Pharmacokinetics, disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical, oral, and intravenous administration.

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v.), oral (p.o.), and topical (TOP) administration of dimethyl sulfoxide (DMSO). The plasma concentration-time curve following a 15-min i.v. infusion of DMSO was described by a two-compartment model. Median and range of alpha (t1/2α ) and beta (t1/2ß ) half-lives were 0.029 (0.026-0.093) and 14.1 (6.6-16.4) hr, respectively. Plasma concentration-time curves of DMSO following p.o. and TOP administration were best described by one-compartment absorption and elimination models. Following the p.o. administration, median absorption (t1/2ab ) and elimination (t1/2e ) half-lives were 0.15 (0.01-0.77) and 15.5 (8.5-25.2) hr, respectively. The plasma concentrations of DMSO were 47.4-129.9 µg/ml, occurring between 15 min and 4 hr. The fractional absorption (F) during a 24-hr period was 47.4 (22.7-98.1)%. Following TOP administrations, the median t1/2ab and t1/2e were 1.2 (0.49-2.3) and 4.5 (2.1-11.0) hr, respectively. Plasma concentrations were 1.2-8.2 µg/ml occurring at 2-4 hr. Fractional absorption following TOP administration was 0.48 (0.315-4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2-6.7) ml hr-1  kg-1 . The corrected clearances (ClF ) for p.o. and TOP administrations were 2.9 (1.1-5.5) and 4.5 (0.52-18.2) ml hr-1  kg-1 .

The Utility of a High-intensity Exercise Protocol to Prospectively Assess ACL Injury Risk.

This study investigated the utility of a 5-min high-intensity exercise protocol (SAFT(5)) to include in prospective cohort studies investigating ACL injury risk. 15 active females were tested on 2 occasions during which their non-dominant leg was analysed before SAFT(5) (PRE), immediately after (POST0), 15 min after (POST15), and 30 min after (POST30). On the first occasion, testing included 5 maximum isokinetic contractions for eccentric and concentric hamstring and concentric quadriceps and on the second occasion, 3 trials of 2 landing tasks (i. e., single-leg hop and drop vertical jump) were conducted. Results showed a reduced eccentric hamstring peak torque at POST0, POST15 and POST30 (p<0.05) and a reduced functional HQ ratio (Hecc/Qcon) at POST15 and POST30 (p<0.05). Additionally, a more extended knee angle at POST30 (p<0.05) and increased knee internal rotation angle at POST0 and POST15 (p<0.05) were found in a single-leg hop. SAFT(5) altered landing strategies associated with increased ACL injury risk and similar to observations from match simulations. Our findings therefore support the utility of a high-intensity exercise protocol such as SAFT(5) to strengthen injury screening tests and to include in prospective cohort studies where time constraints apply.

Asymmetry after hamstring injury in English Premier League: issue resolved, or perhaps not?

Hamstring injuries constitute one of the most concerning injuries in English Premier League football, due to its high primary incidence but also its recurrence. Functional methods assessing hamstring function during high-risk performance tasks such as sprinting are vital to identify potential risk factors. The purpose of this study was to assess horizontal force deficits during maximum sprint running on a non-motorized treadmill in football players with previous history of hamstring strains as a pre-season risk-assessment in a club setting. 17 male football players from one Premier League Club were divided into 2 groups, experimental (n=6, age=24.5±2.3 years) and control (n=11, age=21.3±1.2 years), according to history of previous hamstring injury. Participants performed a protocol including a 10-s maximum sprint on a non-motorized treadmill. Force deficits during acceleration phase and steady state phases of the sprint were assessed between limbs and between groups. The main outcome measures were horizontal and vertical peak forces during the acceleration phase or steady state. There were no significant differences in peak forces between previously injured and non-injured limbs, or between groups, challenging the ideas around functional force deficits in sprint running as a diagnostic measure of hamstring re-injury risk.

Pharmacokinetics and pharmacodynamics of dermorphin in the horse.

Dermorphin is a µ-opioid receptor-binding peptide that causes both central and peripheral effects following intravenous administration to rats, dogs, and humans and has been identified in postrace horse samples. Ten horses were intravenously and/or intramuscularly administered dermorphin (9.3 ± 1.0 µg/kg), and plasma concentration vs. time data were evaluated using compartmental and noncompartmental analyses. Data from intravenous administrations fit a 2-compartment model best with distribution and elimination half-lives (harmonic mean ± pseudo SD) of 0.09 ± 0.02 and 0.76 ± 0.22 h, respectively. Data from intramuscular administrations fit a noncompartmental model best with a terminal elimination half-life of 0.68 ± 0.24 (h). Bioavailability following intramuscular administration was variable (47-100%, n = 3). The percentage of dermorphin excreted in urine was 5.0 (3.7-10.6) %. Excitation accompanied by an increased heart rate followed intravenous administration only and subsided after 5 min. A plot of the mean change in heart rate vs. the plasma concentration of dermorphin fit a hyperbolic equation (simple Emax model), and an EC(50) of 21.1 ± 8.8 ng/mL was calculated. Dermorphin was detected in plasma for 12 h and in urine for 48 or 72 h following intravenous or intramuscular administration, respectively.

Platelet apheresis in a deployed maritime environment: experiences from Operation GRITROCK.

When the Primary Casualty Receiving Facility (PCRF) on Royal Fleet Auxiliary (RFA) ARGUS deployed to Operation GRITROCK in October 2014, platelet apheresis had yet to be proven as a sustainable and usable capability for improving provision of blood products on a maritime platform. This paper explores the difficulties encountered by nurses tasked with setting up this capability once deployed and the requirements needed to ensure that this capability is maintained for future operations.

Pharmacokinetics of dexamethasone following intra-articular, intravenous, intramuscular, and oral administration in horses and its effects on endogenous hydrocortisone.

This study investigated and compared the pharmacokinetics of intra-articular (IA) administration of dexamethasone sodium phosphate (DSP) into three equine joints, femoropatellar (IAS), radiocarpal (IAC), and metacarpophalangeal (IAF), and the intramuscular (IM), oral (PO) and intravenous (IV) administrations. No significant differences in the pharmacokinetic estimates between the three joints were observed with the exception of maximum concentration (Cmax ) and time to maximum concentration (Tmax ). Median (range) Cmax for the IAC, IAF, and IAS were 16.9 (14.6-35.4), 23.4 (13.5-73.0), and 46.9 (24.0-72.1) ng/mL, respectively. The Tmax for IAC, IAF, and IAS were 1.0 (0.75-4.0), 0.62 (0.5-1.0), and 0.25 (0.08-0.25) h, respectively. Median (range) elimination half-lives for IA and IM administrations were 3.6 (3.0-4.6) h and 3.4 (2.9-3.7) h, respectively. A 3-compartment model was fitted to the plasma dexamethasone concentration-time curve following the IV administration of DSP; alpha, beta, and gamma half-lives were 0.03 (0.01-0.05), 1.8 (0.34-2.3), and 5.1 (3.3-5.6) h, respectively. Following the PO administration, the median absorption and elimination half-lives were 0.34 (0.29-1.6) and 3.4 (3.1-4.7) h, respectively. Endogenous hydrocortisone plasma concentrations declined from a baseline of 103.8 ± 29.1-3.1 ± 1.3 ng/mL at 20.0 ± 2.7 h following the administration of DSP and recovered to baseline values between 96 and 120 h for IV, IA, and IM administrations and at 72 h for the PO.

The Forefront of Dentistry-Promising Tech-Innovations and New Treatments.

KNOWLEDGE TRANSFER STATEMENT: This article discusses innovations in technology and treatments that have enormous potential to revolutionize our dental care, including novel concepts in electronic health records, communication between dentists and patients, biologics around diagnosis and treatment, digital dentistry, and, finally, the real-time optimization of information technology. The early implementation and validation of these innovations can drive down their costs and provide better dental and medical services to all members of our society.

Identifying joint-specific gait mechanisms causing impaired gait in alkaptonuria patients.

BACKGROUND: Alkaptonuria is a rare genetic disease that leads to structural joint damage and impaired movement function. Previous research indicates that alkaptonuria affects gait, however the detailed mechanisms are unknown. RESEARCH QUESTION: What are the joint-specific gait mechanisms which contribute to impaired gait in alkaptonuria patients? METHODS: The gait of 36 alkaptonuria patients were compared to those of 21 unimpaired controls. The AKU patients were split into three age groups (young 16-29 years, n = 9, middle 30-49 years, n = 16 and old 50 + years, n = 11), and the kinematic and kinetic gait profiles were compared to speed-matched controls using a spm1d two-sample t-test. RESULTS: The young AKU group showed significant differences in the sagittal plane of the knee joint compared to speed-matched controls. The middle group showed deviations in the knee and hip joints. The old group showed significant differences in multiple joints and planes and exhibited gait mechanisms which may be compensation strategies. SIGNIFICANCE: This study is the first to identify and describe joint-specific mechanisms during gait in alkaptonuria patients. Gait deviations were evident even in young AKU patients, including a 16-year-old, much earlier than previously thought. The knee joint is an important focus of future research and potential interventions as deviations were found across all three AKU age groups.

Insertion/deletion-related polymorphisms in the human T cell receptor beta gene complex.

Insertion/deletion related polymorphisms (IDRP) involving stretches of 15-30 kb within the human TCR-beta gene complex were revealed by pulse-field gel electrophoresis. Two independent IDRP systems were detected by analysis of Sfi I- and Sal I-digested human DNA samples using probes for TCR C and V region gene segments. The allelic nature of these systems was verified in family studies, and mapping data allowed localization of one area of insertion/deletion among the V gene segments and the other near the C region genes. All but one of 50 individuals tested could be typed for the two allelic systems, and gene frequencies for the two allelic forms were 0.37/0.61 and 0.46/0.54, indicating that these polymorphisms are widespread.

A genetically determined insertion/deletion related polymorphism in human T cell receptor beta chain (TCRB) includes functional variable gene segments.

Polymorphism in the human T cell receptor beta chain (TCRB) gene complex includes haplotypes with different numbers of TCRBV genes. An insertion/deletion related polymorphism (IDRP) in the human TCRBV region was found to involve TCRBV gene segments. Inserted TCRB haplotypes contain an additional 21.5 kb in which three TCRBV genes are encoded, members of the TCRBV7, TCRBV9, and TCRBV13 families. Two TCRBV gene segments were present only in inserted haplotypes; one of these, TCRBV7S3, is a functional gene and the other, TCRBV9S2(P), is a pseudogene because of an inframe termination colon. In addition, inserted haplotypes contain two identical copies of the TCRBV13S2 gene, whereas deleted haplotypes have only one copy. Deleted haplotypes could be subdivided into two types, deleted*1 and deleted*2, on the basis of sequence variations in TCRBV6S7 and TCRBV13S2 genes. Both deleted*1 and deleted*2 haplotypes contained the same number of TCRBV genes; both contain 60 genes of which 50 are functional, whereas, inserted haplotypes contained 63 genes of which 52 are functional. Comparisons of inserted region sequences with the homologous region in a deleted haplotype, and with sequences surrounding related TCRBV genes, revealed patterns of similarity that suggest insertion as well as deletion events have occurred in the evolution of the TCRBV gene complex. These data indicate that the genomic TCR repertoire is expanded in individuals who have inserted TCRBV haplotypes. The presence of additional TCRBV genes or, alternatively, the absence of certain TCRBV genes may have an impact upon immune responses and susceptibility to autoimmune diseases.

Allelic variations in the human T cell receptor V beta 6.7 gene products.

Polymorphisms of human TCR gene products have been suggested by the description of a mAb, OT145, that identifies a subset of TCRs in some individuals but not in others (6). Here we demonstrate that this mAb detects a TCR allotype of the V beta 6.7 gene. Two allelic products of this V gene differ by two nonconservative amino acid substitutions. The mAb OT145 appears to react with V beta 6.7 a gene products ("+" allele), but not with V beta 6.7b gene products ("-" allele). This represents the first direct demonstration that TCR V gene allotypes exist and provides a possible explanation for immune responses under the control of TCR V genes and for disease associations with TCR V genes.

Recombination within the HLA-D region. Correlation of molecular genotyping with functional data.

Molecular genotyping of the HLA-D/DR region in a family correlated with serologic and cellular typing data. It was further possible to predict a subtle difference in SB region-related functions from such molecular studies. A family that included an individual who inherited an HLA haplotype with a paternal recombination between HLA-B and the HLA-D/DR region was identified by classic HLA typing techniques. Segregation of HLA-D/DR region genes in this family was studied by Southern blot analysis using cDNA probes for DR alpha, DR beta, DC alpha, DC beta, and SB beta. Restriction enzyme fragment polymorphisms observed for every gene tested were in concordance with assigned HLA haplotypes (including the individual known to have inherited a paternal recombinant haplotype) with one exception: two HLA identical siblings were observed to have different SB beta restriction fragment patterns. Further testing revealed that one individual inherited a maternal HLA haplotype recombinant between the HLA-D/DR region and SB beta. Although both maternal SB alleles typed as SB4, allelic differences could be detected cellularly by primed lymphocytes and by the differential expression of a class II cell surface antigen using monoclonal antibody. Therefore, predicted and nonpredicted recombinant haplotypes were detected in a family by molecular genotyping.

Level of human TCRBV3S1 (V beta 3) expression correlates with allelic polymorphism in the spacer region of the recombination signal sequence.

One of the causes of variations in the expressed human T cell receptor (TCR) BV (V beta) repertoire is genetic variation in the germline DNA. Herein evidence is provided that allelic polymorphism may affect recombination frequency for a specific V gene. Two alleles of the TCR BV3 differ only at a single nucleotide position (C/T) within the 23-bp spacer region of the recombination signal sequence. These alleles are associated with variable percentages of BV3 cells in the peripheral blood, as shown in families and in unrelated normal donors. Individuals homozygous for allele 2 have a mean of 8.1% BV3 cells, heterozygous individuals have a mean of 4.7% BV3 cells, and homozygotes for allele 1 have a mean of 1.2% BV3 cells in CD3+ CD4+ peripheral blood T cells. Since the correlation is tight in unrelated individuals and other genetic differences were not found in the vicinity of BV3, we suggest that the spacer region sequence itself modifies recombination efficiency. This allelic system provides an example of a novel mechanism by which cis-acting genetic elements may affect recombination in a natural in vivo system.

Analysis of tetraplegic reaching in their 3D workspace following posterior deltoid-triceps tendon transfer.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To quantify three-dimensional (3D) reachable workspace in different groups of tetraplegic participants and to assess their reaching performance within this workspace. SETTING: Northwest Regional Spinal Injuries Centre, UK. METHODS: The 3D reachable workspace of three groups of tetraplegics (NON-OP, operated group (OP) and tetraplegic control group (CON(Tetraplegic)) with varying levels of triceps function together with a healthy control group (CON(Healthy))) was defined by reaching to five target positions (anterior, medial, lateral, superior and inferior) located on the periphery of their workspace. Joint angles and inter-joint co-ordination were analysed after a 3D reconstruction of the thorax, humerus and forearm. The performance related variables of movement time, peak velocity, time-to-peak velocity and curvature index were also examined. RESULTS: The reachable volumes covered were consistent with the level of triceps function as CON(Healthy) covered a significantly greater volume than the tetraplegic groups and in turn the OP covered a larger workspace volume than NON-OP. The reduced workspace of tetraplegics was identified as being due to restrictions in workspace above shoulder height and across the body. Co-ordination data identified some differences in movement patterns but when reaching to targets on the workspace there were no significant differences between the OP and NON-OP groups. CONCLUSION: This study provided a detailed assessment of reachable workspace and target reaching. Tetraplegic participants found the superior and medial parts of the workspace were the most challenging directions. Standardised biomechanical analysis of tetraplegic upper-limb function is required for objective assessment.

Inflammatory mediators are potential biomarkers for extracorporeal shockwave therapy in horses.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) can potentially mask painful injuries in equine athletes. Tests to detect whether a horse has received ESWT prior to competition are needed. Extracorporeal shockwave therapy is known to affect inflammatory mediators in other species, and if these mediators are altered in the horse, these could serve as biomarkers of ESWT. OBJECTIVES: To test the hypothesis that a single application of ESWT will alter the circulating protein concentrations of 10 inflammatory mediators in horse plasma. STUDY DESIGN: Prospective repeated measures experimental study. METHODS: Eleven healthy horses were administered a single dose of ESWT on the dorsal surface of proximal MCIII. Blood samples were collected at -168, -144, -120, -96, -72, -70, -68, -66, -48, -24, -6, -4, -2, 0 h before and 2, 4, 6, 24, 48, 72, 96, 168, 336 and 504 h after ESWT. Plasma concentrations of interleukin 1 beta (IL-1ß), IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-15, interferon gamma (IFN-γ), soluble toll-like receptor 2 (sTLR2) and tumour necrosis factor alpha (TNF-α) were measured to assess the effects of ESWT on these mediators. RESULTS: Baseline concentrations of inflammatory mediators did not change substantially during the week prior to ESWT. Plasma concentrations of five inflammatory factors changed following ESWT. IL-1ß and IL-6 were significantly down-regulated (P<0.01), while TNF-α, IL-1RA and TLR2 were significantly up-regulated (P<0.01). The remaining cytokines were not significantly affected by ESWT. MAIN LIMITATIONS: This study was performed in a small number of sedentary, healthy pasture-kept horses using a single dose of ESWT applied to a single location. Additional studies are necessary to determine the effect of ESWT on inflammatory mediators in athletic horses undergoing treatment for musculoskeletal injuries. CONCLUSIONS: Plasma concentrations of TNF-α, IL-1ß, IL-1RA, IL-6 and TLR2 were significantly affected by ESWT, and deserve further investigation as possible biomarkers of ESWT.

A kinematic comparison of gait with a backpack versus a trolley for load carriage in children.

The use of a school trolley is reaching and even surpassing the use of backpacks in many countries, although a recommended load has not been studied. To accomplish this, 3D gait kinematics of the lower limbs and thorax were analysed in 49 students walking unloaded, pulling a school trolley or carrying a backpack, all with either 10%, 15%, or 20% BW. The variables obtained were the degrees of flexion/extension, adduction/abduction and internal/external rotation of the thorax, pelvis, hip, knee and ankle. Statistical parametric mapping was used to evaluate differences between conditions and loads throughout the gait cycle. In the backpack conditions, the magnitudes of the differences decreased from proximal to distal joints compared to the unloaded condition. The use of a school trolley only required minor kinematic adaptations. Therefore, from kinematic analysis, it is recommended to avoid loads above 10% BW for children using a backpack and below 20% BW for children using a trolley.

Vector-field statistics for the analysis of time varying clinical gait data.

BACKGROUND: In clinical settings, the time varying analysis of gait data relies heavily on the experience of the individual(s) assessing these biological signals. Though three dimensional kinematics are recognised as time varying waveforms (1D), exploratory statistical analysis of these data are commonly carried out with multiple discrete or 0D dependent variables. In the absence of an a priori 0D hypothesis, clinicians are at risk of making type I and II errors in their analyis of time varying gait signatures in the event statistics are used in concert with prefered subjective clinical assesment methods. The aim of this communication was to determine if vector field waveform statistics were capable of providing quantitative corroboration to practically significant differences in time varying gait signatures as determined by two clinically trained gait experts. METHODS: The case study was a left hemiplegic Cerebral Palsy (GMFCS I) gait patient following a botulinum toxin (BoNT-A) injection to their left gastrocnemius muscle. FINDINGS: When comparing subjective clinical gait assessments between two testers, they were in agreement with each other for 61% of the joint degrees of freedom and phases of motion analysed. For tester 1 and tester 2, they were in agreement with the vector-field analysis for 78% and 53% of the kinematic variables analysed. When the subjective analyses of tester 1 and tester 2 were pooled together and then compared to the vector-field analysis, they were in agreement for 83% of the time varying kinematic variables analysed. INTERPRETATION: These outcomes demonstrate that in principle, vector-field statistics corroborates with what a team of clinical gait experts would classify as practically meaningful pre- versus post time varying kinematic differences. The potential for vector-field statistics to be used as a useful clinical tool for the objective analysis of time varying clinical gait data is established. Future research is recommended to assess the usefulness of vector-field analyses during the clinical decision making process.

AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation.

Usage of human T-cell receptor V beta, J beta, C beta, and V alpha gene segments is not proportional to gene number.

Certain T-cell receptor (TCR) beta-chain variable (V), joining (J), and constant (C) gene segments, as well as TCR alpha-chain V gene segments, are disproportionally represented in TCR alpha and beta cDNA libraries derived from PHA-stimulated peripheral blood lymphocytes. Sequences of 138 TCR alpha clones and 96 TCR beta clones were determined and of these 128 TCR alpha clones and 88 TCR beta clones were found to contain unique combinations of V, J, and C gene segments or to display diversity in N region nucleotides. The frequency of the V, J, and C genes used in the assembly of unique transcripts was ascertained. Of the 24 reported V beta gene families, 21 were observed among the 88 TCR beta clones including four V beta families (V beta 1, V beta 2, V beta 3, and V beta 4) that were represented in the sample 2 1/2-5 times more frequently than would be expected on the basis of copy number within the gene complex. Seventy-eight percent of the clones were positive for C beta 2 and more than half of the clones (53%) used one of two J beta 2 genes: J beta 2.1 was present in 27 clones and J beta 2.7 in 20 clones. TCR V alpha families were also disproportionately represented in this sample. Twenty-five of 30 V alpha families were observed in the sample of 128 clones including six recently reported V alpha families. Three V alpha families, V alpha 2, V alpha 8, and V alpha 23, accounted for approximately 40% of the TCR alpha clones and were represented at 18%, 9.4%, and 13.3%, respectively. Both V alpha 2 and V alpha 8 gene families contain more than one gene; thus the number of clones observed in these families may, in part, be related to gene number. However, V alpha 23, which appears to be a single-copy gene family, is significantly overrepresented in this sample. Although disproportional usage of V beta genes may be accounted for by superantigen exposure, reasons for disproportional usage of J beta, C beta, and V alpha genes are presently unknown.

The human T-cell receptor variable gene segment TCRBV6S1 has two null alleles.

The extent of polymorphism in TCRBV6S1 was examined by screening 203 individuals of diverse ethnic backgrounds by using SSCP. Three alleles were detected, including two that were described previously (TCRBV6S1*1 and *2P). The third allele (TCRBV6S1*3P), identified in these studies, is a pseudogene because, similar to allele *2P, it contains a substitution of a highly conserved cysteine residue near CDR3. Among a panel of 126 Caucasian donors, alleles *1, *2P, and *3P were observed to have frequencies of 0.72, 0.12, and 0.16, respectively. The extent of this survey suggests that it is unlikely for there to be additional common variants of TCRBV6S1. The approach used here enables rapid typing for polymorphism in a TCRBV gene that results in an allelically determined hole in the TCR repertoire.