Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III.

PURPOSE: Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. METHODS: We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgko and Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. RESULTS: The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. CONCLUSION: The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Airway management and perioperative adverse events in children with mucopolysaccharidoses and mucolipidoses: A retrospective cohort study.

BACKGROUND: Children suffering from mucopolysaccharidoses (subtypes I, II, III, IV, VI, and VII) or mucolipidoses often require anesthesia, but are at high risk for perioperative adverse events. However, the impact of the disease subtype and the standard of care for airway management are still unclear. AIMS: This study aimed to assess independent risk factors for perioperative adverse events in individuals with mucopolysaccharidoses/mucolipidoses and to analyze the interaction with the primary airway technique implemented. METHODS: This retrospective study included individuals with mucopolysaccharidoses/mucolipidoses who underwent anesthesia at two high-volume centers from 2002 to 2016. The data were analyzed in a multivariate hierarchical model, accounting for repeated anesthesia procedures within the same patient and for multiple events within a single anesthesia. RESULTS: Of 141 identified inpatients, 67 (63 mucopolysaccharidoses and 4 mucolipidoses) underwent 269 anesthesia procedures (study cases) for 353 surgical or diagnostic interventions. At least one perioperative adverse event occurred in 25.6% of the cases. The risk for perioperative adverse events was higher in mucopolysaccharidoses type I (OR 8.0 [1.5-42.7]; P = .014) or type II (OR 8.8 [1.3-58.6]; P = .025) than in type III. Fiberoptic intubation through a supraglottic airway was associated with the lowest risk for perioperative adverse events and lowest conversion rate. Direct laryngoscopy was associated with a significantly higher risk for airway management problems than indirect techniques (estimated event rates 47.8% vs 10.1%, OR 24.05 [5.20-111.24]; P < .001). The risk for respiratory adverse events was significantly higher for supraglottic airway (22.6%; OR 31.53 [2.79-355.88]; P = .001) and direct laryngoscopy (14.8%; OR 14.70 [1.32-163.44]; P = .029) than for fiberoptic intubation through a supraglottic airway (2.1%). CONCLUSIONS: The disease subtype and primary airway technique were the most important independent risk factors for perioperative adverse events. Our findings indicate that in MPS/ML children with predicted difficult airway indirect techniques should be favored for the first tracheal intubation attempt.

Nerve transfer from the median to musculocutaneous nerve to induce active elbow flexion in selected cases of arthrogryposis multiplex congenita.

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a rare disease which affects mainly upper and lower extremities. Affected patients are not able to eat unassisted due to elbow contracture and nonexistent active elbow flexion. In traumatic brachial plexus palsies, a nerve transfer from either median or ulnar nerve to the musculocutaneous nerve has proved to induce active elbow flexion, and we report our results of such a procedure in a nontraumatic condition, that is, arthrogryposis. METHODS: We selected four patients with AMC type 1 (6 extremities, 2 males, 2 females) diagnosed with AMC presenting to our institution shortly after birth from 2014 to 2016 to perform a nerve transfer from the median nerve to the musculocutaneous nerve in order to induce active elbow flexion. The indication of application of this surgical procedure was based on active finger and wrist flexion, limited contracture of elbow joints and evidence of flexing muscle fibers detected by sonography. RESULTS: Five nerve transfers were conducted with a follow up of 2-5 years. Two extremities reached active elbow flexion motorgrade M4, two M3, and one M1 at latest follow up. One patient developed a postoperative suture granuloma. One nerve transfer was abandoned due to neuroanatomic variation. One extremity was treated with botulinum toxin in triceps muscle in addition to the nerve transfer. CONCLUSIONS: In this series of selected cases of AMC Type 1 we were able to induce active elbow flexion using a nerve transfer technique developed for traumatic and obstetric brachial plexus palsies. In four extremities the procedure achieved independent hand-to-mouth active elbow flexion. Level of evidence four.

Treatment of pediatric spinal deformity with use of recombinant human bone morphogenetic protein-2.

In pediatric spine surgery nonunion is a challenging issue. Instability may cause neurological impairment and lead to numerous surgeries in order to achieve fusion. The use of rhBMP-2 for pediatric spinal fusion has not been widely reported. In this study, a series of 13 children (14 procedures) that underwent spinal rhBMP-2 application were analyzed in order to measure clinical and radiographic outcome. Therefore, patient data, diagnosis, construct of instrumentation, type of bone graft, quantity of BMP used, and fusion outcome were reviewed. The study cohort included four female and nine male patients with a mean age of 11.2 years (range 2.6-19.2 years) at the time of rhBMP-2 application. Rh-BMP-2 was used in both primary (n = 6) and revision surgery (n = 8) in patients with a high risk for the development of nonunion. The mean follow-up was 51 months (range 12-108 months). Fusion occurred in 11 patients. Complications that may be due to application of rhBMP-2 were seen after four operations. Three patients had an increased body temperature and in one case prolonged wound secretion was evident, treated by local wound care or observation. In one of these patients an extensive postoperative hematoma occurred, necessitating surgical treatment. In conclusion, we could detect high fusion rates following the use of rhBMP-2 in pediatric spine surgery without an increased complication rate attributable to its application. Therefore we consider recombinant human BMP-2 to be an option in selected pediatric spinal procedures, especially in cases with compromised bone healing due to congenital, systemic, or local conditions.

Hip Morphology in MPS-1H Patients: An MRI-based Study.

BACKGROUND: Hip dysplasia is common in mucopolysaccharidosis type-1H (MPS-1H) patients, but its morphology is not completely understood. No magnetic resonance imaging (MRI)-based studies have been reported in the literature. The purpose of this study was to improve knowledge of hip dysplasia pathology by describing the hip morphology of these patients in MRI scans, plain radiographs, and arthrograms. METHODS: We performed a retrospective chart review of 18 MPS-1H patients. Supine anteroposterior pelvic radiographs of 36 hips and MRI scans of 18 hips were analyzed. Six arthrographs were also available. RESULTS: Plain radiographs were available for 18 patients. The mean age was 6.0 (SD=3.8) years. The mean acetabular index (AI) was 36.2 degrees (SD=5.8), and the mean migration percentage was 59.0% (SD=17.2). MRI data were available for 9 patients. The MRI findings were compared with the radiographs of the same patient. The mean AI (39.3 degrees, SD=5.8) was confirmed by the MRI findings (39.1 degrees, SD=5.5). The migration percentage was lower in the MRI scans than in the radiographs. Radiologically, the center-edge angle was negative in all patients, with a mean of -16.8 degrees (SD=7.9), and the MRI images produced a more negative value (-19.6 degrees, SD=7.6). The soft tissue coverage of the femoral head was described with the inclusion of the cartilaginous roof and labrum. The cartilaginous AI was 22.4 degrees (SD=7.5), and the labral AI was 13.5 degrees (SD=6.7). All 6 arthrograms revealed stability during dynamic testing. CONCLUSIONS: This study provides the first description of hip morphology in MPS-1H patients through MRI-based data. The cartilaginous coverage of the hip was increased compared with that of healthy children. The use of radiography alone may lead to a misunderstanding of hip morphology. MRI and arthrogram is highly recommended if surgery is considered.

Anterior distal femoral hemiepiphysiodesis can reduce fixed flexion deformity of the knee: a retrospective study of 83 knees.

Background and purpose - Fixed knee flexion deformity in children is a common problem in various diseases including myelomeningocele and cerebral palsy. Until now, only a few studies focusing on the surgical procedure of anterior distal femoral hemiepiphysiodesis have been published. We analyzed outcome and correction rate in the largest case series to date of patients treated by staples or 8-plates. Patients and methods - We reviewed the medical records of all patients with fixed knee flexion deformity who were treated with anterior distal femoral hemiepiphysiodesis using either staples or 8-plates between the years 2002 and 2017 (73 patients; 130 knees). 49 patients (83 knees) had completed treatment with implant removal at the time of full correction of the deformity or at skeletal maturity and were included. The average age at operation was 12 years (6-20). Patients were assigned to 3 different groups based on their diagnosis: cerebral palsy, myelomeningocele, and the "other" group.d Results - Mean fixed knee flexion deformity improved from 21° (10-60°) to 8° (0-50°) (p < 0.001) with an average correction rate of 0.44° per month (range -2.14° to 1.74°). The correction rate per month was lowest for patients with cerebral palsy (0.20°), followed by the myelomeningocele group (0.50°), and the "other" group (0.58°). Implant loosening occurred in 10% of the treated knees with consecutive re-implantation in 5% of the cases. Interpretation - Anterior distal femoral hemiepiphysiodesis is an effective and safe method for the treatment of fixed knee flexion deformity in children. The optimal timing depends on the remaining individual growth potential, the underlying disease, and the extent of the deformity.

Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I.

Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.

Rebound of ankle valgus deformity in patients with hereditary multiple exostosis.

BACKGROUND: Temporary screw epiphysiodesis of the distal tibia is employed to correct ankle valgus deformity in patients with a wide spectrum of underlying etiologies. For patients with hereditary multiple exostosis it is unclear whether a rebound phenomenon may play a role after screw removal (SR) and successful management of ankle valgus deformity. METHODS: From January 2002 to July 2013, 10 boys and 2 girls with HME and an ankle valgus deformity were included in this study. To be included the following criteria had to be met: patients had to have undergone temporary medial malleolar screw epiphysiodesis, SR at the time of skeletal maturity or correction of the deformity, a follow-up (FU) at least 6 months after SR, and consistent radiographs obtained preoperatively at the time of SR as well at FU. The average age at the time of operation was 11.6±1.5 years (range, 9.6 to 14.7 y). The tibiotalar tilt (TT) was analyzed preoperatively, at SR and at FU. RESULTS: The average preoperative TT was 13.2±4.9 degrees. Twenty-four months (±10) after epiphysiodesis all screws were removed. At SR, the TT was normalized to 0.8±4.8 degrees (P<0.001), according to an average rate of correction of 0.63±0.28 degrees per month. Twenty-two months (±13) after SR, the TT increased up to 3.2±4.9 degrees (P<0.05), a rebound (>5 degrees) occurred in 43%, managed by repeated epiphysiodesis. No deep infections or implant complications occurred. No permanent damage of the physis was observed in any case. CONCLUSIONS: Medial malleolar screw epiphysiodesis is a successful treatment for the correction of ankle valgus deformity in patients with HME. A rebound after SR in the growing child or adolescent occurs in almost 50% of patients with HME, which can easily be managed by repeated epiphysiodesis. Therefore, we do not recommend overcorrection into a slight varus deformity. Because of the varying correction and recurrence rates, close FUs are of paramount importance. LEVEL OF EVIDENCE: Level IV.

Growth modulation with a medial malleolar screw for ankle valgus deformity. 79 children with 125 affected ankles followed until correction or physeal closure.

BACKGROUND AND PURPOSE: Growth modulation with a medial malleolar screw is used to correct ankle valgus deformity in children with a wide spectrum of underlying etiologies. It is unclear whether the etiology of the deformity affects the angular correction rate with this procedure. PATIENTS AND METHODS: 79 children (20 girls) with ankle valgus deformity had growth modulation by a medial malleolar screw (125 ankles). To be included, patients had to have undergone screw removal at the time of skeletal maturity or deformity correction, or a minimum follow-up of 18 months, and consistent radiographs preoperatively and at the time of screw removal and/or follow-up. The patients were assigned to 1 of 7 groups according to their underlying diagnoses. The lateral distal tibial angle (LDTA) was analyzed preoperatively, at screw removal, and at follow-up. RESULTS: Mean age at operation was 11.7 (7.4-16.5) years. The average lateral distal tibial angle normalized from 80° (67-85) preoperatively to 89° (73-97) at screw removal. The screws were removed after an average time of 18 (6-46) months, according to an average rate of correction of 0.65° (0.1-2.2) per month. No significant differences in the correction rate per month were found between the groups (p = 0.3). INTERPRETATION: Growth modulation with a medial malleolar screw is effective for the treatment of ankle valgus deformity in patients with a wide spectrum of underlying diagnoses. The individual etiology of the ankle valgus does not appear to affect the correction rate after growth modulation. Thus, the optimal timing of growth modulation mainly depends on the remaining individual growth and on the extent of the deformity.

Temporary epiphyseodesis for limb-length discrepancy. 8- to 15-year follow-up of 34 children.

BACKGROUND AND PURPOSE: For the treatment of leg-length discrepancies (LLDs) of between 2 and 5 cm in adolescent patients, several epiphyseodesis options exist and various complications have been reported. We reviewed the 8- to 15-year outcome after temporary epiphyseodesis in patients with LLD. PATIENTS AND METHODS: 34 children with LLD of up to 5 cm were included in the study. Mean age at epiphyseodesis was 12.8 (10-16) years. Temporary epiphyseodesis was performed with Blount staples or 8-plates. The LLD was reviewed preoperatively, at the time of implant removal, and at follow-up. Every child had reached skeletal maturity at follow-up. Long-standing anteroposterior radiographs were analyzed with respect to the mechanical axis and remaining LLD at the time of follow-up. Possible complications were noted. RESULTS: The mean LLD changed from 2.3 (0.9-4.5) cm to 0.8 (-1.0 to 2.6) cm at follow-up (p<0.001). 21 patients had a final LLD of <1 cm, and 10 had LLD of <0.5 cm. At the time of follow-up, in 32 patients the mechanical axis crossed within Steven's zone 1. No deep infections or neurovascular lesions were seen. 4 implant failures occurred, which were managed by revision. INTERPRETATION: Temporary epiphyseodesis is an effective and safe option for the treatment of LLD. The timing of the procedure has to be chosen according to the remaining growth, facilitating a full correction of the LLD. If inaccurate placement of staples is avoided, substantial differences between the mechanical axes of both legs at skeletal maturity are rare.

Real-world evidence in achondroplasia: considerations for a standardized data set.

BACKGROUND: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. METHODS: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. RESULTS: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. CONCLUSIONS: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis-A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients.

Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. This retrospective study includes ML patients who underwent anaesthesia in two centres between 2008 and 2022. We reviewed patients' demographics, medical history, disease manifestations, as well as procedure- and outcome-related data. A total of 12 patients (7 MLII, 2 ML intermediate, 3 MLIII) underwent 44 anaesthesia procedures (per patient: median 3, range 1-11). The median age was 3.3 years (range 0.1-19.1). At least one complication occurred in 27.3% of the anaesthesia procedures. The vast majority of complications (94%) occurred in children with MLII and ML intermediate. A predicted difficult airway was found in 100% and 80% of the MLII and ML intermediate patients, respectively. Accordingly, most complications (59%) occurred during the induction of anaesthesia. Altogether, respiratory complications were the most frequent (18%), followed by difficult airway management (14%). The risk for anaesthesia-related complications is alarmingly high in patients with ML, particularly in those with MLII and ML intermediate. Multidisciplinary risk-benefit analysis and thoughtful anaesthesia planning are crucial in these patients.

Cellular localisation of antitumoral 6-alkyl thymoquinones revealed by an alkyne-azide click reaction and the streptavidin-biotin system.

The subcellular distribution and accumulation of thymoquinone 1, a natural anticancer agent, has hitherto been unknown. We prepared 6-(dec-9-ynyl)thymoquinone 3, an alkyne-labelled derivative with anticancer activity similar to that of its parent compound 1. Alkyne 3 was seen, after a Huisgen-type click reaction with 3-azido-7-hydroxycoumarin, to accumulate in distinct compartments of the nuclei of PtK(2) potoroo kidney cells, and in adjoining regions that were stained with an antibody specific for the Golgi apparatus. In contrast, a biotinlabelled thymoquinone 4 seemed to accumulate across the entire cell nucleus upon visualisation with streptavidin; but this was less easily traceable because of co-staining of other structures such as mitochondria. In conclusion, for small drug-like molecules, visualisation by alkyne-azide cycloaddition seems to be superior to conventional visualisation by the biotin-streptavidin system.

Synthesis, anticancer activity, and iron affinity of the Actinoplanes metabolite 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione.

The first synthesis of 7,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione (1), an isofuranonaphthoquinone produced by an Actinoplanes strain is described. Lactone ring opening of 6-methylfuro[3,4-c]furan-1(3H)-one (4) with ortho-lithiated veratrole (3), oxidation of product alcohol 5, and Friedel-Crafts acylation of the resulting aroylcarboxylic acid 7 afforded the mono methyl ether 2 of the target compound. The latter was obtained by demethylation of 2 with BBr(3) in 14% overall yield. While mono ether 2 was distinctly more cytotoxic than catechol 1 against a panel of five cancer cell lines, only the latter showed a siderophore-like binding affinity for Fe(III) with a complex dissociation constant K(D) of approximately 10(-29) M(3) (pM = 25.9).

Disease Manifestations in Mucopolysaccharidoses and Their Impact on Anaesthesia-Related Complications-A Retrospective Analysis of 99 Patients.

Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and adults with MPS undergoing anaesthesia from 2002 until 2018. We retrieved the patients' demographics, medical history, clinical manifestations, and indication by each anaesthesia. Multivariable mixed-effects logistic regression was calculated for a clinical model based on preoperative predictors preselected by lasso regression and another model based on disease subtypes only. Of the 484 anaesthesia cases in 99 patients, 22.7% experienced at least one adverse event. The clinical model resulted in a better forecast performance than the subtype-model (AICc 460.4 vs. 467.7). The most relevant predictors were hepatosplenomegaly (OR 3.10, CI 1.54-6.26), immobility (OR 3.80, CI 0.98-14.73), and planned major surgery (OR 6.64, CI 2.25-19.55), while disease-specific therapies, i.e., haematopoietic stem cell transplantation (OR 0.45, CI 0.20-1.03), produced a protective effect. Anaesthetic complications can best be predicted by surrogates for advanced disease stages and protective therapeutic factors. Further model validation in different cohorts is needed.

Hip pathologies in mucopolysaccharidosis type III.

BACKGROUND: Mucopolysaccharidosis type III (MPS III) comprises a group of rare lysosomal storage diseases. Although musculoskeletal symptoms are less pronounced than in other MPS subtypes, pathologies of hip and spine have been reported in MPS III patients. The purpose of this study was to describe hip pathologies and influencing parameters in MPS III patients. METHODS: A retrospective chart review was performed for 101 MPS III patients. Thirty-two patients met the inclusion criteria of enzymatically or genetically confirmed diagnosis and anteroposterior radiograph of the hips. Modified Ficat classification, Wiberg's center-edge angle, and Reimer's migration percentage were measured. RESULTS: The mean age at data assessment was 11.0 years (SD 5.7). Osteonecrosis of the femoral head was observed in 17/32 patients. No statistically significant association was found between these changes and age, sex, or MPS III subtype. Patients with a severe phenotype showed significantly higher rates of osteonecrosis (14/17) than patients with an intermediate phenotype. Hip dysplasia was present in 9/32 patients and was significantly associated with osteonecrosis of the femoral head (p = 0.04). CONCLUSIONS: The present study demonstrates a high rate of hip pathologies in MPS III patients. Hip dysplasia and severe phenotype were significantly correlated with osteonecrosis of the femoral head. Therefore, radiographs of the hips are highly recommended in baseline and follow-up assessments of MPS III patients. TRIAL REGISTRATION: Retrospectively registered.

Is hematopoietic stem cell transplantation a therapeutic option for mucolipidosis type II?

BACKGROUND: Mucolipidosis type II (MLII) is an ultra-rare lysosomal storage disorder caused by defective lysosomal enzyme trafficking. Clinical hallmarks are craniofacial dysmorphia, cardiorespiratory dysfunction, hepatosplenomegaly, skeletal deformities and neurocognitive retardation. Death usually occurs in the first decade of life and no cure exists. Hematopoietic stem cell transplantation (HSCT) has been performed in few MLII patients, but comprehensive follow-up data are extremely scarce. METHODS: MLII diagnosis was confirmed in a female three-month-old patient with the mutations c.2213C > A and c.2220_2221dup in the GNPTAB gene. At nine months of age, the patient received HSCT from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor. RESULTS: HSCT resulted in a sustained reduction of lysosomal storage und bone metabolism markers. At six years of age, the patient showed normal cardiac function, partial respiratory insufficiency and moderate hepatomegaly, whereas skeletal manifestations had progressed. However, the patient could walk and maintained an overall good quality of life. Neurocognitive testing revealed a developmental quotient of 36%. The patient died at 6.6 years of age following a human metapneumovirus (hMPV) pneumonia. CONCLUSIONS: The exact benefit remains unclear as current literature vastly lacks comparable data on MLII natural history patients. In order to evaluate experimental therapies, in-depth prospective studies and registries of untreated MLII patients are indispensable.

Total synthesis and anticancer activities of (-)- and (+)-thespesone.

The natural p-naphthoquinone (-)-thespesone 1 and its (+)-enantiomer were synthesized for the first time by bisacylation of a 5-lithiodihydrobenzofuran 2' with 4-methyl-3-tert-butoxycyclobut-3-ene-1,2-dione 3. The racemate of the required 2-arylpropan-1-ol precursor 10 was kinetically resolved by an enzyme-catalyzed acetylation exclusively of the (S)-enantiomer. Saponification of this acetate mediated by the same enzyme, porcine pancreas lipase (PPL), afforded the (S)-2-arylpropan-1-ol in 96% ee. Its unreacted (R)-enantiomer could be obtained with 77% ee. (-)-(S)-thespesone was far more efficacious against a panel of six cancer cell lines including multiresistant ones than its (+)-enantiomer and also when compared to thymoquinone, an established natural antitumoral p-quinone from Nigella sativa. Unlike the latter, (-)-thespesone was well tolerated by nonmalignant fibroblasts.

Terpene conjugates of the Nigella sativa seed-oil constituent thymoquinone with enhanced efficacy in cancer cells.

Thymoquinone (TQ; 1) is a weak anticancer constituent of black seed oil. Derivatives bearing terpene-terminated 6-alkyl residues were tested in cells of human HL-60 leukemia, 518A2 melanoma, multidrug-resistant KB-V1/Vbl cervix, and MCF-7/Topo breast carcinomas, as well as in non-malignant human foreskin fibroblasts. Derivatives with a short four-atom spacer between quinone and cyclic monoterpene moieties were more antiproliferative than analogues with longer spacers. 6-(Menthoxybutyryl)thymoquinone (3a) exhibited single-digit micromolar IC(50) (72 h) values in all four cell lines. It was seven times more active than TQ (1) in 518A2 melanoma cells and four times in KB-V1/Vbl cervix carcinoma cells, while only half as toxic in the fibroblasts. Compound 3a was also not a substrate for the P-gp and BCRP drug transporters of the resistant cancer cells. The caryophyllyl and germacryl conjugates 3e and 3f specifically inhibited the growth of the resistant MCF-7 breast carcinoma cells. Conjugation of TQ with the triterpene betulinic acid via the OH group as in 3g led to a loss in activity, while conjugation via the carboxylic acid afforded compound 4 with nanomolar IC(50) (72 h) activity against HL-60 cells. All anticancer-active derivatives of TQ (1) induced apoptosis associated with DNA laddering, a decrease in mitochondrial membrane potential and a slight increase in reactive oxygen species.

Does eight-plate epiphysiodesis of the proximal tibia in treating angular deformity create intra-articular deformity?

AIMS: Eight-plates are used to correct varus-valgus deformity (VVD) or limb-length discrepancy (LLD) in children and adolescents. It was reported that these implants might create a bony deformity within the knee joint by change of the roof angle (RA) after epiphysiodesis of the proximal tibia following a radiological assessment limited to anteroposterior (AP) radiographs. The aim of this study was to analyze the RA, complemented with lateral knee radiographs, with focus on the tibial slope (TS) and the degree of deformity correction. METHODS: A retrospective, single-centre study was conducted. The treatment group (n = 64 knees in 44 patients) was subclassified according to the implant location in two groups: 1) medial hemiepiphysiodesis; and 2) lateral hemiepiphysiodesis. A third control group consisted of 25 untreated knees. The limb axes and RA were measured on long standing AP leg radiographs. Lateral radiographs of 40 knees were available for TS analysis. The mean age of the patients was 10.6 years (4 to 15) in the treatment group and 8.4 years (4 to 14) in the control group. Implants were removed after a mean 1.2 years (0.5 to 3). RESULTS: No significant differences in RA (p = 0.174) and TS (p = 0.787) were observed. The limb axes were significantly corrected in patients with VVD (p < 0.001). The change in tibial slope (∆TS) did not correlate (r = -0.026; p = 0.885) to the plate's position on the physis when assessed by lateral radiographs. CONCLUSION: We were not able to confirm the reported change in the bony morphology of the proximal tibia on AP radiographs in our patient population. In addition, no significant change in TS was detected on the lateral radiographs. A significant correction of the VVD in the lower limb axes was evident. Position of the implant did not correlate with TS change. Therefore, eight-plate epiphysiodesis is a safe and effective procedure for correcting VVD in children without disturbing the knee joint morphology. Cite this article: Bone Joint J 2020;102-B(10):1412-1418.