The translational importance of establishing biomarkers of human spinal cord injury

The evaluation of such novel therapies for acute spinal cord injury in clinical trials is extremely challenging. Our current dependence upon the clinical assessment of neurologic impairment renders many acute SCI patients ineligible for trials because they are not examinable. Furthermore, the difficulty in predicting neu-rologic recovery based on the early clinical assessment forces investigators to recruit large cohorts to have sufficient power. Biomarkers that objectively classify injury severity and better predict neurologic outcome would be valuable tools for translational research. As such, the objective of the present review was to de-scribe some of the translational challenges in acute spinal cord injury research and examine the potential utility of neurochemical biomarkers found within cerebrospinal fluid and blood. We focus on published efforts to establish biological markers for accurately classifying injury severity and precisely predict neuro-logical outcome.     

Phase II study of HCVIDD/MA in patients with newly diagnosed peripheral T‐cell lymphoma

A phase II study was performed to evaluate the efficacy of hyper‐fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine (HCVIDD/MA) in patients with newly diagnosed peripheral T‐cell lymphoma (PTCL), excluding ALK‐positive anaplastic large cell lymphoma. Fifty‐three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression (n = 13) or prolonged thrombocytopenia (n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression‐free survival (PFS) was 7·5 months. With a median follow‐up of 7·6 years, 5‐year PFS and overall survival (OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer‐cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/MA for the first‐line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at www.clinicaltrials.gov as #NCT00290433.     

The effects of folate-conjugated gold nanorods in combination with plasmonic photothermal therapy on mouth epidermal carcinoma cells

The use of lasers has emerged to be highly promising for cancer therapy modalities, most commonly, the photothermal therapy method. Unfortunately, the most common disadvantage of laser therapy is its nonselectivity and requirement of high power density. The use of plasmonic nanoparticles as highly enhanced photoabsorbing agents has thus introduced a much more selective and efficient cancer therapy strategy. In this study, we aimed to demonstrate the selective targeting and destruction of mouth epidermal carcinoma cells (KB cells) using the photothermal therapy of folate-conjugated gold nanorods (F-GNRs). Considering the beneficial characteristics of GNRs and overexpression of the folate receptor by KB cells, we selected F-GNRs as a targeted photothermal therapy agent. Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was determined by flow cytometry using an annexin V–fluorescein isothiocyanate/propidium iodide apoptosis detection kit. No cell damage or cytotoxicity from the individual treatment of laser light or F-GNRs was observed. However, a 56 % cell lethality was achieved for KB cells using combined plasmonic photothermal therapy of 20 μM F-GNRs with seven pulses of laser light and 6-h incubation periods. Cell lethality strongly depends on the concentration of F-GNRs and the incubation period that is mainly due to the induction of apoptosis. This targeted damage is due to the F-GNRs present in the cancer cells strongly absorbing near-infrared laser light and rapidly converting it to heat. This new therapeutic avenue for cancer therapy merits further investigation using in vivo models for application in humans.     

Tolerogenic effect of mouse fibroblasts on dendritic cells

There is controversy about the immunomodulatory effect of fibroblasts on dendritic cells (DCs). To clarify this issue, in this study, we have evaluated different features of fibroblast‐primed DCs including their ability to express co‐inhibitory and co‐stimulatory molecules, pro‐inflammatory and anti‐inflammatory cytokines and their ability to induce T‐cell proliferation. We also examined migratory capacity of DCs to lymphatic tissues and present fibroblast‐derived antigens after encountering fibroblasts. The results of our in vitro study showed that both co‐inhibitory (programmed death ligand 1 and ligand 2 and B7H4) and co‐stimulatory (CD86) molecules were up‐regulated when DCs were co‐cultured with fibroblasts. In an animal model, we showed that intra‐ peritoneal injection (IP) of both syngeneic and allogeneic fibroblasts significantly increased both total DC count and expression level of co‐inhibitory and co‐stimulatory molecules on DCs. Priming of DCs with syngeneic and allogeneic fibroblasts reduced the proliferation of CD4⁺ and CD8⁺ T cells. Even activation of fibroblast‐ primed DCs failed to restore their ability to induce T‐cell proliferation. Likewise, priming of DCs with fibroblasts blocked the ability of ovalbumin‐pulsed DCs to induce proliferation of ovalbumin‐specific CD4⁺ T cells. Compared with non‐activated DCs, fibroblast‐primed DCs had significantly higher expression levels of interleukin‐10 and indoleamine 2, 3 dioxygenase. Fibroblast‐primed DCs had a significantly reduced interleukin‐12 expression level compared with that of activated DCs. After priming with fibroblasts, DCs were able to migrate to lymphatic tissues and present fibroblast‐derived antigens (ovalbumin). In conclusion, after priming with fibroblasts, DCs gain tolerogenic features. This finding suggests the potential role of fibroblasts in the maintenance of immune tolerance.     

A Novel Method of Urinary Sphincter Deficiency: Serial Histopathology Evaluation in a Rat Model of Urinary Incontinence

In this study, a novel technique of irreversible sphincter deficiency by pudendal nerve transection (PNT) using 40 female rats for studying the pathophysiology of stress urinary incontinence associated with childbirth was developed. Of the 40 rats, 10 served as controls and the remaining underwent bilateral PNT at the anastomotic lumbosacral trunk level. Urethral morphological changes following bilateral PNT were assessed with serial hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining methods at 50, 90, and 130 days post‐intervention. Leak point pressure (LPP) measurement was used to determine the effect of pudendal injury on urethral outlet resistance after the transection. H&E and IHC staining showed irreversible loss of striated muscle mass of the sphincter region and increase in collagen deposition compatible with muscle atrophy. LPP measurements also significantly decreased following bilateral PNT. In conclusion, a novel method of irreversible sphincter insufficiency was developed. This model effectively decreased urethral outlet resistance and caused irreversible striated muscle atrophy. It was suggested that this technique can be used to develop a permanent sphincter deficiency model for the preclinical testing of treatment modalities exclusively triggering the pudendal nerve. Anat Rec, 299:173–180, 2016. © 2015 Wiley Periodicals, Inc.     

GCK and HNF1A mutations in Canadian families with maturity onset diabetes of the young (MODY)

Maturity onset diabetes of the young (MODY) is a genetically heterogeneous form of type 2 diabetes that is characterized by autosomal dominant inheritance, onset in early adulthood and a primary defect in insulin secretion. Mutations in at least six genes have been shown to underlie MODY, including mutations in GCK (encoding glucokinase, also called MODY2) and mutations in HNF1A (encoding hepatocyte nuclear factor-1alpha, also called MODY3). We sequenced genomic DNA from probands of seven Canadian MODY families. In four probands, we detected four novel GCK mutations, namely IVS2-7G>A, G72R, T206R and S263P. In three other probands, we detected three HNF1A mutations, of which two were novel, namely 1051delCA and Q250X, and one had been previously reported, namely R131Q. The novel mutations expand the spectrum of MODY mutations. In addition, knowledge of the specific defect can be used to pre-symptomatically identify family members at risk for developing MODY.     

Assessment of health facility quality improvements,United Republic of Tanzania

ObjectiveTo identify contextual factors associated with quality improvements in primary health-care facilities in the United Republic of Tanzania between two star rating assessments, focusing on local district administration and proximity to other facilities.MethodsFacilities underwent star rating assessments in 2015 and between 2017 and 2018; quality was rated from zero to five stars. The consolidated framework for implementation research, adapted to a low-income context, was used to identify variables associated with star rating improvements between assessments. Facility data were obtained from several secondary sources. The proportion of the variance in facility improvement observed at facility and district levels and the influence of nearby facilities and district administration were estimated using multilevel regression models and a hierarchical spatial autoregressive model, respectively.FindingsStar ratings improved at 4028 of 5595 (72%) primary care facilities. Factors associated with improvement included: (i) star rating in 2015; (ii) facility type (e.g. hospital) and ownership (e.g. public); (iii) participation in, or eligibility for, a results-based financing programme; (iv) local population density; and (v) distance from a major road. Overall, 20% of the variance in facility improvement was associated with district administration. Geographical clustering indicated that improvement at a facility was also associated with improvements at nearby facilities.ConclusionAlthough the majority of facilities improved their star rating, there were substantial variations between facilities. Both district administration and proximity to high-performing facilities influenced improvements. Quality improvement interventions should take advantage of factors operating above the facility level, such as peer learning and peer pressure.     

Auditory attention in autism spectrum disorder: An exploration of volumetric magnetic resonance imaging findings

Studies have shown that individuals with autism spectrum disorder (ASD) tend to perform significantly below typically developing individuals on standardized measures of attention, even when controlling for IQ. The current study sought to examine within ASD whether anatomical correlates of attention performance differed between those with average to above-average IQ (AIQ group) and those with low-average to borderline ability (LIQ group) as well as in comparison to typically developing controls (TDC). Using automated volumetric analyses, we examined regional volume of classic attention areas including the superior frontal gyrus, anterior cingulate cortex, and precuneus in ASD AIQ (n = 38) and LIQ (n = 18) individuals along with 30 TDC. Auditory attention performance was assessed using subtests of the Test of Memory and Learning (TOMAL) compared among the groups and then correlated with regional brain volumes. Analyses revealed group differences in attention. The three groups did not differ significantly on any auditory attention-related brain volumes; however, trends toward significant size–attention function interactions were observed. Negative correlations were found between the volume of the precuneus and auditory attention performance for the AIQ ASD group, indicating larger volume related to poorer performance. Implications for general attention functioning and dysfunctional neural connectivity in ASD are discussed.