Transplanting neural progenitor cells to restore connectivity after spinal cord injury.

Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.

Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.

Hereditary spastic paraplegia (HSP) is a disease in which dieback degeneration of corticospinal tracts, accompanied by axonal swellings, leads to gait deficiencies. SPG4-HSP, the most common form of the disease, results from mutations of human spastin gene (SPAST), which is the gene that encodes spastin, a microtubule-severing protein. The lack of a vertebrate model that recapitulates both the etiology and symptoms of SPG4-HSP has stymied the development of effective therapies for the disease. hSPAST-C448Y mice, which express human mutant spastin at the ROSA26 locus, display corticospinal dieback and gait deficiencies but not axonal swellings. On the other hand, mouse spastin gene (Spast)-knockout (KO) mice display axonal swellings but not corticospinal dieback or gait deficiencies. One possibility is that reduced spastin function, resulting in axonal swellings, is not the cause of the disease but exacerbates the toxic effects of the mutant protein. To explore this idea, Spast-KO and hSPAST-C448Y mice were crossbred, and the offspring were compared with the parental lines via histological and behavioral analyses. The crossbred animals displayed axonal swellings as well as earlier onset, worsened gait deficiencies and corticospinal dieback compared with the hSPAST-C448Y mouse. These results, together with observations on changes in histone deacetylases 6 and tubulin modifications in the axon, indicate that each of these three transgenic mouse lines is valuable for investigating a different component of the disease pathology. Moreover, the crossbred mice are the best vertebrate model to date for testing potential therapies for SPG4-HSP.

Targeted Combined Endpoint Improvement in Patient and Disease Domains in Atopic Dermatitis: A Treat-to-Target Analysis of Adults with Moderate-to-Severe Atopic Dermatitis Treated with Upadacitinib.

A treat-to-target approach was recently developed to guide systemic treatment for adults with atopic dermatitis (AD). Recommendations outlined criteria for a 3-month initial acceptable treatment target and a 6-month optimal target, evaluated using global assessment of patient-reported disease severity, as well as Eczema Area and Severity Index, itch assessed on an 11-point numerical rating scale, Dermatology Life Quality Index, or Patient-Oriented Eczema Measure. Achievement of these targets with once-daily upadacitinib (15 mg and 30 mg) monotherapy was evaluated using integrated adult data from the Measure Up 1 and 2 phase 3 studies. Among the 852 patients treated with upadacitinib 15 mg or 30 mg, the 3-month initial acceptable target was achieved by >80%, >78%, and ≥87% of patients, and the 6-month optimal target was achieved by ≥53%, >61%, and >73% of patients at weeks 2, 16, and 52, respectively. Achievement of all 6 individual criteria for each of the target goals also increased over time. These findings suggest that upadacitinib 15 mg and 30 mg may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.

A low-fat diet improves fatigue in multiple sclerosis: Results from a randomized controlled trial.

BACKGROUND: Fatigue can be a disabling multiple sclerosis (MS) symptom with no effective treatment options. OBJECTIVE: Determine whether a low-fat diet improves fatigue in people with MS (PwMS). METHODS: We conducted a 16-week randomized controlled trial (RCT) and allocated PwMS to a low-fat diet (active, total daily fat calories not exceeding 20%) or wait-list (control) group. Subjects underwent 2 weeks of baseline diet data collection (24-hour diet recalls (24HDRs)), followed by randomization. The active group received 2 weeks of nutrition counseling and underwent a 12-week low-fat diet intervention. One set of three 24HDRs at baseline and week 16 were collected. We administered a food frequency questionnaire (FFQ) and Modified Fatigue Impact Scale (MFIS) every 4 weeks. The control group continued their pre-study diet and received diet training during the study completion. RESULTS: We recruited 39 PwMS (20-active; 19-control). The active group decreased their daily caloric intake by 11% (95% confidence interval (CI): -18.5%, -3.0%) and the mean MFIS by 4.0 (95% CI: -12.0, 4.0) compared to the control (intent-to-treat). Sensitivity analysis strengthened the association with a mean MFIS difference of -13.9 (95% CI: -20.7, -7.2). CONCLUSIONS: We demonstrated a significant reduction in fatigue with a low-fat dietary intervention in PwMS.

Spinal Interneurons as Gatekeepers to Neuroplasticity after Injury or Disease.

Spinal interneurons are important facilitators and modulators of motor, sensory, and autonomic functions in the intact CNS. This heterogeneous population of neurons is now widely appreciated to be a key component of plasticity and recovery. This review highlights our current understanding of spinal interneuron heterogeneity, their contribution to control and modulation of motor and sensory functions, and how this role might change after traumatic spinal cord injury. We also offer a perspective for how treatments can optimize the contribution of interneurons to functional improvement.

Granzyme B in epithelial barrier dysfunction and related skin diseases.

The predominant function of the skin is to serve as a barrier-to protect against external insults and to prevent water loss. Junctional and structural proteins in the stratum corneum, the outermost layer of the epidermis, are critical to the integrity of the epidermal barrier as it balances ongoing outward migration, differentiation, and desquamation of keratinocytes in the epidermis. As such, epidermal barrier function is highly susceptible to upsurges of proteolytic activity in the stratum corneum and epidermis. Granzyme B is a serine protease scarce in healthy tissues but present at high levels in tissues encumbered by chronic inflammation. Discovered in the 1980s, granzyme B is currently recognized for its intracellular roles in immune cell-mediated apoptosis as well as extracellular roles in inflammation, chronic injuries, tissue remodeling, as well as processing of cytokines, matrix proteins, and autoantigens. Increasing evidence has emerged in recent years supporting a role for granzyme B in promoting barrier dysfunction in the epidermis by direct cleavage of barrier proteins and eliciting immunoreactivity. Likewise, granzyme B contributes to impaired epithelial function of the airways, retina, gut, and vessels. In the present review, the role of granzyme B in cutaneous epithelial dysfunction is discussed in the context of specific conditions with an overview of underlying mechanisms as well as utility of current experimental and therapeutic inhibitors.

Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse.

Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.

Diagnostic Accuracy of Synovial Lactate, Polymerase Chain Reaction, or Clinical Examination for Suspected Adult Septic Arthritis.

BACKGROUND: Adult septic arthritis can be challenging to differentiate from other causes of acute joint pain. The diagnostic accuracy of synovial lactate and polymerase chain reaction (PCR) remains uncertain. OBJECTIVE: Our aim was to quantify the diagnostic accuracy of synovial lactate, PCR, and clinical evaluation for adults with possible septic arthritis in the emergency department (ED). METHODS: We report a prospective sampling of ED patients aged ≥ 18 years with knee symptoms concerning for septic arthritis. Clinicians and research assistants independently performed history and physical examination. Serum and synovial laboratory testing was ordered at the discretion of the clinician. We analyzed frozen synovial fluid specimens for l- and d-lactate and PCR. The criterion standard for septic arthritis was bacterial growth on synovial culture and treated by consultants with operative drainage, prolonged antibiotics, or both. Diagnostic accuracy measures included sensitivity, specificity, likelihood ratios, interval likelihood ratios, and receiver operating characteristic area under the curve. RESULTS: Seventy-one patients were included with septic arthritis prevalence of 7%. No finding on history or physical examination accurately ruled in or ruled out septic arthritis. Synovial l- and d-lactate and PCR were inaccurate for the diagnosis of septic arthritis. Synovial white blood cell count and synovial Gram stain most accurately rule in and rule out septic arthritis. CONCLUSIONS: Septic arthritis prevalence in ED adults is lower than reported previously. History and physical examination, synovial lactate, and PCR are inadequate for the diagnosis of septic arthritis. Synovial white blood cell count and Gram stain are the most accurate tests available for septic arthritis.

How Do You Measure Up: Quality Measurement for Improving Patient Care and Establishing the Value of Infectious Diseases Specialists.

The shift from volume-based to value-based reimbursement has created a need for quantifying clinical performance of infectious diseases (ID) physicians. Nationally recognized ID specialty-specific quality measures will allow stakeholders, such as patients and payers, to determine the value of care provided by ID physicians and will promote clinical quality improvement. Few ID-specific measures have been developed; herein, we provide an overview of the importance of quality measurement for ID, discuss issues in quality measurement specific to ID, and describe standards by which candidate quality measures can be evaluated. If ID specialists recognize the need for quality measurement, then ID specialists can direct ID-related quality improvement, quantify the impact of ID physicians on patient outcomes, compare their performance to that of peers, and convey to stakeholders the value of the specialty.

A Cluster of Cefepime-induced Neutropenia During Outpatient Parenteral Antimicrobial Therapy.

A cluster of cefepime-induced neutropenia (CIN) was identified from June 2017 to May 2018 in a regional outpatient parenteral antimicrobial therapy population. Our data suggest prolonged courses of cefepime (≥2 weeks), administered by rapid intravenous push, were associated with a higher risk of CIN.

Kinetic Contributions of The Upper Limbs During Counter-Movement Verical Jumps With and Without Arm Swing.

Mosier, EM, Fry, AC, and Lane, MT. Kinetic contributions of the upper limbs during countermovement. J Strength Cond Res 33(8): 2066-2073, 2019-This study examined the kinetic contributions of the upper extremities during countermovement vertical jumps (CMVJs) while using arm swing (AS) or no arm swing (NAS) conditions. Fourteen healthy men ((Equation is included in full-text article.)± SD; age = 24.1 ± 3.9 years) volunteered for this investigation. Subjects performed in random order a total of 6 jumps consisting of 3 AS and 3 NAS CMVJs. A motion capture system was used to analyze the kinetic data. Paired samples t-tests were used to examine the subjects' mean differences in the AS and NAS CMVJ trials (p<0.05). Results for all subjects were determined for each jump subjects were determined for each jump performed, with statistical analyses performed on mean values for all 3 jumps per subject. The AS significantly increased the vertical jump height (VJH) by an average of 0.07 ± 0.03 m (3.0 ± 1.3 inches). Dual-energy X-ray absorptiometry scans determined that the upper limbs were 12.0% of the total body mass. Movement of the upper limbs during the AS CMVJ produced 32.2 ± 7.0% of the total mean ground reaction force (GRF), and 11.3 ± 2.2% during the NAS CMVJ. The enhancement of performance when jumping using an AS resulted in a 13.6% increase in VJH. The contribution of the upper limbs during the AS CMVJ averaged 31.5% of the peak GRF, which occurred immediately before takeoff. The upper extremities can greatly influence vertical jump performances and the accompanying kinetics. When analyzing jump GRFs, one must be aware of how much the upper limbs contribute to these forces. In addition, proper AS mechanics must be emphasized when instructing correct jump technique.

LaSr3 NiRuO4 H4 : A 4d Transition-Metal Oxide-Hydride Containing Metal Hydride Sheets.

The synthesis of the first 4d transition metal oxide-hydride, LaSr3 NiRuO4 H4 , is prepared via topochemical anion exchange. Neutron diffraction data show that the hydride ions occupy the equatorial anion sites in the host lattice and as a result the Ru and Ni cations are located in a plane containing only hydride ligands, a unique structural feature with obvious parallels to the CuO2 sheets present in the superconducting cuprates. DFT calculations confirm the presence of S=1/2 Ni+ and S=0, Ru2+ centers, but neutron diffraction and µSR data show no evidence for long-range magnetic order between the Ni centers down to 1.8 K. The observed weak inter-cation magnetic coupling can be attributed to poor overlap between Ni 3dz2 and H 1s in the super-exchange pathways.

Forelimb muscle plasticity following unilateral cervical spinal cord injury.

INTRODUCTION: Motor dysfunction and muscle atrophy are well documented in the lower extremity after spinal cord injury. However, the extent and time course of myoplastic changes in forelimb musculature is not clear. METHODS: Forelimb muscle morphology and fiber type were evaluated after high cervical hemilesion injury in rats. RESULTS: There was significant atrophy of the ipsilateral extensor carpi radialis longus (ECRL) muscle at 2 weeks postinjury, which was subsequently reversed at 8 weeks postinjury. The triceps muscle showed minimal evidence of atrophy after spinal injury. No significant changes in fiber type were observed. CONCLUSIONS: These findings indicate a robust capacity for spontaneous myoplasticity after C2 hemisection injury but highlight differential capacity for plasticity within the forelimb muscles.

Highly efficient recombinant production and purification of streptococcal cysteine protease streptopain with increased enzymatic activity.

Streptococcus pyogenes produces the cysteine protease streptopain (SpeB) as a critical virulence factor for pathogenesis. Despite having first been described seventy years ago, this protease still holds mysteries which are being investigated today. Streptopain can cleave a wide range of human proteins, including immunoglobulins, the complement activation system, chemokines, and structural proteins. Due to the broad activity of streptopain, it has been challenging to elucidate the functional results of its action and precise mechanisms for its contribution to S. pyogenes pathogenesis. To better study streptopain, several expression and purification schemes have been developed. These methods originally involved isolation from S. pyogenes culture but were more recently expanded to include recombinant Escherichia coli expression systems. While substantially easier to implement, the latter recombinant approach can prove challenging to reproduce, often resulting in mostly insoluble protein and poor purification yields. After extensive optimization of a wide range of expression and purification conditions, we applied the autoinduction method of protein expression and developed a two-step column purification scheme that reliably produces large amounts of purified soluble and highly active streptopain. This method reproducibly yielded 3 mg of streptopain from 50 mL of expression culture at >95% purity, with an activity of 5306 ± 315 U/mg, and no remaining affinity tags or artifacts from recombinant expression. This improved method therefore enables the facile production of the important virulence factor streptopain at higher yields, with no purification scars that might bias functional studies, and with an 8.1-fold increased enzymatic activity compared to previously described procedures.

Impact of Sepsis Classification and Multidrug-Resistance Status on Outcome Among Patients Treated With Appropriate Therapy.

OBJECTIVE: To assess the impact of sepsis classification and multidrug-resistance status on outcome in patients receiving appropriate initial antibiotic therapy. DESIGN: A retrospective cohort study. SETTING: Barnes-Jewish Hospital, a 1,250-bed teaching hospital. PATIENTS: Individuals with Enterobacteriaceae sepsis, severe sepsis, and septic shock who received appropriate initial antimicrobial therapy between June 2009 and December 2013. INTERVENTIONS: Clinical outcomes were compared according to multidrug-resistance status, sepsis classification, demographics, severity of illness, comorbidities, and antimicrobial treatment. MEASUREMENTS AND MAIN RESULTS: We identified 510 patients with Enterobacteriaceae bacteremia and sepsis, severe sepsis, or septic shock. Sixty-seven patients (13.1%) were nonsurvivors. Mortality increased significantly with increasing severity of sepsis (3.5%, 9.9%, and 28.6%, for sepsis, severe sepsis, and septic shock, respectively; p < 0.05). Time to antimicrobial therapy was not significantly associated with outcome. Acute Physiology and Chronic Health Evaluation II was more predictive of mortality than age-adjusted Charlson comorbidity index. Multidrug-resistance status did not result in excess mortality. Length of ICU and hospital stay increased with more severe sepsis. In multivariate logistic regression analysis, African-American race, sepsis severity, Acute Physiology and Chronic Health Evaluation II score, solid-organ cancer, cirrhosis, and transfer from an outside hospital were all predictors of mortality. CONCLUSIONS: Our results support sepsis severity, but not multidrug-resistance status as being an important predictor of death when all patients receive appropriate initial antibiotic therapy. Future sepsis trials should attempt to provide appropriate antimicrobial therapy and take sepsis severity into careful account when determining outcomes.

Perceptions and behaviours of infectious diseases physicians when managing urinary tract infections due to MDR organisms.

OBJECTIVES: The objective of this study was to attain a better understanding of infectious diseases (ID) physicians' experience with MDR organism (MDRO) urinary tract infections (UTIs) by means of a survey on disease perception, diagnostic management and treatment preferences. METHODS: A nine-question survey was developed and distributed to members of the North American Emerging Infections Network (EIN) in September 2013. RESULTS: Seven hundred and fourteen out of 1461 EIN members responded to the survey (49%). The responses of 603 responders were studied. Most providers perceived an increase in the incidence of MDRO UTIs over the past 3 years (75% of adult ID responders and 63% of paediatric ID responders). One hundred and thirty-four (22%) responders prefer intravenous over oral administration of antimicrobials when both are available, 171 (28%) prefer longer durations of therapy when comparing an MDRO with a susceptible isolate of the same species and 142 (24%) order a repeat urine culture as 'proof of cure' after treating an MDRO UTI. Nevertheless, 530 (88%) responders perceived MDRO UTIs to be of similar severity as non-MDRO UTIs. Fifty-five percent of providers prescribed fosfomycin for MDRO UTI at least once; the most common prescribing pattern (among a wide spectrum of approaches) was a single dose (16%). CONCLUSIONS: Future studies on MDRO UTIs should clarify the role of resistance in patient outcomes and the comparative efficacy of different antimicrobials. Of particular interest is fosfomycin, which is unrelated to other antibiotic classes and may take a more prominent role in treating MDRO cystitis.

Accuracy of a vertical jump contact mat for determining jump height and flight time.

Several devices are available to measure vertical jump (VJ) height based on flight time, VJ reach height, or ground reaction forces. The purpose of this study was to determine the accuracy of a VJ mat for measuring flight time and VJ height compared with a VJ tester or a force plate. Seventeen men and 18 women (X ± SD; age = 20.9 ± 0.7 years, height = 176.1 ± 0.9 cm, weight = 72.6 ± 13.5 kg) served as subjects. Subjects performed counter-movement vertical jumps while standing on both a force plate (1,000 Hz) and a VJ mat. A Vertec VJ tester was used to measure jump reach. Compared with the force plate, the VJ mat reported greater VJ height (VJ mat = 0.50 ± 0.12 m, force plate = 0.34 ± 0.10 m) and flight time (VJ mat = 0.629 ± 0.078 seconds, force plate = 0.524 ± 0.077 seconds). Comparison of VJ heights from the VJ mat and the Vertec revealed no significant differences (Vertec = 0.48 ± 0.11 m). Regression analyses indicated strong relationships between testing methods and suggested that high VJ performances may be underestimated with the VJ mat. This particular VJ mat compared favorably with the Vertec but not the force plate. It seems that the different flight times derived from the VJ mat may permit the VJ mat to be in closer agreement with VJ heights from the Vertec. Also, the VJ mat may not be an appropriate tool for assessing high VJ performances (i.e., ≥0.70 m; ≈28 inches). Practitioners and researchers using similar VJ mats may not obtain accurate flight times and may underestimate high performers.