Effect of personalized spinal profile on its biomechanical response in an EMG-assisted optimization musculoskeletal model of the trunk.

Recent developments in musculoskeletal (MS) modeling have been geared towards model customization. Personalization of the spine profile could affect estimates of spinal loading and stability, particularly in the upright standing posture where large inter-subject variations in the lumbar lordosis have been reported. This study investigates the biomechanical consequences of changes in the spinal profile. In 31 participants (healthy and with back pain), (1) the spine external profile was measured, (2) submaximal contractions were recorded in a dynamometer to calibrate the EMG-driven MS model and finally (3) static lifting in the upright standing challenging spine stability while altering load position and magnitude were considered. EMG signals of 12 trunk muscles and angular kinematics of 17 segments were recorded. For each participant, the MS model was constructed using either a generic or a personalized spinal profile and 17 biomechanical outcomes were computed, including individual muscle forces, ratios of muscle group forces, spinal loading and stability parameters. According to the ANOVA results and corresponding effect sizes, personalizing the spine profile induced medium and large effects on about half MS model outcomes related to the trunk muscle forces and negligible to small effects on spinal loading and stability as more aggregate outcomes. These effects are explained by personalized spine profiles that were a little more in extension as well as more pronounced spine curvatures (lordosis and kyphosis). These findings suggest that spine profile personalization should be considered in MS spine modeling as it may impact muscle force prediction and spinal loading.

Comparison of sedation with dexmedetomidine/atipamezole administered subcutaneously at GV20 acupuncture point with usual routes of administration in dogs presented for orthopaedic radiographs.

OBJECTIVES: To evaluate the efficacy of subcutaneous administration of dexmedetomidine/atipamezole at the Governing Vessel 20 (GV20) acupuncture point compared with other administration routes (intramuscular and intravenous) in dogs presented for orthopaedic radiographs. MATERIALS AND METHODS: Prospective, randomised, blinded, controlled clinical study. Sixty-four client-owned dogs were randomly injected with 200 µg/m2 of dexmedetomidine intramuscular (lumbar muscles) (n=20), intravenous (n=23) or subcutaneous at the GV20 point (n=21). Following radiographs, dogs received 2000 µg/m2 of atipamezole intramuscular (n=31), or subcutaneous at the GV20 point (n=27). Degree and time to sedation and recovery were assessed using a sedation scale and a Dynamic and Interactive Visual Analog Scale (DIVAS). Clinical physiological variables and adverse events were used. Statistical linear mixed-effect models (analysis of variance) and Cox models were performed. Significance was set at P-value <0.05. RESULTS: Sedation was insufficient to perform orthopaedic radiographs in six dogs in the intramuscular group. The time to sedation was significantly longer, and sedation scale and DIVAS scores were significantly lower in the intramuscular group. The intravenous group had significantly higher sedation scale and DIVAS scores than the GV20 group. No significant differences were observed between the intramuscular and GV20 recovery groups, although the time effect was significantly more pronounced in the GV20 recovery group. CLINICAL SIGNIFICANCE: Subcutaneous administration of dexmedetomidine and atipamezole at GV20 provided effective sedation and recovery in dogs undergoing orthopaedic radiographic studies. GV20 administration provided a clinically similar level of sedation to the intravenous route, and greater and faster sedation and similar recovery to intramuscular.

User-centered development process of an operating interface to couple a robotic glove with a virtual environment to optimize hand rehabilitation following a stroke.

Introduction: Task-specific neurorehabilitation is crucial to optimize hand recovery shortly after a stroke, but intensive neurorehabilitation remains limited in resource-constrained healthcare systems. This has led to a growing interest in the use of robotic gloves as an adjunct intervention to intensify hand-specific neurorehabilitation. This study aims to develop and assess the usability of an operating interface supporting such a technology coupled with a virtual environment through a user-centered design approach. Methods: Fourteen participants with hand hemiparesis following a stroke were invited to don the robotic glove before browsing through the operating interface and its functionalities, and perform two mobility exercises in a virtual environment. Feedback was collected for improving technology usability. Participants completed the System Usability Scale and ABILHAND questionnaires and their recommendations were gathered and prioritized in a Pugh Matrix. Results: The System Usability Scale (SUS) score for the operating interface was excellent (M = 87.0 SD = 11.6). A total of 74 recommendations to improve the user interface, calibration process, and exercise usability were identified. Conclusion: The application of a full cycle of user-centred design approach confirms the high level of usability of the system which is perceived by end users as acceptable and useful for intensifying neurorehabilitation.

The density of calretinin striatal interneurons is decreased in 6-OHDA-lesioned mice.

Interneurons play a significant role in the functional organization of the striatum and some of them display marked plastic changes in dopamine-depleted conditions. Here, we applied immunohistochemistry on brain sections from 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease and sham animals to characterize the regional distribution and the morphological and neurochemical changes of striatal interneurons expressing the calcium-binding protein calretinin (CR). Two morphological subtypes of calretinin-immunostained (CR +) interneurons referred, respectively, as small- and medium-sized CR + interneurons were detected in 6-OHDA- and sham-lesioned animals. The small cells (9-12 µm) prevail in the anterior and dorsal striatal regions; they stain intensely for CR and display a single slightly varicose and moderately arborized process. The medium-sized CR + interneurons (15-20 µm) are more numerous than the small CR + cells and rather uniformly distributed within the striatum; they stain weakly for CR and display 2-3 long, slightly varicose and poorly branched dendrites. The density of medium CR + interneurons is significantly decreased in the dopamine-depleted striatum (158 ± 15 neurons/mm3), when compared to sham animals (370 ± 41 neurons/mm3), whereas that of the small-sized CR + interneurons is unchanged (174 ± 46 neurons/mm3 in 6-OHDA-lesioned striatum and 164 ± 22 neurons/mm3 in sham-lesioned striatum). The nucleus accumbens is populated only by medium-sized CR + interneurons, which are distributed equally among the core and shell compartments and whose density is unaltered after dopamine denervation. Our results provide the first evidence that the medium-sized striatal interneurons expressing low level of CR are specifically targeted by dopamine denervation, while the small and intensely immunoreactive CR + cells remain unaffected. These findings suggest that high expression of the calcium-binding protein CR might protect striatal interneurons against an increase in intracellular calcium level that is believed to arise from altered glutamate corticostriatal transmission in Parkinson's disease.

Subjective self-assessment of physical activity is negatively affected by monitoring awareness in subjects with mild cognitive impairment: a crossover randomised controlled trial.

OBJECTIVE: Physical activity plays an important role in maintaining mental and physical health. This study assessed the effect of physical activity monitoring awareness on the physical activity level and subjective self-assessment of physical activity in middle-aged subjects with normal cognitive function (NCF) and mild cognitive impairment (MCI). PATIENTS AND METHODS: Thirty-five subjects aged 50-65 years with NCF and MCI were randomised into two experimental groups, each taking part in two one-week intervention periods. Subjects in group A were not aware that their physical activity was monitored in the first week (phase I) and were aware of the monitoring in the second week (phase II), whereas it was the opposite order for group B. Physical activity was assessed using the ActiGraph GT9X accelerometer and International Physical Activity Questionnaire (IPAQ). RESULTS: A total of 32 subjects (MCI: n = 12, NCF: n = 20) completed both intervention periods, with MCI subjects having significantly lower objectively assessed physical activity than NCF participants. Moreover, subjectively assessed physical activity in the MCI group was significantly higher when the participants were unaware of physical activity monitoring. A significant phase-group interaction was found in total (MET-min/d: p = 0.0072; min/d: p = 0.0194) and moderate (MET-min/d: p = 0.0015; min/d: p = 0.0020) physical activity as well as energy expenditure (p = 0.0366) assessed by the IPAQ and in the percentage of sedentary behaviour (p = 0.0330) and the average number of steps (p = 0.0342) assessed by ActiGraph. CONCLUSIONS: The awareness of physical activity assessment might decrease the ability to subjectively assess physical activity in subjects with MCI.

Incidental bilateral calcaneal fractures following overground walking with a wearable robotic exoskeleton in a wheelchair user with a chronic spinal cord injury: is zero risk possible?

Many individuals with spinal cord injury (SCI) rely on wheelchairs as their primary mode of locomotion leading to reduced weight-bearing on the lower extremities, which contributes to severe bone loss and increased risk of fragility fractures. Engaging in a walking program may reverse this vicious cycle, as this promotes lower extremity weight-bearing and mobility, which may reduce bone loss and fragility fracture risk. However, fragility fracture risk associated with the use of wearable robotic exoskeletons (WREs) in individuals with SCI needs consideration. A 35-year-old man with chronic complete sensorimotor SCI (neurological level = T6) and low initial bone mineral density enrolled in a 6- to 8-week WRE-assisted walking program after successfully completing an initial clinical screening process and two familiarization sessions with the WRE. However, after the first training session with the WRE, he developed bilateral localized ankle edema. Training was suspended, and a CT-scan revealed bilateral calcaneal fractures, which healed with conservative treatment over a 12-week period. Opportunities for improving clinical screening and WRE design are explored. The relevance of developing clinical practice guidelines for safe initiation and progression of intensity during WRE-assisted walking programs is highlighted. This case of bilateral calcaneal fractures illustrates that aiming for "zero risk" during WRE-assisted walking programs may not be realistic. Although WREs are a relatively new technology, current evidence confirms their potential to greatly improve health and quality of life in individuals with chronic SCI. Hence, ensuring their safe use remains a key priority.

Broader Geographic Sampling Increases Extent of Intermediate Host Specificity for a Trematode Parasite (Notocotylidae: Quinqueserialis quinqueserialis).

Knowledge of helminth life cycles is essential to understanding their host specificity, geographic distribution, and transmission. Many helminth life cycle descriptions are based on field collections in a limited part of the parasite's range. However, it is important to determine whether helminth life cycles and host specificity remain consistent across their geographic range so that we may better understand their life history and transmission ecology. Here, we investigated whether the life cycle of a widespread trematode, Quinqueserialis quinqueserialis (Notocotylidae) varies across its geographic range. Four species of planorbid snails; Gyraulus circumstriatus, Gyraulus crista, Planorbula sp., and Promenetus exacuous, were collected at 5 locations in Canada (3 in Manitoba, 2 in Northwest Territories). Snails and parasite larvae were morphologically and genetically identified to species. The total prevalence of Q. quinqueserialis infections in snail hosts among the 5 locations was 2.3% (n = 1,017). Three species of snails were infected with Q. quinqueserialis rediae: G. circumstriatus, G. crista, and P. exacuous. Two of the 3 species of snails were infected in central (Manitoba) and northern locations (Northwest Territories) within Canada, which indicates limited life cycle variation across a large geographic range. This is the first report of snails naturally infected with Q. quinqueserialis in Canada. These novel host records demonstrate that this trematode species is not as host-specific for first intermediate host species as previously described.

Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice.

The loss of nigrostriatal dopamine neurons in Parkinson's disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson's disease.

Wheelchair use and lipophilic statin medications may influence bone loss in chronic spinal cord injury: findings from the FRASCI-bone loss study.

We identified a protective bone effect at the knee with lipophilic statin use in individuals with chronic spinal cord injury. Lipophilic statin users gained bone at the knee compared to non-users and wheelchair users lost bone compared to walkers. Ambulation and or statins may be effective osteogenic interventions in chronic spinal cord injury (SCI). INTRODUCTION: SCI increases the risk of osteoporosis and low-impact fractures, particularly at the knee. However, during the chronic phase of SCI, the natural history and factors associated with longitudinal change in bone density remain poorly characterized. In this study, we prospectively assessed factors associated with change in bone density over a mean of 21 months in 152 men and women with chronic SCI. METHODS: A mixed model procedure with repeated measures was used to assess predictors of change in bone mineral density (PROC MIXED) at the distal femur and proximal tibia. Factors with a p value of <0.10 in the univariate mixed models, as well as factors that were deemed clinically significant (gender, age, and walking status), were assessed in multivariable models. Factors with a p value of ≤0.05 were included in the final model. RESULTS: We found no association between bone loss and traditional osteoporosis risk factors, including age, gender, body composition, or vitamin D level or status (normal or deficient). In both crude and fully adjusted models, wheelchair users lost bone compared to walkers. Similarly, statin users gained bone compared to nonusers. CONCLUSIONS: The statin finding is supported by reports in the general population where statin use has been associated with a reduction in bone loss and fracture risk. Our results suggest that both walking and statins may be effective osteogenic therapies to mitigate bone loss and prevent osteoporosis in chronic SCI. Our findings also suggest that loss of mechanical loading and/or neuronal factors contribute more to disuse osteoporosis than traditional osteoporosis risk factors.

Serotonin hyperinnervation of the striatum with high synaptic incidence in parkinsonian monkeys.

The chronic use of L-Dopa for alleviating the motor symptoms of Parkinson's disease often produces adverse effects such as dyskinesia. Unregulated release of dopamine by serotonin axons following L-Dopa administration is a major presynaptic determinant of these abnormal involuntary movements. The present study was designed to characterize the reorganization of serotonin striatal afferents following dopaminergic denervation in a primate model of Parkinson's disease. Our sample comprised eight cynomolgus monkeys: four that were rendered parkinsonian following MPTP administration and four controls. The state of striatal serotonin and dopamine innervation was evaluated by means of immunohistochemistry with antibodies against serotonin transporter (SERT) and tyrosine hydroxylase. A detailed stereological investigation revealed a significant increase in the number of serotonin axon varicosities in the striatum of MPTP-intoxicated monkeys. This increase is particularly pronounced in the sensorimotor territory of the striatum, where the dopamine denervation is the most severe. Electron microscopic examinations indicate that, in contrast to the nucleus accumbens where the dopamine innervation is preserved, the SERT+ axon varicosities observed in the sensorimotor territory of the putamen establish twice as many synaptic contacts in MPTP-intoxicated monkeys than in controls. These findings demonstrate the highly plastic nature of the serotonin striatal afferent projections, a feature that becomes particularly obvious in the absence of striatal dopamine. Although the number of dorsal raphe serotonin neurons remains constant in parkinsonian monkeys, as shown in the present study, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the potential unregulated and ectopic release of dopamine by serotonin axons after L-Dopa treatment of Parkinson's disease.

Active and passive heat stress similarly compromise tolerance to a simulated hemorrhagic challenge.

Passive heat stress increases core and skin temperatures and reduces tolerance to simulated hemorrhage (lower body negative pressure; LBNP). We tested whether exercise-induced heat stress reduces LBNP tolerance to a greater extent relative to passive heat stress, when skin and core temperatures are similar. Eight participants (6 males, 32 ± 7 yr, 176 ± 8 cm, 77.0 ± 9.8 kg) underwent LBNP to presyncope on three separate and randomized occasions: 1) passive heat stress, 2) exercise in a hot environment (40°C) where skin temperature was moderate (36°C, active 36), and 3) exercise in a hot environment (40°C) where skin temperature was matched relative to that achieved during passive heat stress (∼38°C, active 38). LBNP tolerance was quantified using the cumulative stress index (CSI). Before LBNP, increases in core temperature from baseline were not different between trials (1.18 ± 0.20°C; P > 0.05). Also before LBNP, mean skin temperature was similar between passive heat stress (38.2 ± 0.5°C) and active 38 (38.2 ± 0.8°C; P = 0.90) trials, whereas it was reduced in the active 36 trial (36.6 ± 0.5°C; P ≤ 0.05 compared with passive heat stress and active 38). LBNP tolerance was not different between passive heat stress and active 38 trials (383 ± 223 and 322 ± 178 CSI, respectively; P = 0.12), but both were similarly reduced relative to active 36 (516 ± 147 CSI, both P ≤ 0.05). LBNP tolerance is not different between heat stresses induced either passively or by exercise in a hot environment when skin temperatures are similarly elevated. However, LBNP tolerance is influenced by the magnitude of the elevation in skin temperature following exercise induced heat stress.

Lifting strategies of expert and novice workers during a repetitive palletizing task.

Thirty manual material handlers (15 experts and 15 novices) were invited to perform series of box transfers under conditions similar to those of large distribution centers. The objective of the present study was to verify whether multiple box transfers leading to fatigue would also lead to differences between expert and novice workers in joint motions and in back loading variables (L5/S1 moments). The task consisted in transferring 24 15-kg boxes from one pallet to another (4 layers of boxes; 6 boxes/layer: 3 in the front row, 3 in the back) at a self-determined pace and then at an imposed pace of 9 lifts/min for a total of 240 lifts. The underlying idea was to set a challenging task that would force the experts to use their skills. Full-body 3D kinematic data were collected as well as external foot forces. A dynamic 3D linked segment model was used to estimate the net moments at L5/S1. The results clearly show that the experts bent their lumbar spine less (10° less) and were closer (4 cm) to the box than novice workers. Knee flexions were similar in both groups except when the box was lifted from ground level (expert ≈ 71°, novice ≈ 48°). The peak resultant moment was not statistically different (expert = 168 Nm, novice = 184 Nm) although experts had lower values on average than novices when lifting heights (and deposit heights) of the boxes increased. Therefore, experts differed from novice workers mostly in the posture-related variables. These differences are especially important to consider when the box is located on the ground, as the back posture and back loading are then at their greatest magnitude and could have a major impact on the distribution of internal forces on the spine.

Effect of treatment for paediatric cancers on balance: what do we know? A review of the evidence.

This review aims to explore the literature investigating balance outcomes in survivors of childhood cancer. A structured search of five databases resulted in 16 articles included in this review. Nearly all were classified as Level 4 evidence using the updated Oxford Centre for Evidence-Based Medicine Levels of Evidence. Balance abilities have been investigated solely in survivors of acute lymphoblastic leukaemia or central nervous system tumours. The literature tends to support the idea that survivors present with balance difficulties but the results need to be closely scrutinised. Several studies report results using the same experimental group, while other studies use balance outcome measures that have not had their psychometric properties assessed with this population. There are also few studies that evaluate dynamic balance abilities in survivors of paediatric cancers, which may be more influential on functional tasks. Furthermore, very few of the included studies investigate how the found balance deficits affect this population's daily lives, which would be necessary in order to determine if intervention should be geared towards this area. Directions for future research should also include multi-centred, clinically oriented trials to evaluate balance abilities in survivors of childhood cancers compared with healthy control subjects in order to strengthen the literature.

Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy.

BACKGROUND: Fatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument. PATIENTS AND METHODS: The Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes. RESULTS: A total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155). CONCLUSIONS: In patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.

Effects of rolling resistances on handrim kinetics during the performance of wheelies among manual wheelchair users with a spinal cord injury.

STUDY DESIGN: Repeated cross-sectional study. OBJECTIVES: To compare the effects of rolling resistances (RRs) on handrim kinetic intensity at the non-dominant upper limb and on handrim kinetic symmetry during wheelies performed by manual wheelchair users (MWUs) with spinal cord injury (SCI). SETTING: Pathokinesiology Laboratory. METHODS: Sixteen individuals with SCI who were able to perform wheelies participated in this study. During a laboratory assessment, participants randomly performed wheelies on four RRs: natural high-grade composite board, 5-cm thick soft foam, 5-cm thick memory foam, and with the rear wheels blocked by wooden blocks. Four trials were conducted for each of the RRs. Participant's wheelchair was equipped with instrumented wheels to record handrim kinetics, whereas the movements of the wheelchair were recorded with a motion analysis system. RESULTS: The net mean and peak total forces, including its tangential and mediolateral components, were greater during take-off compared with the other phases of the wheelie, independently of RR. During take-off, the greatest net mean and peak total and tangential forces were reached with the wheels blocked. Symmetrical tangential and mediolateral force intensities were applied at the dominant and non-dominant handrims. CONCLUSION: Wheelies performed on low or moderate density foam generate similar forces at the handrim than on a natural surface and significantly less forces than with the wheels blocked. Hence, when teaching individuals with an SCI to perform a stationary wheelie, the use of low or moderate density foam represents a valuable alternative for minimizing upper limb effort and may also optimize quasi-static postural steadiness.

Mean arterial pressure following prolonged exercise in the heat: influence of training status and fluid replacement.

Prolonged exercise in the heat without fluid replacement represents a significant challenge to the regulation of mean arterial pressure (MAP). It is unknown, however, if MAP is equally challenged during the post-exercise period, and whether regular endurance exercise training can provide any benefit to its regulation. We examined MAP (Finometer) in eight trained (T) and eight untrained (UT) individuals prior to, and following, 120 min of cycling at 42 °C with (HYD) and without (DEHY) fluid replacement. Exercise during DEHY induced significant hyperthermia (T: 39.20 ± 0.52 °C vs UT: 38.70 ± 0.36 °C, P = 0.941) and body weight losses (T: 3.4 ± 1.2% vs UT: 2.7 ± 0.9%, P = 0.332), which did not differ between groups. Although MAP was equally reduced 5 min into the post-exercise period of DEHY (T: -20 ± 11 mmHg vs UT: -22 ± 13 mmHg, P = 0.800), its subsequent recovery was significantly different between groups (P = 0.037). While MAP returned to pre-exercise values in UT (-1 ± 3 mmHg), it remained reduced in T (-9 ± 3 mmHg, P = 0.028). No differences in MAP post-exercise were observed between groups during HYD. These data suggest that trained men exhibit a greater level of post-exercise hypotension following prolonged exercise in the heat without fluid replacement. Furthermore, fluid replacement reverses the sustained post-exercise hypotension observed in trained individuals.

Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity.

Mucolipidosis II (ML II alpha/beta), or I-cell disease, is a rare genetic disease in which activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent. GlcNAc-phosphotransferase is a multimeric enzyme encoded by two genes, GNPTAB and GNPTG. A spectrum of mutations in GNPTAB has been recently reported to cause ML II alpha/beta. Most of these mutations were found to be private or rare. However, the mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We analysed 44 patients who were either homozygous or compound heterozygous for this deletion (22 Italians, 8 Arab-Muslims, 1 Turk, 3 Argentineans, 3 Brazilians, 2 Irish travellers and 5 Portuguese) and 16 carriers (15 Canadians and 1 Italian) for three intragenic polymorphisms: c.-41_-39delGGC, c.18G>A and c.1932A>G as well as two microsatellite markers flanking the GNPTAB gene (D12S1607 and D12S1727). We identified a common haplotype in all chromosomes bearing the c.3503_3504delTC mutation. In summary, we showed that patients carrying the c.3503_3504delTC deletion presented with a common haplotype, which implies a common origin of this mutation. Additionally, the level of diversity observed at the most distant locus indicates that the mutation is relatively ancient (around 2063 years old), and the geographical distribution further suggests that it probably arose in a peri-Mediterranean region.