Dissection of the Temporofrontal Extreme Capsule Fasciculus Using Diffusion MRI Tractography and Association with Lexical Retrieval.

The well-known arcuate fasciculus that connects the posterior superior temporal region with the language production region in the ventrolateral frontal cortex constitutes the classic peri-Sylvian dorsal stream of language. A second temporofrontal white matter tract connects ventrally the anterior to intermediate lateral temporal cortex with frontal areas via the extreme capsule. This temporofrontal extreme capsule fasciculus (TFexcF) constitutes the ventral stream of language processing. The precise origin, course, and termination of this pathway has been examined in invasive tract tracing studies in macaque monkeys, but there have been no standard protocols for its reconstruction in the human brain using diffusion imaging tractography. Here we provide a protocol for the dissection of the TFexcF in vivo in the human brain using diffusion magnetic resonance imaging (MRI) tractography which provides a solid basis for exploring its functional role. A key finding of the current dissection protocol is the demonstration that the TFexcF is left hemisphere lateralized. Furthermore, using the present dissection protocol, we demonstrate that the TFexcF is related to lexical retrieval scores measured with the category fluency test, in contrast to the classical arcuate fasciculus (the dorsal language pathway) that was also dissected and was related to sentence repetition.

Characterization of host response, resorption, and strength properties, and performance in the presence of bacteria for fully absorbable biomaterials for soft tissue repair.

PURPOSE: The objective was to evaluate the host response, resorption, and strength properties, and to assess the performance in the presence of bacteria for Phasix™ Mesh (Phasix™) and Gore® Bio-A® Tissue Reinforcement (Bio-A®) in preclinical models. METHODS: In a rat model, one mesh (2 × 2 cm) was implanted subcutaneously in n = 60 rats. Animals were euthanized after 2, 4, 8, 12, 16, or 24 weeks (n = 5/mesh/time point), and implant sites were assessed for host inflammatory response and overall fibrotic repair thickness. In a rabbit model, meshes (3.8 cm diameter) were bilaterally implanted in subcutaneous pockets in n = 20 rabbits (n = 10 rabbits/mesh) and inoculated with 108 CFU clinically isolated methicillin-resistant Staphylococcus aureus (MRSA). One mesh type was implanted per animal. Animals were euthanized after 7 days, and implants were assessed for abscess formation, bacterial colonization, and mechanical strength. RESULTS: In the rat study, Phasix™ and Bio-A® exhibited similar biocompatibility, although Bio-A® demonstrated a significantly greater inflammatory response at 4 weeks compared to Phasix™ (p < 0.01). Morphometric analysis demonstrated rapid resorption of Bio-A® implants with initially thicker repair sites at 2, 4, 8, and 12 weeks (p < 0.0001), which transitioned to significantly thinner sites compared to Phasix™ at 16 and 24 weeks (p < 0.0001). In the rabbit bacterial inoculation study, Phasix™ exhibited significantly lower abscess score (p < 0.001) and bacterial colonization (p < 0.01), with significantly greater mechanical strength than Bio-A® (p < 0.001). CONCLUSIONS: Host response, resorption, repair thickness, strength, and bacterial colonization suggest a more stable and favorable outcome for monofilament, macroporous devices such as Phasix™ relative to multifilament, microporous devices such as Bio-A® over time.

Compartment syndrome causes systemic inflammation in a rat.

AIMS: Compartment syndrome results from increased intra-compartmental pressure (ICP) causing local tissue ischaemia and cell death, but the systemic effects are not well described. We hypothesised that compartment syndrome would have a profound effect not only on the affected limb, but also on remote organs. METHODS: Using a rat model of compartment syndrome, its systemic effects on the viability of hepatocytes and on inflammation and circulation were directly visualised using intravital video microscopy. RESULTS: We found that hepatocellular injury was significantly higher in the compartment syndrome group (192 PI-labelled cells/10(-1) mm(3), standard error of the mean (sem) 51) compared with controls (30 PI-labelled cells/10(-1) mm(3), sem 12, p < 0.01). The number of adherent venular white blood cells was significantly higher for the compartment syndrome group (5 leukocytes/30s/10 000 µm(2), sem 1) than controls (0.2 leukocytes/30 s/10 000 µm(2), sem 0.2, p < 0.01). Volumetric blood flow was not significantly different between the two groups, although there was an increase in the heterogeneity of perfusion. CONCLUSIONS: Compartment syndrome can be accompanied by severe systemic inflammation and end organ damage. This study provides evidence of the relationship between compartment syndrome in a limb and systemic inflammation and dysfunction in a remote organ. Cite this article: Bone Joint J 2016; 98-B:1132-7.

Contribution of inflammation to cellular injury in compartment syndrome in an experimental rodent model.

Compartment syndrome, a devastating consequence of limb trauma, is characterised by severe tissue injury and microvascular perfusion deficits. We hypothesised that leucopenia might provide significant protection against microvascular dysfunction and preserve tissue viability. Using our clinically relevant rat model of compartment syndrome, microvascular perfusion and tissue injury were directly visualised by intravital video microscopy in leucopenic animals. We found that while the tissue perfusion was similar in both groups (38.8% (standard error of the mean (sem) 7.1), 36.4% (sem 5.7), 32.0% (sem 1.7), and 30.5% (sem 5.35) continuously-perfused capillaries at 45, 90, 120 and 180 minutes compartment syndrome, respectively versus 39.2% (sem 8.6), 43.5% (sem 8.5), 36.6% (sem 1.4) and 50.8% (sem 4.8) at 45, 90, 120 and 180 minutes compartment syndrome, respectively in leucopenia), compartment syndrome-associated muscle injury was significantly decreased in leucopenic animals (7.0% (sem 2.0), 7.0%, (sem 1.0), 9.0% (sem 1.0) and 5.0% (sem 2.0) at 45, 90, 120 and 180 minutes of compartment syndrome, respectively in leucopenia group versus 18.0% (sem 4.0), 23.0% (sem 4.0), 32.0% (sem 7.0), and 20.0% (sem 5.0) at 45, 90, 120 and 180 minutes of compartment syndrome in control, p = 0.0005). This study demonstrates that the inflammatory process should be considered central to the understanding of the pathogenesis of cellular injury in compartment syndrome.

Nuclear matrix binding protein SMAR1 regulates T-cell differentiation and allergic airway disease.

Asthma is a complex airway allergic disease involving the interplay of various cell types, cytokines, and transcriptional factors. Though many factors contribute to disease etiology, the molecular control of disease phenotype and responsiveness is not well understood. Here we report an essential role of the matrix attachment region (MAR)-binding protein SMAR1 in regulating immune response during allergic airway disease. Conditional knockout of SMAR1 in T cells rendered the mice resistant to eosinophilic airway inflammation against ovalbumin (OVA) allergen with low immunoglobulin E (IgE) and interleukin-5 (IL-5) levels. Moreover, a lower IgE/IgG2a ratio and higher interferon-γ (IFN-γ) response suggested aberrant skewing of T-cell differentiation toward type 1 helper T cell (Th1) response. We show that SMAR1 functions as a negative regulator of Th1 and Th17 differentiation by interacting with two potential and similar MAR regions present on the promoters of T-bet and IL-17. Thus, we present SMAR1 as a regulator of T-cell differentiation that favors the establishment of Th2 cells by modulating Th1 and Th17 responses.

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation and controls genes involved in glycolysis, angiogenesis, migration and invasion. Overexpression of HIF-1α has been demonstrated in many common human cancers. METHODS: Luciferase reporter gene assay under hypoxia and normoxia was used to demonstrate transcriptional inhibition of HIF-1 by P276-00. Detailed studies such as western blotting, reverse-transcriptase-PCR and immunofluorescence were carried out to elucidate its mechanism of action. Cytotoxic potential of P276-00 under normoxia and hypoxia was determined on prostate cancer cells using CCK-8 assay, and cell-cycle analysis was carried out using flow cytometry. Antiangiogenic activity of P276-00 was demonstrated by migration assay and tube-formation assay. Efficacy study of P276-00 was performed in a PC-3 xenograft model. RESULTS: P276-00 inhibits transcriptional activation of HIF-1 under hypoxia. It suppressed hypoxia-mediated nuclear HIF-1α expression, as well as phosphorylation of Akt and 4E-BP1 and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor. Under hypoxia, P276-00 did not exhibit enhanced cytotoxic activity in prostate cancer cells but arrested them in the G2/M phase of the cell cycle. The tubular formation of human umbilical vein endothelial cells and migration of prostate cancer cells were also inhibited by P276-00 in vitro. In addition, it demonstrated significant in vivo efficacy in the PC-3 xenograft model. CONCLUSIONS: Given its low toxicity profile, its demonstrated antitumor activity and its potential to inhibit the HIF-1 pathway, P276-00 should be considered as antiangiogenic chemotherapy for prostate cancer.

Assessment of hepatic inflammation after spinal cord injury using intravital microscopy.

OBJECTIVES: The liver has been shown to play a particularly important role in the initiation and progression of the early systemic inflammatory response (SIR) to spinal cord injury (SCI). The purpose of this study was to determine the time course of leucocyte recruitment to the liver, and to determine the effect of injury severity on the magnitude of leucocyte recruitment and hepatic injury. METHODS: Rats were randomly assigned to one of the following groups: uninjured, sham-injured (laminectomy and no cord injury), cord compressed or cord transected. At 30 min and 90 min after SCI rats had the left lobe of their livers externalised and visualised using intravital video microscopy. RESULTS: Thirty minutes after injury the total number of leucocytes per post-sinusoidal venule was significantly increased after cord transection compared to that in uninjured and sham-injured rats (P<0.05). Of these leucocytes, significantly more were adherent to venule walls (P<0.05). At 90 min the total number of leucocytes per post-sinusoidal venule and the number of adherent and rolling leucocytes was significantly increased after cord transection and cord compression (P<0.05). DISCUSSION: This is the first study to use intravital microscopy to visualise systemic inflammation in the liver following SCI. We have demonstrated immediate leucocyte recruitment to the liver within 30 min after injury and have shown that systemic inflammation increases with time after injury and with severity of injury.

Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus.

The acute inflammatory response elicited by adenovirus vectors results in loss of gene expression and tissue injury in the target organ. This acute inflammation is now believed to be the major limiting factor for the use of adenovirus vectors in gene therapy. While exploring the level of acute inflammation caused by the adenovirus encoding the gene for the anti-inflammatory enzyme heme oxygenase-1, we discovered that this adenovirus not only did not elicit acute inflammation, but could prevent the inflammation caused by a second adenovirus. Here we describe a new approach to gene therapy, which uses the encoding of the potent anti-inflammatory enzyme heme oxygenase-1 to prevent early host inflammatory responses normally associated with adenovirus vectors.

Anticipation in familial cavernous angioma: ascertainment bias or genetic cause.

OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

Allergic rhinitis.

Allergic rhinitis is a common disease with characteristic symptoms affecting the eyes, ears, and face as well as the nose. A detailed history is the foundation of a correct diagnosis. Laboratory tests may be needed to supplement this in atypical presentations. A combination of pharmacotherapy, immunotherapy, and environmental control may be required to control and prevent symptoms.

Detection of C-reactive protein, streptolysin O, and anti-streptolysin O antibodies in immune complexes isolated from the sera of patients with acute rheumatic fever.

Circulating immune complexes (IC) of 42 patients with acute rheumatic fever from Santiago, Chile, were studied. The complexes were isolated by polyethylene glycol precipitation and were analyzed for antibodies, antigens, and C-reactive protein. We found the complexes to be enriched in antibody to streptolysin O, particularly in the group of patients with elevated levels of IC. IgM was the predominant class of Ig present in the complexes. Western blots from 12 patients to detect antigens in the complexes showed proteins of m.w. 50,000, 60,000, and 69,000, consistent with the polypeptides of streptolysin O. Such antigens were absent in the complexes from patients with post-streptococcal glomerulonephritis and pharyngitis. Eluted antibodies from these protein bands on the nitrocellulose sheets reacted with the streptolysin O in Western blots and neutralized the hemolytic activity of streptolysin O in a microhemolysin assay. In addition, isolated complexes from several sera showed the presence of C-reactive protein bound to complexes. In vitro experiments demonstrated that [125I]C-reactive protein was not precipitated by polyethylene glycol either alone or when added to monomeric IgG, whereas it precipitated significantly when added to aggregated IgG. The detectable C-reactive protein in isolated complexes and sera samples increased after treatment with sodium dodecyl sulfate. These data suggest that circulating immune complexes in acute rheumatic fever contain streptolysin O and its antibody and raise interesting questions regarding the pathogenetic significance of C-reactive protein in the complexes.