Acetabular rim extension using a personalized titanium implant for treatment of hip dysplasia in dogs: short-term results

Hip dysplasia (HD) is a common orthopedic problem in young dogs. To decrease the laxity of the hip joint related to HD, the surgical treatments are recommended to increase femoral head coverage. ACEtabular rim eXtension (ACE-X) using a personalized 3-dimensional printed titanium shelf implant is a new surgical treatment to increase femoral head coverage and decrease laxity of the dysplastic hip joint, however, the efficacy is less know. Client-owned dogs older than 6 months with clinical signs of coxofemoral joint subluxation and radiographic evidence of HD with no or mild osteoarthritis (OA) were included. The Norberg angle (NA), linear percentage of femoral head overlap (LFO), and percentage of femoral head coverage (PC) were investigated radiographically and with computed tomography (CT) before and after surgery. OA was graded (scores 0–3) according to the maximum osteophyte size measured on CT. In addition, joint laxity (Ortolani) test results, gait analysis, and the Helsinki chronic pain index (HCPI) questionnaire were obtained at preoperative, immediately postoperative and at 1.5- and 3-month evaluations. Acetabular rim extension was performed in 61 hips of 34 dogs; NA, LFO, and PC were significantly higher immediately postoperatively and at the 1.5- and 3-month follow-up examinations compared with preoperative values (p < 0.05). Osteophyte size gradually increased over time (p < 0.05). The OA score significantly increased between preoperatively and directly postoperatively, and between preoperatively and at 3-month follow-up (p < 0.05). The laxity test normalized in 59 out of 61 hips after surgery, and the HCPI questionnaire showed that the pain score decreased significantly at 1.5 and 3 months, postoperatively. The force plate showed no significant improvement during the 3 months follow-up. Although pain reduction by the implant was unclear in short-term results, a personalized shelf implant significantly increased femoral head coverage and eliminated subluxation of the dysplastic hip joint. Further studies are required to study the long-term efficacy of gait, chronic pain, and progression of osteoarthritis

Emerging organoid-immune co-culture models for cancer research: from oncoimmunology to personalized immunotherapies

In the past decade, treatments targeting the immune system have revolutionized the cancer treatment field. Therapies such as immune checkpoint inhibitors have been approved as first-line treatment in a variety of solid tumors such as melanoma and non-small cell lung cancer while other therapies, for instance, chimeric antigen receptor (CAR) lymphocyte transfer therapies, are still in development. Although promising results are obtained in a small subset of patients, overall clinical efficacy of most immunotherapeutics is limited due to intertumoral heterogeneity and therapy resistance. Therefore, prediction of patient-specific responses would be of great value for efficient use of costly immunotherapeutic drugs as well as better outcomes. Because many immunotherapeutics operate by enhancing the interaction and/or recognition of malignant target cells by T cells, in vitro cultures using the combination of these cells derived from the same patient hold great promise to predict drug efficacy in a personalized fashion. The use of two-dimensional cancer cell lines for such cultures is unreliable due to altered phenotypical behavior of cells when compared with the in vivo situation. Three-dimensional tumor-derived organoids, better mimic in vivo tissue and are deemed a more realistic approach to study the complex tumor-immune interactions. In this review, we present an overview of the development of patient-specific tumor organoid-immune co-culture models to study the tumor-specific immune interactions and their possible therapeutic infringement. We also discuss applications of these models which advance personalized therapy efficacy and understanding the tumor microenvironment such as: (1) Screening for efficacy of immune checkpoint inhibition and CAR therapy screening in a personalized manner. (2) Generation of tumor reactive lymphocytes for adoptive cell transfer therapies. (3) Studying tumor-immune interactions to detect cell-specific roles in tumor progression and remission. Overall, these onco-immune co-cultures might hold a promising future toward developing patient-specific therapeutic approaches as well as increase our understanding of tumor-immune interactions

Berardinelli-Seip syndrome and achalasia: a shared pathomechanism?

International audienceBerardinelli-Seip congenital lipodystrophy (BSCL) is an uncommon autosomal recessive disorder. Patients with BSCL present with a distinct phenotype since subcutaneous fat is largely lacking and musculature has become more prominent. During childhood, diabetes and acanthosis nigricans evolve and female patients may develop hirsutism. Different genes encoding this entity have been described. Achalasia is a rare esophageal motility disorder, characterized by its distinct motility pattern with absent or incomplete lower esophageal sphincter (LES) relaxations. The exact cause of achalasia is yet unknown. Here, we describe a patient with achalasia in the context of BSCL, which might be linked by a shared pathophysiologic background, as evaluated in this case report. CONCLUSION: In a BSCL patient presenting with gastrointestinal symptoms, a motility disorder of the gastrointestinal tract should be considered. WHAT IS KNOWN: • Berardinelli-Seip congenital lipodystrophy (BSCL) and achalasia are both disorders characterized by low prevalence. What is New: • Co-existence of both diseases is described in this report. Linkage by a potential common pathophysiologic background is discussed in this paper

Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode

International audienceLoss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2 −/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2 −/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2 −/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2 −/− BAT properties. Finally, Bscl2 −/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals. Berardinelli and Seip congenital lipodystrophy (BSCL) is a rare autosomal genetic disease characterized by an almost complete lack of white adipose tissue (WAT) 1,2. BSCL is associated with metabolic disturbances, including insulin resistance, hypertriglyceridaemia, and liver steatosis. The most severe form of BSCL is caused by bi-allelic mutations in BSCL2, which encodes seipin, an endoplasmic reticulum (ER) protein of unknown function 3. Seipin deficiency strongly impairs adipocyte differentiation in vitro 4,5. In yeast and in cultured human cells, seipin deficiency alters lipid droplet (LD) morphology, with either a few giant or multiple small LDs 6–9. Recently, seipin was reported to be essential for the initiation of LD formation in yeast 10. In accordance with a potential role in triglyc-eride (TG) synthesis pathway, seipin was shown to interact with 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and lipin 1 11,12. Finally, seipin has been shown to promote TG storage through an interaction with the calcium pump SERCA2 in drosophila 13. Nevertheless, the precise biological role of seipin and the exact pathways in which it is implicated remain unclear. A major breakthrough in the understanding of the pathophysiology of BSCL2 came with the generation of global knockout (KO) mice for Bscl2. Bscl2 −/− mice display severe lipodystrophy, with at least a 90% decrease in WAT mass and the development of insulin resistance and hepatic steatosis, thus recapitulating the main features of the human BSCL phenotype 14–16. Adipose-specific Bscl2 −/− mice exhibit progressive lipodystrophy associated with similar metabolic complications 17 , whereas the transgenic overexpression of Bscl2 in WAT from Bscl2 −/− mice is sufficient to rescue the phenotype 18. Finally, thiazolidinedione (TZD) treatment in global or adipose-specific Bscl2 KO mice promotes an increase in WAT mass, leading to an improvement of the metabolic

Deformable titanium for acetabular revision surgery: a proof of concept

Abstract Custom-made triflange acetabular implants are increasingly used in complex revision surgery where supporting bone stock is diminished. In most cases these triflange cups induce stress-shielding. A new concept for the triflange is introduced that uses deformable porous titanium to redirect forces from the acetabular rim to the bone stock behind the implant and thereby reduces further stress-shielding. This concept is tested for deformability and primary stability. Three different designs of highly porous titanium cylinders were tested under compression to determine their mechanical properties. The most promising design was used to design five acetabular implants either by incorporating a deformable layer at the back of the implant or by adding a separate generic deformable mesh behind the implant. All implants were inserted into sawbones with acetabular defects followed by a cyclic compression test of 1800N for 1000 cycles. The design with a cell size of 4 mm and 0.2 mm strut thickness performed the best and was applied for the design of the acetabular implants. An immediate primary fixation was realized in all three implants with an incorporated deformable layer. One of the two implants with a separate deformable mesh needed fixation with screws. Cyclic tests revealed an average additional implant subsidence of 0.25 mm that occurred in the first 1000 cycles with minimal further subsidence thereafter. It is possible to realize primary implant fixation and stability in simulated large acetabular revision surgery using a deformable titanium layer behind the cup. Additional research is needed for further implementation of such implants in the clinic

Correction to: Berardinelli-Seip syndrome and achalasia: a shared pathomechanism? (European Journal of Pediatrics, (2015), 174, 7, (975-980), 10.1007/s00431-015-2556-y)

Although the patient has provided consent for publication of this case report and accompanying images, after publication of this article it has come to the authors' attention that Fig. 1 needs changes to better protect the privacy of the patient. A modified Fig. 1 is included in this Erratum. The original Fig. 1 has been removed to protect the patient's privacy

Você conhece esta síndrome? Do you know this syndrome?

A lipodistrofia generalizada congênita (síndrome de Berardinelli-Seip), doença autossômica recessiva, caracteriza-se por escassez do tecido subcutâneo. A falta de tecido adiposo propicia disfunção metabólica dos lípides e carboidratos, resistência periférica à insulina, hipertrigliceridemia e hipermetabolismo. Outros achados são acantose nigricante, acromegalia, hepatomegalia e alterações musculares, ósseas, cardiovasculares e neurológicas. Relata-se o caso de paciente com essa síndrome, cujo diagnóstico foi realizado em um serviço de dermatologia.<br>Congenital generalized lipodystrophy (Berardinelli-Seip syndrome) is a recessive autossomic disease characterized by absence of subcutaneous tissue. The fat tissue absence leads to metabolic dysfunction of lipids and carbohydrates, peripheral insulin resistance and increased seric levels of triglycerides and also a higher metabolic rate. Other findings are acanthosis nigricans, acromegaly, hepatomegaly and muscular, bony, cardiovascular and neurological abnormalities. A case of a patient with this syndrome is reported, whose diagnosis was made in a dermatology ambulatory