Articular cartilage is a highly specialized tissue whose remarkable properties of deformability, resistance to mechanical loading, and low-friction gliding are essential to joint function. Due to its ...role as a cushion in bone articulation, articular cartilage is subject to many types of damaging insults, including decades of wear and tear, and acute joint injuries. However, this built-for-life tissue has a very poor intrinsic ability in adulthood to durably heal defects created by damaging insults. Consequently, articular cartilage progressively deteriorates and is eventually eroded, exposing the subchondral bone to the joint space, triggering inflammation and osteophyte development, and generating severe pain and joint incapacitation. The disease is called osteoarthritis (OA) and is today the leading cause of pain and disability in the human population. Researchers and clinicians have worked for decades to develop strategies to treat OA and restore joint function, but they are still far from being able to offer patients effective preventive or restorative treatments. Novel ideas, knowledge and technologies that nurture hope for major new breakthroughs are therefore sought. In this review, we first outline the composition, structure, and functional properties of normal human adult articular cartilage, as a reference for tissue conservation and regenerative strategies. We then describe current options that have been used clinically and in pre-clinical trials to treat osteoarthritic patients, and we discuss the benefits and inadequacies of these treatment options. Next, we review research efforts that are currently ongoing to try and achieve durable repair of functional cartilage tissue. Methods include engineering of tissue implants and we discuss the needs and options for tissue scaffolds, cell sources, and growth and differentiation factors to generate de novo or repair bona fide articular cartilage.
Cherubism: best clinical practice Papadaki, Maria E; Lietman, Steven A; Levine, Michael A ...
Orphanet journal of rare diseases,
05/2012, Letnik:
7 Suppl 1, Številka:
S1
Journal Article
Recenzirano
Odprti dostop
Cherubism is a skeletal dysplasia characterized by bilateral and symmetric fibro-osseous lesions limited to the mandible and maxilla. In most patients, cherubism is due to dominant mutations in the ...SH3BP2 gene on chromosome 4p16.3. Affected children appear normal at birth. Swelling of the jaws usually appears between 2 and 7 years of age, after which, lesions proliferate and increase in size until puberty. The lesions subsequently begin to regress, fill with bone and remodel until age 30, when they are frequently not detectable.Fibro-osseous lesions, including those in cherubism have been classified as quiescent, non-aggressive and aggressive on the basis of clinical behavior and radiographic findings. Quiescent cherubic lesions are usually seen in older patients and do not demonstrate progressive growth. Non-aggressive lesions are most frequently present in teenagers. Lesions in the aggressive form of cherubism occur in young children and are large, rapidly growing and may cause tooth displacement, root resorption, thinning and perforation of cortical bone.Because cherubism is usually self-limiting, operative treatment may not be necessary. Longitudinal observation and follow-up is the initial management in most cases. Surgical intervention with curettage, contouring or resection may be indicated for functional or aesthetic reasons. Surgical procedures are usually performed when the disease becomes quiescent. Aggressive lesions that cause severe functional problems such as airway obstruction justify early surgical intervention.
Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause ...severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.
Articular cartilage repair techniques are challenging. Human embryonic stem cells and induced pluripotent stem cells (iPSCs) theoretically provide an unlimited number of specialized cells which could ...be used in articular cartilage repair. However thus far chondrocytes from iPSCs have been created primarily by viral transfection and with the use of cocultured feeder cells. In addition chondrocytes derived from iPSCs have usually been formed in condensed cell bodies (resembling embryoid bodies) that then require dissolution with consequent substantial loss of cell viability and phenotype. All of these current techniques used to derive chondrocytes from iPSCs are problematic but solutions to these problems are on the horizon. These solutions will make iPSCs a viable alternative for articular cartilage repair in the near future.
BACKGROUND:Previous studies have demonstrated the influence of heritable factors on the development of nontraumatic osteonecrosis of the femoral head (ONFH). We hypothesized that genetic variation is ...associated with an increased risk of ONFH, and that variants could be identified by a genomewide association study (GWAS).
METHODS:Using data collected from the MyCode Community Health Initiative, we identified 118 adult patients with radiographically confirmed nontraumatic ONFH. Study patients were statistically compared with a control population of 56,811 unrelated individuals without a diagnosis of ONFH. A case-control GWAS was performed to identify single nucleotide variants (SNVs) associated with ONFH. Sensitivity analyses were performed to evaluate the association of the top SNVs with (cortico)steroid-associated ONFH and ONFH with femoral head collapse. Gene-based analyses were performed to identify potential causal genes.
RESULTS:Of the 118 patients, 114 (96.6%) had bilateral ONFH at a median of 5 years of follow-up; 90.7% had at least one 3-week steroid prescription compared with 68.3% in controls. A GWAS identified 4 SNVs reaching genomewide significance. rs116468452 near CACNA1E was significantly associated with ONFH (p = 3.26 × 10, odds ratio OR = 5.6, 95% confidence interval CI = 3.21 to 9.76). rs10953090 in SAMD9 was significantly associated with ONFH in the steroid-exposed subset (p = 2.96 × 10, OR = 2.57, 95% CI = 1.84 to 3.58). rs112467115 in PI4K1B showed enhanced association in the collapsed subset (p = 7.82 × 10, OR = 4.5, 95% CI = 2.60 to 7.79). Gene-based analyses identified PPARGC1B as the only gene significantly associated with ONFH after Bonferroni correction (p = 1 × 10), with the lead SNV being rs78814834 (OR = 2.86, 95% CI = 1.87 to 4.38).
CONCLUSIONS:We identified 4 SNVs and 1 gene, PPARGC1B, associated with ONFH.
LEVEL OF EVIDENCE:Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
In this review, we define hypercalcemia levels, common causes for hypercalcemia in children, and treatment in order to aid the practicing pediatrician.
One rare cause of hypercalcemia in the child is ...familial hypocalciuric hypercalcemia (also termed familial benign hypercalcemia). Mutations that inactivate the Ca-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous.
Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However, the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due to osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are, therefore, effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.
Though bulk stool remains the gold standard specimen type for enteropathogen diagnosis, rectal swabs may offer comparable sensitivity with greater ease of collection for select pathogens. This study ...sought to evaluate the validity and reproducibility of rectal swabs as a sample collection method for the molecular diagnosis of
Paired rectal swab and bulk stool samples were collected from 86 children ages 0-4 years living in southwest Niger, with duplicate samples collected among a subset of 50 children. Infection was detected using a previously validated real-time PCR diagnostic targeting the small subunit ribosomal RNA gene.
was detected in 65.5% (55/84) of bulk stool samples and 44.0% (37/84) of swab samples. The kappa evaluating test agreement was 0.81 (95% CI: 0.54-1.00) among duplicate stool samples (
= 49) and 0.75 (95% CI: 0.47-1.00) among duplicate rectal swabs (
= 48). Diagnostic sensitivity was 93% (95% CI: 84-98) by bulk stool and 63% (95% CI: 49-75) by rectal swabs. When restricting to the lowest three quartiles of bulk stool quantitation cycle values (an indication of relatively high parasite load), sensitivity by rectal swabs increased to 78.0% (95% CI: 64-89,
< 0.0001). These findings suggest that rectal swabs provide less sensitive and reproducible results than bulk stool for the real-time PCR diagnosis of
However, their fair sensitivity for higher parasite loads suggests that swabs may be a useful tool for detecting higher burden infections when stool collection is excessively expensive or logistically challenging.
Patients with soft-tissue sarcomas generally present with a mass that is increasing in size; the presence or absence of pain
is not typically predictive of malignancy. While magnetic resonance ...imaging (MRI) can identify a few soft-tissue lesion types
as benign, diagnosis of most lesions requires a careful biopsy, preferably performed by or in consultation with the surgeon
who would do an eventual resection. If biopsy confirms a diagnosis of sarcoma, MRI-guided surgical resection with a wide margin
is the mainstay of treatment. Neoadjuvant radiation therapy and chemotherapy have not been of proven benefit in well-controlled
studies but are frequently used as adjuncts. Resections with wide margins are generally associated with a low (< 10%) risk
of recurrence.
To describe the process of preimplantation genetic diagnosis (PGD), which allows the selection of embryos without mutations for implantation, with specific application for mutations in GNAS.
We ...identified a GNAS mutation in a patient with a severe form of Albright hereditary osteodystrophy and pseudohypoparathyroidism type 1a with phocomelia and performed PGD on embryos derived by in vitro fertilization in order to deliver an unaffected infant.
After in vitro fertilization, embryos that were homozygous normal for GNAS were identified and implanted into the mother. Ultrasonography 34 days after embryo transfer showed a viable singleton intrauterine pregnancy. A normal-appearing male infant was born at 36.5 weeks of gestation. Newborn screening revealed normal results of thyroid function tests, and a buccal swab obtained when the child was 1 year old verified normal GNAS gene sequences.
PGD is an alternative that can be offered for many genetic diseases and represents a method to decrease and potentially eliminate the transmission of severe genetic diseases. Patients with multiple endocrine neoplasia (MEN) type 2 with known RET gene mutations as well as those with other heritable disorders are candidates for PGD. Successful PGD in patients with MEN has not yet been reported and has met with some early difficulties, but it is believed that this technique will eventually be successful for MEN and other hereditary endocrine disorders.
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