TBCK syndrome: a rare multi-organ neurodegenerative disease.

TBCK syndrome is an autosomal recessive disorder primarily characterized by global developmental delay, hypotonia, abnormal magnetic resonance imaging (MRI), and distinctive craniofacial phenotypes. High variability is observed among affected individuals and their corresponding variants, making clinical diagnosis challenging. Here, we discuss recent breakthroughs in clinical considerations, TBCK function, and therapeutic development.

Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice.

TBCK-related encephalopathy is a rare pediatric neurodegenerative disorder caused by biallelic loss-of-function variants in the TBCK gene. After receiving anecdotal reports of neurologic phenotypes in both human and mouse TBCK heterozygotes, we quantified if TBCK haploinsufficiency causes a phenotype in mice and humans. Using the tbck+/- mouse model, we performed a battery of behavioral assays and mTOR pathway analysis to investigate potential alterations in neurophysiology. We conducted as well a phenome-wide association study (PheWAS) analysis in a large adult biobank to determine the presence of potential phenotypes associated to this variant. The tbck+/- mouse model demonstrates a reduction of exploratory behavior in animals with significant sex and genotype interactions. The concurrent PheWAS analysis of 10,900 unrelated individuals showed that patients with one copy of a TBCK loss-of-function allele had a significantly higher rate of acquired toe and foot deformities, likely indicative of a mild peripheral neuropathy phenotype. This study presents an example of what may be the underappreciated occurrence of mild neurogenic symptoms in heterozygote individuals of recessive neurogenetic syndromes.

Performing Human Skeletal Muscle Xenografts in Immunodeficient Mice.

Treatment effects observed in animal studies often fail to be recapitulated in clinical trials. While this problem is multifaceted, one reason for this failure is the use of inadequate laboratory models. It is challenging to model complex human diseases in traditional laboratory organisms, but this issue can be circumvented through the study of human xenografts. The surgical method we describe here allows for the creation of human skeletal muscle xenografts, which can be used to model muscle disease and to carry out preclinical therapeutic testing. Under an Institutional Review Board (IRB)-approved protocol, skeletal muscle specimens are acquired from patients and then transplanted into NOD-Rag1null IL2rγnull (NRG) host mice. These mice are ideal hosts for transplantation studies due to their inability to make mature lymphocytes and are thus unable to develop cell-mediated and humoral adaptive immune responses. Host mice are anaesthetized with isoflurane, and the mouse tibialis anterior and extensor digitorum longus muscles are removed. A piece of human muscle is then placed in the empty tibial compartment and sutured to the proximal and distal tendons of the peroneus longus muscle. The xenografted muscle is spontaneously vascularized and innervated by the mouse host, resulting in robustly regenerated human muscle that can serve as a model for preclinical studies.

Editorial Commentary: Don't Float Away-Medial Collateral Ligament and Medial Meniscus Will Protect Your Anterior Cruciate Ligament Reconstruction if You Respect Them.

As the understanding of the intrinsic reliance of the anterior cruciate ligament on the medial collateral ligament (MCL) has grown, we have delved further into trying to understand what specific function needs to be restored in their combined injury. At the same time, we have expanded our knowledge of the relation between the MCL and the medial meniscus. It is a great step forward for our knowledge to begin to infer medial stability from the status of the medial meniscus in these complex cases. In my practice, this manifests as understanding that a floating meniscus indicates deep MCL injury, which makes me more likely to treat a moderate MCL injury operatively. I look forward to the continued understanding of the dynamic positioning of the medial meniscus and its treatment in combined anterior cruciate ligament-MCL injuries.

Treating Insecure Attachment in Group Therapy: Attachment Theory Meets Modern Psychoanalytic Technique.

Attachment theory is a comprehensive, empirically supported theory of emotional, relational, and neurophysiological development. Modern psychoanalysis is a theory of technique that addresses early psychological deficits and conflicts considered beyond the reach of traditional psychoanalysis. Both orientations have influenced the theory and practice of group psychotherapy and emphasize personality maturation as a treatment goal. This paper explores their potential synergies when treating preoedipal, insecurely attached emotional states, disrupted emotional self-regulation, and impaired mentalization. Theoretical and technical applications are suggested that may enhance the treatment of disordered attachment in group psychotherapy. By addressing insecure attachment as resistance, modern psychoanalytic techniques may engage the emotional substrates of the attachment process to facilitate the expansion of relational capacities, mentalization, self-regulation, the differentiation of self/other representations, and epistemic trust.

Technique for Arthroscopically Assisted Superficial and Deep Medial Collateral Ligament-Meniscotibial Ligament Repair With Internal Brace Augmentation.

Deep medial collateral ligament (MCL) injury leads to meniscal lift-off and extrusion of the medial meniscus, resulting in instability and increased medial compartment pressures with subsequent cartilage damage. Repair of the deep MCL meniscotibial ligament in concert with superficial MCL repair or reconstruction is intended to restore the native anatomy , stability, and function of the medial meniscus. We present an arthroscopically assisted technique using standard arthroscopy portals and a medial open approach.

Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn.

PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T-cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency-related genes. 13,476 distinct variants and 8,502 distinct predicted protein-impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency.

On Attacking and Being Attacked in Group Psychotherapy.

Verbal attacks are unavoidable within long-term psychotherapy groups. This article examines the inherent therapeutic value of potentially destructive exchanges. Group leader attempts to objectively define and regulate "attacks" are critiqued. A case example illustrates how leader interventions using induced feelings can enhance the therapeutic process and subsequent relational repair. Leader difficulties in identifying with the relational positions involved (attacker, victim, bystander) are explored, and a framework is offered for illuminating unconscious, dissociated, or unformulated emotional communications. It is argued that leader resistances may inadvertently promote and maintain group members' damaging tendency to direct aggression toward rather than away from the self. Instead of being avoided or controlled, verbal attacking can be considered meaningful developmental progress and leveraged clinically to promote emotional maturation within the group.

Nursing Assistant Perceptions of Their Role in Quality Improvement Processes in Nursing Homes.

Nursing assistants provide the majority of direct resident care in nursing homes and are centrally involved in implementing quality improvement (QI), yet little is known about their experiences in QI. Interviews with nursing assistants found that respondents perceive themselves as having a unique and important role in QI. They described key outcomes of QI as positive gains in the daily lives of residents, improved work processes, and increased time between staff and residents.

Adeno-associated virus 8-mediated gene therapy for choroideremia: preclinical studies in in vitro and in vivo models.

BACKGROUND: Choroideremia (CHM) is a slowly progressive X-linked retinal degeneration that results in a loss of photoreceptors, retinal pigment epithelium and choroid. CHM, the gene implicated in choroideremia, encodes Rab escort protein-1 (REP-1), which is involved in the post-translational activation via prenylation of Rab proteins. METHODS: We evaluated AAV8.CBA.hCHM, a recombinant adeno-associated virus serotype 8 (rAAV8) vector, which targets retinal cells efficiently, for both therapeutic effect and safety in vitro and in vivo in a murine model. In vitro studies included western blot analyses and prenylation assays. In vivo studies included ophthalmoscopy, pupillometry, histology and immunofluorescence analysis. RESULTS: Infection with AAV8.CBA.hCHM induced the expression of REP-1 protein in a dose-responsive fashion. Transduction with AAV8.CBA.hCHM reverses the biochemical and pathogenetic defects in CHM both in vitro and in vivo and showed no safety concerns in the in vivo investigations performed in the present study. CONCLUSIONS: AAV8 is a promising vector for human clinical gene therapy trials for choroideremia.

AAV-mediated gene therapy for choroideremia: preclinical studies in personalized models.

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1(st) or 2(nd) decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.

Decreased ratios of lateral to medial patellofemoral forces and pressures after lateral retinacular release and gender knees in total knee arthroplasty.

PURPOSE: To demonstrate that lateral to medial patellofemoral force and pressure ratios could be a surrogate marker of retinacular tension and patellar tracking. METHODS: The patellofemoral forces of six knees from three fresh-frozen half-body female cadavers were evaluated with a capacitive sensor under simulated operative conditions in six staged clinical scenarios: native knees, knee arthroplasty without patellar resurfacing, resurfaced knee and patella, resurfaced knee and patella with lateral release, gender-specific knee arthroplasty with patella resurfacing, and gender-specific knee arthroplasty with lateral release. Maximum force and peak pressure were simultaneously recorded during three to four ranges of motion. Average values were compared between lateral and medial patellofemoral compartments as an objective measure of patellar tracking for the different settings. RESULTS: Significant differences in lateral and medial force and pressure differentials were seen in most scenarios despite clinically normal patellar tracking. Lateral to medial ratios of maximum force and peak pressure significantly increased after TKA (2.9, 2.1) and after patella resurfacing (2.8, 2.6) compared to the native knee (1.6, 1.8). Addition of a lateral release in resurfaced knees decreased the ratio of lateral to medial patellofemoral forces and pressures as did gender knee arthroplasty (1.5 and 1.1, 2 and 1.3, respectively). Pressure and force values most closely resembled the native knee in the resurfaced knee/resurfaced patella with lateral release and in the gender knee arthroplasty scenarios. CONCLUSIONS: Use of lateral to medial patellofemoral force ratios as a surrogate objective marker for patellar tracking was validated in this study by decreasing ratios observed after lateral release in TKA and with gender-specific implants.

Renal trauma from recreational accidents manifests different injury patterns than urban renal trauma.

PURPOSE: The majority of blunt renal trauma is a consequence of motor vehicle collisions and falls. Prior publications based on urban series have shown that significant renal injuries are almost always accompanied by gross hematuria alone or microscopic hematuria with concomitant hypotension. We present a series of blunt renal trauma sustained during recreational pursuits, and describe the mechanisms, injury patterns and management. MATERIALS AND METHODS: Database review from 1996 to 2009 identified 145 renal injuries. Children younger than age 16 years, and trauma involving licensable motor vehicles, penetrating injuries and work related injuries were excluded from analysis. Grade, hematuria, hypotension, age, gender, laterality, mechanism, management, injury severity score and associated injuries were recorded. RESULTS: We identified 106 patients meeting the criteria and 85% of the injuries were snow sport related. Age range was 16 to 76 years and 92.5% of patients were male. There were 39 grade 1 injuries, 30 grade 2, 22 grade 3, 12 grade 4 and 3 grade 5 injuries. Gross hematuria was present in 56.7%, 77.2% and 83.3% of grade 2, grade 3 and grade 4 injuries, respectively. None of the patients with grade 2 or greater injuries and microscopic hematuria had hypotension except 1 grade 5 pedicle injury. The nephrectomy and renorrhaphy rate for grade 1 to grade 4 injuries was 0%. CONCLUSIONS: Compared to urban series of blunt renal trauma, recreationally acquired injuries appear to follow different patterns, including a paucity of associated injuries or hypotension. If imaging were limited to the presence of gross hematuria, or microscopic hematuria with hypotension, 23% of grade 2 to grade 4 injuries would be missed. Men are at higher risk than women. However, operative intervention is rarely helpful.

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies.

Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

Determinants of patient satisfaction following surgery for multidirectional instability.

Fifty shoulders in 46 patients underwent stabilization surgery for multidirectional instability. Univariate analysis showed no significant differences (P>0.05) for age, gender, or workers' compensation in patient satisfaction or American Shoulder and Elbow Surgeons (ASES) score. Only the ASES score was lower with prior surgery (P=0.001). There was a significantly increased ASES score (P<0.05) for arthroscopic versus open treatment. Subjective variable analysis showed that satisfaction and ASES score were significantly associated with questions regarding pain, instability, and upper extremity use (P<0.01). Increased range of motion showed a trend toward higher ASES scores (P<0.074). Patient satisfaction (P=0.013) was associated with greater forward elevation and greater external rotation (P=0.056). Multivariate analysis (P<0.05) showed that independent determinants of patient satisfaction with outcome included change in instability symptoms and ASES score. Subjective variables of symptoms and motion had the greatest correlation with patient satisfaction and ASES score following surgery for multidirectional shoulder instability. To improve patient satisfaction, an expanded focus on these subjective points may be beneficial.