Fatigue in pediatric inflammatory bowel diseases: A systematic review and a single center experience.

OBJECTIVES: We aimed to review the literature on fatigue in pediatric inflammatory bowel diseases (PIBD), to explore how it is measured, and approximate its rate in an inception pediatric cohort. METHODS: Studies on fatigue were systematically reviewed and selected by two authors. Next, we retrieved the two fatigue-related questions of the IMPACT-III questionnaire at 4 and 12 months after diagnosis from a prospectively maintained cohort of PIBD patients, each scoring 0-100 (lower scores imply more fatigue), and 44 healthy controls. RESULTS: The systematic review identified 14 studies reporting fatigue in children, of which nine had fatigue as the primary outcome and only two provided rates of fatigue. No standalone index was identified for measuring fatigue specifically for PIBD. Of 80 children included in the inception cohort, 62 (78%) scored an average of ≤75 on the two IMPACT-III questions (approximating at least mild fatigue), 26 (33%) scored ≤50 (at least moderate fatigue) and nine (11%) scored ≤25 (severe fatigue). In comparison, only four (9%) healthy children scored at least moderate fatigue (p = 0.007). Fatigue rates at 12 months were only slightly and nonsignificantly lower. Fatigue of any severity was reported in 92% children with active disease versus 63% of those in clinical remission (p = 0.01). CONCLUSION: Literature reporting on fatigue in PIBD is scarce, and no PIBD-specific tool is available to measure fatigue. In our cohort, fatigue-related questions were frequently scored low in children with IBD, mainly among children with active disease but also during clinical remission.

Use of a colorimeter is a viable method to measure melanin and erythema content in the context of laser beam attenuation by use of a class IV laser in different tissues in dogs.

OBJECTIVE: Patient factors may alter laser photon attenuation, but these factors have not been adequately evaluated in live dogs. Our objective was to evaluate class IV laser beam attenuation (LBA) by canine tissues using a colorimeter to evaluate melanin and erythema indices. We hypothesized that greater melanin and erythema indices and unclipped hair would increase LBA, and these properties would vary among tissues. ANIMALS: 20 client-owned dogs. PROCEDURES: Between October 1 and December 1, 2017, colorimeter measurements and LBA in various tissues before and after clipping overlying hair were evaluated. Data were analyzed using generalized linear mixed models. Statistical significance was set at P < .05. RESULTS: LBA was greater in unclipped (98.6 ± 0.4%) than clipped hair (94.6 ± 0.4%). The least LBA occurred in the pinna (93%) while the greatest occurred in the caudal vertebra (100%) and caudal semitendinosis muscles (100%). Each mm of tissue thickness resulted in LBA of 11.6%. Each unit increase in melanin index resulted in a 3.3% increase in LBA. There was no association of LBA with erythema index. CLINICAL RELEVANCE: To our knowledge, this is the first study that evaluated LBA by different tissues in live dogs using a colorimeter to evaluate melanin and erythema indices. We recommend clipping hair prior to photobiomodulation to decrease laser beam attenuation and using increased laser doses in thicker tissues and dogs with high melanin content. The colorimeter may be helpful in customizing patient treatment dosimetry. Future studies are necessary to determine therapeutic laser doses for adequate photobiomodulation effects.

Social Support and Symptoms of Depression in Late Life: Bidirectional Associations over Time.

Social support functions as an effective buffer against depression, especially among older adults with limited social networks. For the current study, we examined longitudinal bidirectional associations between social support and depression among those 75+ years of age. We recruited and followed a sample of Israeli adults 75+ years of age (N = 824; M = 80.84; range 75-96 years). Structured interviews were conducted in the homes of participants at three annual points of measurement. Participants reported depressive symptoms and emotional and instrumental support received from friends and family. We examined a cross-lagged, longitudinal structural equation model (SEM) in which social support and depressive symptoms predict each other over time, covarying for previously reported social support and depressive symptoms. We found that both depressive symptoms and social support are largely consistent in late life. Depressive symptoms and social support reported at baseline predict levels reported 1 and 2 years thereafter. Cross-over effects emerged over time. Depressive symptoms predicted lower social support in future, and social support at baseline predicted depressive symptoms 2 years later. These findings suggest that associations between depressive symptoms and social support are bidirectional in late life. Further research is needed to replicate findings in other cultures and over longer periods, ideally until end of life.

Bilateral renal descensus and intravesicular ureteroneocystostomy for treatment of bilateral ureteral ligation and transection that occurred during ovariohysterectomy in two cats.

CASE DESCRIPTION: 6-month-old and 7-month-old spayed female domestic shorthair cats were referred because of complications associated with inadvertent bilateral ureteral ligation and transection during ovariohysterectomy. CLINICAL FINDINGS: Both cats had a 1- to 2-day history of lethargy, inappetence, and vomiting. Initial exam findings included lethargy, signs of abdominal pain, anuria, and dehydration. Clinicopathologic testing revealed azotemia and hyperkalemia. Abdominal ultrasonography revealed peritoneal effusion and bilateral pyelectasia in both cats and retroperitoneal effusion in one. Fluid analysis in both cats supported a diagnosis of uroabdomen. TREATMENT AND OUTCOME: Exploratory celiotomy was performed in both cats, and bilateral ureteral ligation and transection was confirmed. Bilateral renal descensus and ureteroneocystostomy with an intravesicular mucosal apposition technique was successfully performed in both cats. Clinicopathologic evaluation performed 1 day after surgery in one cat and 5 days after surgery in the other revealed complete resolution of azotemia. Ultrasonographic examination of the urogenital tract performed approximately 4 months after surgery in the first cat and 1 month after surgery in the second cat revealed complete resolution of renal pelvic dilation bilaterally. CLINICAL RELEVANCE: Bilateral intravesicular ureteroneocystostomy in conjunction with bilateral renal descensus was used successfully to treat bilateral ureteral transection that occurred in 2 cats during routine ovariohysterectomy. Limited treatment options currently exist for this serious complication, and euthanasia is often considered. This technique, which relies on the use of the natural surrounding tissues for successful treatment, can offer a potential treatment option to correct this uncommon but devastating complication.

Dynamics of replication origin over-activation.

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models.

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.

Suite of clinically relevant functional assays to address therapeutic efficacy and disease mechanism in the dystrophic mdx mouse.

Duchenne muscular dystrophy (DMD) is a progressive primary myodegenerative disease caused by a genetic deficiency of the 427-kDa cytoskeletal protein dystrophin. Despite its single-gene etiology, DMD's complex pathogenesis remains poorly understood, complicating the extrapolation from results of preclinical studies in genetic homologs to the design of informative clinical trials. Here we describe novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. By coupling force transduction, high-precision motion tracking, and respiratory measurements, we have achieved a suite of integrative physiological tests that provide novel insights regarding normal and pathological responses to muscular exertion. A common feature of these physiological assays is the precise tracking and analysis of volitional movement, thereby optimizing the relevance to clinical tests. Unexpectedly, the measurable biological distinction between dystrophic and control mice at early time points in the disease process is better resolved with these tests than with the majority of previously used, labor-intensive studies of individual muscle function performed ex vivo. For example, the dramatic loss of volitional movement following a novel, standardized grip test distinguishes control mice from mdx mice by a 17.4-fold difference of the means (3.5 ± 2.2 vs. 60.9 ± 12.1 units of activity, respectively; effect size 1.99). The findings have both mechanistic and translational implications of potential significance to the fields of basic myology and neuromuscular therapeutics.NEW & NOTEWORTHY This study uses novel phenotypic assays which when applied to the mdx mouse resemble recently used primary end points for DMD clinical trials. A measurable distinction between dystrophic and control mice was seen at early time points in vivo compared with invasive muscle studies performed ex vivo. These assays shed light on normal and pathological responses to muscular exertion and have significant mechanistic and translational implications for the fields of basic myology and neuromuscular therapeutics.