Conservative treatment of 3- and 4-part proximal humeral fractures: Can poor outcomes be predicted?

PURPOSE: 3- and 4-part proximal humeral fractures are frequently treated conservatively. This study aims to combine radiographic, and patient reported outcome data to identify factors leading to poor outcomes following conservative treatment. METHODS: A retrospective local database analysis identified 3- and 4-part fractures. Radiographic and functional outcomes including Oxford Shoulder Score (OSS), QuickDash (QD), Subjective Shoulder Score (SSV) and VAS pain scores were collected. RESULTS: 104 patients were included at mean follow-up of 55 months. Analysis highlighted significant OSS differences in 3- versus 4-part (p = 0.027), dominant arm injury (p = 0.046), age > 65 (p = 0.006), varus coronal neck-shaft angle < 115 versus 115-155 degrees (p = 0.008), posterior head tilt > 155 degrees (p = 0.005), greater tuberosity (GT) displacement > 5 mm (p = 0.001), GT comminution (p = 0.01), medial calcar hinge displacement > 2 mm (p = 0.032). According to QD scores; age > 65 (p = 0.012), varus neck-shaft angle (p = 0.01), GT displacement > 5 mm (p = 0.001), GT comminution (p = 0.01), medial calcar hinge displacement > 2 mm (p = 0.006). SSV varied significantly with 3- versus 4-part fractures (p = 0.005), age > 65 (p = 0.04), varus neck-shaft angle (p = 0.001), posterior head tilt (p = 0.005), GT displacement > 5 mm (p = 0.001), GT comminution (p = 0.003), and medial calcar hinge displacement > 2 mm (p = 0.001). CONCLUSION: We highlight risk factors for unfavourable outcomes following conservative management, aiding surgeons in shared decision-making and patient expectation management.

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy.

Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.

Enzymatically degradable poly(ethylene glycol) hydrogels for the 3D culture and release of human embryonic stem cell derived pancreatic precursor cell aggregates.

This study aimed to develop a three dimensional culture platform for aggregates of human embryonic stem cell (hESC)-derived pancreatic progenitors that enables long-term culture, maintains aggregate size and morphology, does not adversely affect differentiation and provides a means for aggregate recovery. A platform was developed with poly(ethylene glycol) hydrogels containing collagen type I, for cell-matrix interactions, and peptide crosslinkers, for facile recovery of aggregates. The platform was first demonstrated with RIN-m5F cells, showing encapsulation and subsequent release of single cells and aggregates without adversely affecting viability. Aggregates of hESC-derived pancreatic progenitors with an effective diameter of 82 (15)µm were either encapsulated in hydrogels or cultured in suspension for 28 days. At day 14, aggregate viability was maintained in the hydrogels, but significantly reduced (88%) in suspension culture. However by day 28, viability was reduced under both culture conditions. Aggregate size was maintained in the hydrogels, but in suspension was significantly higher (∼ 2-fold) by day 28. The ability to release aggregates followed by a second enzyme treatment to achieve single cells enabled assessment by flow cytometry. Prior to encapsulation, there were 39% Pdx1(+)/Nkx6.1(+) cells, key endocrine markers required for ß-cell maturation. The fraction of doubly positive cells was not affected in hydrogels but was slightly and significantly lower in suspension culture by 28 days. In conclusion, we demonstrate that a MMP-sensitive PEG hydrogel containing collagen type I is a promising platform for hESC-derived pancreatic progenitors that maintains viable aggregates, aggregate size, and progenitor state and offers facile recovery of aggregates.

Priming mortality salience: supraliminal, subliminal and "double-death" priming techniques.

The study examined whether successively presented subliminal and supraliminal morality salience primes ("double death" prime) would have a stronger influence on death thought accessibility than subliminal or supraliminal primes alone. A between-subjects 2 (subliminal prime/control) × 2 (supraliminal prime/control) design was used. The supraliminal prime prompted participants to answer questions about death. For the subliminal prime, the word death was presented outside of awareness. Both priming techniques differed significantly from a control in ability to elicit mortality salience. There was an interactive influence of both primes. Implications for unconscious neutral networks relating to death are discussed.

Tissue engineering approaches to cell-based type 1 diabetes therapy.

Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of insulin-producing pancreatic ß-cells. Cell-based therapies, involving the transplantation of functional ß-cells into diabetic patients, have been explored as a potential long-term treatment for this condition; however, success is limited. A tissue engineering approach of culturing insulin-producing cells with extracellular matrix (ECM) molecules in three-dimensional (3D) constructs has the potential to enhance the efficacy of cell-based therapies for diabetes. When cultured in 3D environments, insulin-producing cells are often more viable and secrete more insulin than those in two dimensions. The addition of ECM molecules to the culture environments, depending on the specific type of molecule, can further enhance the viability and insulin secretion. This review addresses the different cell sources that can be utilized as ß-cell replacements, the essential ECM molecules for the survival of these cells, and the 3D culture techniques that have been used to benefit cell function.

Spinal interleukin-10 therapy to treat peripheral neuropathic pain.

INTRODUCTION: Current research indicates that chronic peripheral neuropathic pain includes a role for glia and the actions of proinflammatory factors. This review briefly discusses the glial and cytokine responses that occur following peripheral nerve damage in support of utilizing anti-inflammatory cytokine interleukin-10 (IL-10) therapy to suppress chronic peripheral neuropathic pain. SPINAL NONVIRAL INTERLEUKIN-10 GENE THERAPY: IL-10 is one of the most powerful endogenous counter-regulators of proinflammatory cytokine function that acts in the nervous system. Subarachnoid (intrathecal) spinal injection of the gene encoding IL-10 delivered by nonviral vectors has several advantages over virally mediated gene transfer methods and leads to profound pain relief in several animal models. NONVIRAL GENE DELIVERY: Lastly, data are reviewed that nonviral deoxyribonucleic acid (DNA) encapsulated by a biologically safe copolymer, poly(lactic-co-glycolic) acid (PLGA), thought to protect DNA, leads to significantly improved therapeutic gene transfer in animal models, which additionally and significantly extends pain relief. CONCLUSIONS: The impact of these early studies exploring anti-inflammatory genes emphasizes the exceptional therapeutic potential of new biocompatible intrathecal nonviral gene delivery approaches such as PLGA microparticles. Ultimately, ongoing expression of therapeutic genes is a viable option to treat chronic neuropathic pain in the clinic.

Control of neural cell composition in poly(ethylene glycol) hydrogel culture with soluble factors.

Poly(ethylene glycol) (PEG) hydrogels are being developed as cell delivery vehicles that have great potential to improve neuronal replacement therapies. Current research priorities include (1) characterizing neural cell growth within PEG hydrogels relative to standard culture systems and (2) generating neuronal-enriched populations within the PEG hydrogel environment. This study compares the percentage of neural precursor cells (NPCs), neurons, and glia present when dissociated neural cells are seeded within PEG hydrogels relative to standard monolayer culture. Results demonstrate that PEG hydrogels enriched the initial cell population for NPCs, which subsequently gave rise to neurons, then to glia. Relative to monolayer culture, PEG hydrogels maintained an increased percentage of NPCs and a decreased percentage of glia. This neurogenic advantage of PEG hydrogels is accentuated in the presence of basic fibroblast growth factor and epidermal growth factor, which more potently increase NPC and neuronal expression markers when applied to cells cultured within PEG hydrogels. Finally, this work demonstrates that glial differentiation can be selectively eliminated upon supplementation with a γ-secretase inhibitor. Together, this study furthers our understanding of how the PEG hydrogel environment influences neural cell composition and also describes select soluble factors that are useful in generating neuronal-enriched populations within the PEG hydrogel environment.

Bimanual strategies for object retrieval in infants and young children.

Age differences in goal-directed bimanual coordination were studied in typically developing infants aged 9-29 months, compared to a group of children aged 4-6 years and a group of adults, using an object retrieval task. This task required one hand to open and hold the lid of a transparent box, while the second hand retrieved a small toy from inside the box. Well-coordinated retrieval strategies with differentiated use of the two hands were not established in the majority of infants until 18 months of age. Temporal analysis of the hand actions revealed that, unlike adults who perform the task with close synchronization of the hands at the start, the infants performed the task sequentially and did not activate the second hand until the first hand had started to lift the lid. The children's hand preferences for the two-hand actions also contrasted with those of adults. In children aged 27-29 months and 4-6 years, there was a preference for using the right-hand to lift the lid while in right-handed adults, the reverse pattern was observed. The results suggest that although bimanual coordination starts to develop in the second year of life, the adult pattern of performance on this task is not observed before 6 years of age. It is likely that further maturation of the brain networks involved in bimanual coordination, and in particular functional interhemispheric transfer via the corpus callosum, is required before automatization of bimanual hand actions is achieved.

The administration of BDNF and GDNF to the brain via PLGA microparticles patterned within a degradable PEG-based hydrogel: Protein distribution and the glial response.

Tailored delivery of neurotrophic factors (NFs) is a critical challenge that continues to inhibit strategies for guidance of axonal growth in vivo. Of particular importance is the ability to recreate innervation of distant brain regions by transplant tissue, for instance rebuilding the nigrostriatal track, one focus in Parkinson's disease research. Many strategies have utilized polymer drug delivery to target NF release in space and time, but combinatorial approaches are needed to deliver multiple NFs at relevant therapeutic times and locations without toxic side effects. Here we engineered a paradigm of PLGA microparticles entrapped within a degradable PEG-based hydrogel device to locally release two different types of NFs with two different release profiles. Hydrogel/microparticle devices were developed and analyzed for their ability to release GDNF in the caudal area of the brain, near the substantia nigra, or BDNF in the rostral area, near the striatum. The devices delivered their respective NFs in a region localized to within 100 µm of the bridge, but not exclusively to the targeted rostral or caudal ends. BDNF was slowly released over a 56-day period, whereas a bolus of GDNF was released around 28 days. The timed delivery of NFs from implanted devices significantly reduced the microglial response relative to sham surgeries. Given the coordinated drug delivery ability and reduced localized inflammatory response, this multifaceted PEG hydrogel/PLGA microparticle strategy may be a useful tool for further development in combining tissue engineering and drug delivery, and recreating the nigrostriatal track.

Trophic factors GDNF and BDNF improve function of retinal sheet transplants.

The aim of this study was to compare glial-derived neurotrophic factor (GDNF) treatment with brain-derived neurotrophic factor (BDNF) treatment of retinal transplants on restoration of visual responses in the superior colliculus (SC) of the S334ter line 3 rat model of rapid retinal degeneration (RD). RD rats (age 4-6 weeks) received subretinal transplants of intact sheets of fetal retina expressing the marker human placental alkaline phosphatase (hPAP). Experimental groups included: (1) untreated retinal sheet transplants, (2) GDNF-treated transplants, (3) BDNF-treated transplants, (4) none surgical, age-matched RD rats, (5) sham surgery RD controls, (6) progenitor cortex transplant RD controls, and (7) normal pigmented rat controls. At 2-8 months after transplantation, multi-unit visual responses were recorded from the SC using a 40 ms full-field stimulus (-5.9 to +1 log cd/m(2)) after overnight dark-adaptation. Responses were analyzed for light thresholds, spike counts, response latencies, and location within the SC. Transplants were grouped into laminated or rosetted (more disorganized) transplants based on histological analysis. Visual stimulation of control RD rats evoked no responses. In RD rats with retinal transplants, a small area of the SC corresponding to the position of the transplant in the host retina, responded to light stimulation between -4.5 and -0.08 log cd/m(2), whereas the light threshold of normal rats was at or below -5 log cd/m(2) all over the SC. Overall, responses in the SC in rats with laminated transplants had lower response thresholds and were distributed over a wider area than rats with rosetted transplants. BDNF treatment improved responses (spike counts, light thresholds and responsive areas) of rats with laminated transplants whereas GDNF treatment improved responses from rats with both laminated and rosetted (more disorganized) transplants. In conclusion, treatment of retinal transplants with GDNF and BDNF improved the restoration of visual responses in RD rats; and GDNF appears to exert greater overall restoration than BDNF.