesses factors associated with co-prescription of antibiotics and artemether-lumefantrine (AL) for patients presenting with fever in rural Tanzania. From June 2009 to September 2011, a cohort event monitoring program was conducted among all patients treated at 8 selected health facilities in Ifakara and Rufiji Health and Demographic Surveillance System (HDSS).It included all patients presenting with fever and prescribed with AL. Logistic regression was used to model the predictors on the outcome variable which is co-prescription of AL and antibiotics on a single clinical visit. A cohort of 11,648 was recruited and followed up with 92% presenting with fever. Presumptive treatment was used in 56% of patients treated with AL. On average 2.4 (1 -- 7) drugs was prescribed per encounter, indicating co-prescription of AL with other drugs. Children under five had higher odds of AL and antibiotics co-prescription (OR = 0.63, 95% CI: 0.46 -- 0.85) than those aged more than five years. Patients testing negative had higher odds (OR = 2.22, 95%CI: 1.65 -- 2.97) of AL and antibiotics co-prescription. Patients receiving treatment from dispensaries had higher odds (OR = 1.45, 95% CI: 0.84 -- 2.30) of AL and antibiotics co-prescription than those from served in health centres even though the deference was not statistically significant. Regardless the fact that Malaria is declining but due to lack of laboratories and mRDT in most health facilities in the rural areas, clinicians are still treating malaria presumptively. This leads them to prescribe more drugs to treat all possibilities

Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro

Although peroxisome proliferator-activated receptor gamma (PPARγ) agonist have been shown to inhibit hepatocellular carcinoma (HCC) development, the role of PPARγ in hepatocarcinogenesis remains unclear. We investigated the therapeutic efficacy of PPAR

Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection

Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169+ sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4+CD25+ T cells and an increased number of B220+CD19+ B cells. The reduction in CD4+CD25+ T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

A Protein Aggregation Based Test for Screening of the Agents Affecting Thermostability of Proteins

To search for agents affecting thermal stability of proteins, a test based on the registration of protein aggregation in the regime of heating with a constant rate was used. The initial parts of the dependences of the light scattering intensity (I) on temperature (T) were analyzed using the following empiric equation: I = Kagg(T−T0)2, where Kagg is the parameter characterizing the initial rate of aggregation and T0 is a temperature at which the initial increase in the light scattering intensity is registered. The aggregation data are interpreted in the frame of the model assuming the formation of the start aggregates at the initial stages of the aggregation process. Parameter T0 corresponds to the moment of the origination of the start aggregates. The applicability of the proposed approach was demonstrated on the examples of thermal aggregation of glycogen phosphorylase b from rabbit skeletal muscles and bovine liver glutamate dehydrogenase studied in the presence of agents of different chemical nature. The elaborated approach to the study of protein aggregation may be used for rapid identification of small molecules that interact with protein targets

Phylodynamics of HIV-1 Subtype B among the Men-Having-Sex-with-Men (MSM) Population in Hong Kong

The men-having-sex-with-men (MSM) population has become one of the major risk groups for HIV-1 infection in the Asia Pacific countries. Hong Kong is located in the centre of Asia and the transmission history of HIV-1 subtype B transmission among MSM remained unclear. The aim of this study was to investigate the transmission dynamics of HIV-1 subtype B virus in the Hong Kong MSM population. Samples of 125 HIV-1 subtype B infected MSM patients were recruited in this study. Through this study, the subtype B epidemic in the Hong Kong MSM population was identified spreading mainly among local Chinese who caught infection locally. On the other hand, HIV-1 subtype B infected Caucasian MSM caught infection mainly outside Hong Kong. The Bayesian phylogenetic analysis also indicated that 3 separate subtype B epidemics with divergence dates in the 1990s had occurred. The first and latest epidemics were comparatively small-scaled; spreading among the local Chinese MSM while sauna-visiting was found to be the major sex partner sourcing reservoir for the first subtype B epidemic. However, the second epidemic was spread in a large-scale among local Chinese MSM with a number of them having sourced their sex partners through the internet. The epidemic virus was estimated to have a divergence date in 1987 and the infected population in Hong Kong had a logistic growth throughout the past 20 years. Our study elucidated the evolutionary and demographic history of HIV-1 subtype B virus in Hong Kong MSM population. The understanding of transmission and growth model of the subtype B epidemic provides more information on the HIV-1 transmission among MSM population in other Asia Pacific high-income countries

Dpr Acts as a Molecular Switch, Inhibiting Wnt Signaling when Unphosphorylated, but Promoting Wnt Signaling when Phosphorylated by Casein Kinase Iδ/ε

The Wnt pathway is a key regulator of development and tumorigenesis. Dpr (Dact/Frodo) influences Wnt signaling in part through the interaction of its PDZ-B domain with Dsh's PDZ domain. Studies have shown that XDpr1a and its close relative, Frodo, are involved in multiple steps of the Wnt pathway in either inhibitory or activating roles. We found that XDpr1a is phosphorylated by casein kinase Iδ/ε (CKIδ/ε), an activator of Wnt signaling, in the presence of XDsh. Abrogating XDpr1a's ability to bind XDsh through mutation of XDpr1a's PDZ-B domain blocks CK1δ/ε's phosphorylation of XDpr1a. Conversely, XDsh possessing a mutation in its PDZ domain that is unable to bind XDpr1a does not promote XDpr1a phosphorylation. Phosphorylation of XDpr1a and XDsh by CKIδ/ε decreases their interaction. Moreover, the phosphorylation of XDpr1a by CKIδ/ε not only abrogates XDpr1a's promotion of β-catenin degradation but blocks β-catenin degradation. Our data suggest that XDpr1a phosphorylation by CKIδ/ε is dependent on the interaction of XDpr1a's PDZ-B domain with XDsh's PDZ domain, and that the phosphorylation state of XDpr1a determines whether it inhibits or activates Wnt signaling

Detection of oligoclonal IgG kappa and IgG lambda bands in cerebrospinal fluid and serum with Hevylite™ antibodies. comparison with the free light chain oligoclonal pattern

<p>Abstract</p> <p>Background</p> <p>Oligoclonal IgG bands in cerebrospinal fluid that are absent in serum indicate intrathecal IgG synthesis and are a sensitive marker of CNS inflammatory diseases, in particular multiple sclerosis. It may be of interest to determine whether these bands are predominantly IgGκ or IgGλ.</p> <p>Methods</p> <p>We have used Hevylite™ antibodies and developed a technique for detection of oligoclonal IgGκ and IgGλ bands by means of isoelectric focusing followed by immunoblotting. The same technique was used for oligoclonal free κ and free λ detection. Among several techniques tested, affinity immunoblotting appears to be the most sensitive; it can detect less than 1 ng of IgGκ or IgGλ paraprotein. We compared oligoclonal IgG profiles with those of oligoclonal IgGκ and IgGλ. There was good agreement concerning the presence or absence of intrathecal synthesis. We observed the ratios between oligoclonal IgGκ and IgGλ bands, and they did not always match the ratios between free κ and free λ bands. We were also able to detect antigen-specific CSF-restricted oligoclonal IgGκ and IgGλ bands in neuroborreliosis. It remains to be determined subsequently by a clinically-oriented prospective study, whether predominant IgGκ/IgGλ or free κ/free λ can be observed more frequently in particular diseases with oligoclonal IgG synthesis.</p> <p>Discussion</p> <p>Very sensitive detection of oligoclonal IgGκ and IgGλ bands in cerebrospinal fluid with Hevylite antibodies is feasible; detection of antigen-specific IgGκ or IgGλ is possible as well. In particular situations, e.g. when difficulties arise in distinguishing between oligoclonal and monoclonal pattern, the test may be of considerable clinical value.</p