Stem cells research prospects towards precision medicine.

The human body possesses an endogenous regeneration system based on stem cells, which may be found in practically every tissue type. They are classified as embryonic stem cells (ESCs) or nonembryonic stem cells (NESCs). Despite its enormous promise, the use of ESCs is presently limited because of ethical and scientific issues. Stem cells have the potential to improve healthcare by using and boosting the body's inherent regenerative capabilities. Although the stem cells offer an enormous promise for tissue regeneration and repair, much more about their biology, administration, and safety must be studied before they may be employed therapeutically. Stem cells and their derivatives will have enormous medical promise in the future. Current animal and laboratory investigations are looking into the viability of bringing stem cell therapy into clinical practice for regeneration in muscular dystrophy, intervertebral disc degeneration, cerebral infarctions, and transplantation medicine. This article delves into the many aspects at play, as well as current situation and possible issues with stem cell treatment in patient care and management (Fig. 1, Ref. 86). Keywords: stem cells, tissue engineering, regenerative medicine, stem cell application.

Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.

TNF plays an integral role in inflammatory bowel disease (IBD), as evidenced by the dramatic therapeutic responses in Crohn's disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we investigated the role of TNF signaling in Wnt/ß-catenin-mediated intestinal stem cell and progenitor cell expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, intestinal stem cell and progenitor cell Wnt/ß-catenin signaling correlates with inflammation status. TNF-deficient (Tnf-/-) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow (BM) chimera mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IECs. Wild-type→Tnfr1/2-/- BM chimera mice with chronic dextran sodium sulfate colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/ß-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/ß-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced ß-catenin activation in nontransformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together, these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/ß-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.

Periprosthetic subtrochanteric femoral fracture in a megaprosthesis of the knee.

We report a rare case of periprosthetic posttraumatic fracture of subtrochanteric region of femur after a megaprosthesis of the knee, done for resistant nonunion of distal femur with secondary osteoarthrosis in a 51 years old man. Treatment with a locking femoral plate was able to achieve primary union with a good result.

Single Nucleotide Polymorphisms in Cytokine Genes are Associated with the Susceptibility to Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common type of cancer among men in the Indian subcontinent. Cytokines regulate inflammation and angiogenesis in a variety of cancers. Genetic variability in the cytokine genes can potentially influence the predisposition to oral carcinogenesis. The aim of the current study was to investigate the associations of SNPs in cytokine genes with the susceptibility of oral squamous cell carcinoma. In the present study, we have analyzed the allelic frequency of 32 single nucleotide polymorphisms (SNPs) using MassArray-based iPLEX assay in 16 cytokine genes in 166 OSCC patients and 151 healthy subjects from central India. Out of 32 SNPs analyzed, five SNPs were significantly associated with the risk of OSCC. AA and GG genotypes of IL-1ß +3953 were associated with an increased and decreased risk of OSCC, respectively. In several genetic models, GG genotype and G allele in IL-12A 3'UTR G>A were found to be associated with an increased risk of OSCC. Similarly, the GG genotype of IL-12B +1188 T>G was associated with increased susceptibility to OSCC. We conclude that SNPs in the genes coding for IL-1ß, IL-12A and IL-12B are associated with increased genetic susceptibility to OSCC in the central Indian population.

Outcome of surgical treatment of type IV capitellum fractures in adults.

OBJECTIVE: Fractures of the capitellum and trochlea constitute less than 1% of all elbow fractures and a shear fracture involving the capitellum and extending medially into most of the trochlea is rarely reported. Type IV capitellum fracture is still controversial in regard to its radiographic appearance, surgical approach and osteosynthesis. We report 10 cases of type IV capitellum fracture with a view to elucidating its clinical features and treatment outcome. METHODS: We treated 10 patients of type IV capitellum fracture with a mean age of 32 years. A uniform surgical approach and postoperative rehabilitation were followed. RESULTS: Nine patients presented to us after a mean of 4 days of injury and one patient was nonunion after 6 months of injury who had been treated conservatively by a bone setter. Double arc sign was absent in 6 cases. Intraoperatively 6 capitellotrochlear fragments were devoid of soft tissue attachments. By Mayo Elbow Performance Score evaluation, 7 patients got excellent, 2 good and 1 fair results. One patient with associated elbow dislocation developed heterotopic ossification. There was no case of avascular necrosis, osteoarthrosis or fixation failures. CONCLUSIONS: Type IV capitellum fractures are rare and belong to complex articular injuries. A good functional outcome can only be achieved with open reduction and stable internal fixation followed by early mobilization. Preoperative radiographic assessment and computed tomography help surgeons in choosing the right surgical approach and implants. Good surgical technique and stable internal fixation are the keys to early mobilization and good functional outcome.

Prolonged asymptomatic venom induced consumption coagulopathy: Caused by hemotoxic snake bite.

Envenoming and deaths resulting from snake bite are a particularly important public health problem in the tropical world, with the highest burden in rural areas of South East Asia and Africa. Snake bite is one of the most severe "Neglected Tropical Diseases" in the world and more importantly in this part of India. We present a case of hemotoxic snake bite where the coagulation parameters remained deranged for a longer time without any active bleeding manifestations, despite treatment with Anti-Snake Venom (ASV) as per the National Treatment Guidelines. Indian Snake Bite Management Protocol emphasizes on the Role of Whole Blood Clotting Time (WBCT) as a bedside, accessible and feasible test for assessment of coagulopathy even in rural settings. Certain scenarios where the patients present late to our hospital with Snake Bite and Venom Induced Consumption Coagulopathy (VICC), the decision regarding ASV prescription in such patients is quite tricky, and needs to be individualized.

Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis.

BACKGROUND & AIMS: Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin(552)). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of beta-catenin during intestinal inflammation. METHODS: The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice named I-pik3r1KO. Acute inflammation was induced in mice and intestines were analyzed by biochemical and histologic methods. The effects of chemically blocking PI3K in colitic interleukin-10(-/-) mice were examined. Biopsy samples from patients were examined. RESULTS: Compared with wild-type, I-pik3r1KO mice had reduced T-cell-mediated Akt and beta-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K-Akt signaling increased nuclear total beta-catenin and P-beta-catenin(552) levels and reduced N-terminal beta-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10(-/-) mice impaired colitis-induced epithelial Akt and beta-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-beta-catenin(552) throughout expanded crypts and increased messenger RNA expression of beta-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples. CONCLUSIONS: PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation. PI3K-induced and Akt-mediated beta-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.

Treatment of resistant nonunion of supracondylar fractures femur by megaprosthesis.

PURPOSE: Resistant nonunion of distal femoral fractures in the elderly is a great challenge to treat because it is often associated with multiple problems like poor bone quality, arthritis, disuse osteopenia, joint contractures, and implant failure. We treated ten patients with megaprosthesis and report the outcome. METHODS: Ten elderly patients of resistant nonunion of distal femoral fractures with arthritis knee were treated with megaprosthesis. The median patient age was 74 years (68-85 years). All these patients had undergone at least two prior operative procedures and were operated by us, 24-33 months following the first index surgery. Modular Resection System was used in all the patients. RESULTS: Eight patients were available for follow-up. Median follow-up period was 4 years. Two patients required extended local wound care for wound skin necrosis. One patient sustained traumatic periprosthetic subtrochanteric fracture following a subsequent trauma. No thromboembolic complications were seen. All knees showed satisfactory alignment and range of motion. Postoperative, median knee society pain score, and knee society function score were 84 (80-88) and 88 (84-92) at last follow-up. CONCLUSION: Megaprosthesis can be offered as a one-stage salvage procedure for difficult nonunion in distal femoral fractures associated with bone loss, osteoporosis, and secondary knee arthritis.

Neglected reverse Essex-Lopresti injury with ulnar nerve compression.

A 45 year old woman was diagnosed as having anteromedial radial head dislocation and distal radius fracture five months after her injury on right forearm. The radial head dislocation led to ulnar nerve compression. She had severe restriction of her elbow movements. She was treated with arthrolysis, decompression of the ulnar nerve and radial head resection. The reverse Essex Lopresti injury and radial head dislocation compressing the ulnar nerve has not been reported in English language literature to the best of our knowledge. A mechanism is proposed for the injury. In acute presentations, restoration of both the radioulnar joints should be done and neglected nature of such injury leads to suboptimal outcomes.

Monteggia fracture dislocation equivalents--analysis of eighteen cases treated by open reduction and internal fixation.

OBJECTIVE: Monteggia fracture dislocation equivalent, though already described by Bado, is still an unclassified entity. We aimed to retrospectively analyze 18 cases of Monteggia variants and discuss the injury mechanisms, management, and outcome along with a review of the literature. METHODS: A retrospective record of Monteggia fracture dislocation (2003-2008) was reviewed from medical record department of our institute. Classic Monteggia fracture dislocation, children below 12 years or adults over 50 years, as well as open grade II and III cases were excluded from this study. Monteggia variant inclusion criteria included fracture of the proximal ulna together with a fracture of the radial head or neck and skeletal maturity. Totally 26 patients were identified with Monteggia variants and 18 were available for follow-up, including 11 males and 7 females with the mean age of 35 years. The ulna fracture was treated by compression plating along with tension band wiring. Radial head/neck was reconstructed in 12 patients while excised in 6 patients. RESULTS: Follow-up ranged from 1-4 years, mean 2.6 years. Patients were assessed clinicoradiologically. Mayo Elbow Performance Score was employed to assess the outcomes. At final follow-up, the results were excellent in 10 patients, good in 4, fair in 2 and poor in 2. Mean range of motion of the elbow was 20 degree 116 degree, 50 degree and 55 degree for extension, flexion, pronation and supination, respectively. Two patients had complications in the form of heterotopic ossification and stiffness of the elbow. One nonunion ulna, primarily treated by tension band wiring, was managed by refixation with locking reconstruction plate and bone grafting. Bone grafting was only required in this patient for nonunion. Another patient had implants removed on his request. The results in our series closely correlated with extent of intraarticular damage, coronoid fracture and comminuted fractures. CONCLUSIONS: Monteggia fracture dislocation equivalents are rare injuries and pre-surgery recognition by radiographs and 3-D CT helps make optimal plan. The poor results usually relate to intraarticular damage, coronoid fractures and comminution of the ulna and radial head fractures.

Nonunion of coronal shear fracture of femoral condyle.

Isolated coronal fractures of femoral condyle are rare in adults and nonunion of Hoffa fracture is reported only a few times in the literature. We analyzed six cases of nonunion of Hoffa fractures over a period of three years. Three patients were treated conservatively and three patients had fixation failures. Delay of presentation was 2 months to one year. Treatment protocol consisted of open reduction, excision of pseudoarthrosis, bone grafting and internal fixation along with knee arthrolysis. Union was achieved in all patients at mean 16 weeks. The treatment of nonunion of Hoffa fractures requires careful preoperative planning and meticulous surgical technique. The literature regarding the controversies in fracture management and surgical technique are reviewed.

Total hip replacement as primary treatment of unstable intertrochanteric fractures in elderly patients.

Fifty-three patients with A2.2 and A2.3 intertrochanteric fracture according to the Muller classification were treated with total hip replacement between April 2000 and February 2004. The average age of the patients was 77 years. Average follow-up period was 3.7 years. We studied postoperative complications, mortality rate, functional outcome using the Harris hip score, time to return to normal activities, and radiographic evidence of healing. Two patients died on the third and fifth postoperative days. Seven more patients died within one year. The Harris hip score at one month was 66 +/- 7 (mean +/- standard deviation); at three months 72 +/- 6; at one year 74 +/- 5; at three years 76 +/- 6 and in the 27 patients who completed five year follow-up it was 76 +/- 8. Mobilisation and weight-bearing was started immediately in the postoperative period. Average time taken to return to normal daily activities was 28 days (range 24-33). No loosening or infection of the implants was observed. Total hip arthroplasty is a valid treatment option for mobile and mentally healthy elderly patients with intertrochanteric fractures. This procedure offers quick recovery with little risk of mechanical failure, avoids the risks associated with internal fixation and enables the patient to maintain a good level of function immediately after surgery.

Fractures of capitellum: a review of 14 cases treated by open reduction and internal fixation with Herbert screws.

Fourteen patients with displaced fractures of the humeral capitellum were treated by open reduction and internal fixation of the capitellar fragments with Herbert screws. As per Bryan and Morrey classification, there were seven type I fractures, one type II fracture, three type III fractures, and three non-unions. Patient outcomes were evaluated using the Mayo elbow performance score. The follow-up period ranged from three to seven years (mean 4.8 years). All patients had a stable, pain-free elbow with good range of motion at follow-up. There was no evidence of avascular necrosis or degenerative change.

Autogenous non-vascularized fibula for treatment of giant cell tumor of distal end radius.

INTRODUCTION: Giant cell tumor of distal end of radius is treated by wide resection and intralesional procedures with former having better results. The various modalities for the defect created are vascularized/non-vascularized bone graft, osteoarticular allografts and custom-made prosthesis. We report outcome of wide resection and non-vascularized fibular grafting in biopsy-proven giant cell tumors. PATIENTS AND METHODS: Nine patients with mean age of 40 years with Campanacci grade II giant cell tumor of distal radius were managed with radical excision of the tumor and reconstruction with ipsilateral free fibular graft. RESULTS: Mean follow-up time was 56 months. One patient developed recurrence and was treated by amputation. All other patients showed a good union at fibular graft-radius junction. In wrist, average range of motion achieved at last follow-up was 40° of dorsiflexion, 30° of palmar flexion, 45° each of supination and pronation. Major complications encountered included graft fracture (2), wrist subluxation (2), tourniquet palsy (1), aseptic graft resorption (1) and tumor recurrence (1). CONCLUSION: Reconstruction after wide excision by non-vascularized fibular graft is a viable alternative for giant cell tumors of the lower end of radius though it is a challenging procedure and may be accompanied by major complications.

Spondyloptosis of C6-C7: a rare case report.

A 35 years old female presented to us after falling from a height. She complained of a neck pain and a complete quadriplegia and was diagnosed as having spondyloptosis of the C6-C7. Skeletal traction was performed on her. CT scan showed fractures of the C5, C6, and C7 vertebral body. The patient underwent anterior approach partial corpectomy with anterior cervical locking plate and strut grafting from ipsilateral iliac crest. Intraoperatively it was found that the disc was completely ruptured and there was a dural tear and cerebrospinal fluid leak. Her postoperative period was complicated by cerebrospinal fluid collection and posterior instrumentation was not performed due to the poor general condition. She had no neural recovery at the last follow-up. Spondyloptosis is a severe and highly unstable injury with a three column ligamentous disruption and may be complicated, as in our case, with a dural tear. Management of these cases is fraught with complications, and prognosis for neural recovery is dismal.

Traumatic bilateral hip dislocation with bilateral sciatic nerve palsy.

Bilateral hip dislocation rarely occurs. In this paper, a case of bilateral hip dislocation associated with bilateral sciatic nerve palsy resulted from a road traffic accident is reported. Both hips were emergently reduced under general anaesthesia. Acetabular reconstruction was done bilaterally due to the unstable hips. The patient subsequently developed heterotopic ossification and avascular necrosis on the left hip and underwent total hip arthroplasty. The sciatic nerve on the right side achieved complete recovery but that on the left side only partly recovered and was augmented by tendon transfer. Such injuries are serious and one should be aware of the complications because they can resurface and so patients should be followed up for a long time. To the best of our knowledge, this kind of injury has not been reported in the English language literature.

Neglected isolated fracture of the trochlea humeri.

A 15 years old girl was found to have isolated trochlea fracture 10 weeks after an injury caused by a fall on her left elbow. Movement of the elbow was severely restricted. Radiographs showed a half moon-shaped and anterosuperiorly displaced osteochondral fragment. Medial approach capsulotomy of the elbow and excision of the intraarticular adhesions were done to expose the isolated trochlea fracture. Headless screws were used for fixation, combined with bone grafting. The follow-up showed union and excellent functional recovery of the elbow. Isolated trochlea fracture in adults is rare and usually associated with capitellar fractures and/or elbow dislocations. A neglected trochlea fracture is rarely reported in the English language literature to the best of our knowledge. Recognition of isolated trochlea fracture is vital to apprehend the pathomechanics of the injury and to devise a suitable treatment approach.

Management of massive posttraumatic bone defects in the lower limb with the Ilizarov technique.

Massive bone defects have been treated by various methods with variable success rates. The Ilizarov technique has been advocated as a preferred method for treatment of large segmental defects. Twenty five patients with massive post traumatic bone defects of the lower limb (22 tibiae, 3 femurs) were treated using Ilizarov's technique. After radiological evaluation, the patients were subjected to bone transport. Bifocal osteosynthesis was performed in all except those needing >12 cm of bone transport. Distraction was started between day 4 and 7 at the rate of 1 mm per day in four increments. All were males with a mean gap of 8.9 cm (range: 5-17 cm), mean age of 28.24 years (16-40) and having undergone a mean of 2.6 previous surgeries. Mean time in Ilizarov frame was 8.8 months and external fixator index was 0.98 months. Mean duration of follow-up after frame removal was 23.5 months. Union was achieved in 23 (92%) cases. Bone grafting was required in 9 (36%) According to ASAMI criteria, bone results were excellent in 13, good in 1, and poor in 11 patients. Functional results were excellent in 6 patients, good in 9, fair in 4, and poor in 6 patients. A total of 72 complications occurred (2.88 complications per patient). Union was achieved in all except two patients. The Ilizarov external fixator offers a limb salvage solution even in large bone defects but the surgeon should set realistic goals both for himself and his patients while offering this method of treatment.

Product development studies of amino acid conjugate of Aceclofenac.

The prodrugs designed by classical approach increase lipophilicity of the drug, which decreases the water solubility thus decreasing the concentration gradient, which controls drug absorption. To overcome the limitations of traditional prodrug approach, water soluble prodrugs can be designed by adding selected amino acid to the drug moiety that are the substrates for the enzyme located at the intestinal brush border thus overcoming pharmaceutical problem without compromising bioavailability. ACaa (Amino acid conjugate of Aceclofenac) was synthesized by conjugation with l-phenylalanine by conventional coupling method using N, N-dicyclohexylcarbodiimide and ACaa was characterized by melting point, TLC, photomicrograph, UV, FT-IR, FT-NMR, MS-FAB, XRD and DSC. As a part of product development study ACaa was subjected to studies like In-vivo in albino rats and in-vitro like ACaa reversion to AC (Aceclofenac) in aqueous buffers of pH 1.21, 2.38. 3.10, 6.22 and 7.41, at a constant concentration (0.05M), ionic strength (micro = 0.5) and at a temperature of 37 degrees C +/- 0.5 degrees C, ACaa showed negligible reversion (2.15 %) up to 24 hrs study at acidic pH thus suggesting stability in acidic environment of stomach, the rate of reversion increased as pH of medium increased. pH- partition profile, pH- solubility profile and micromeritic studies were also carried out in comparison to pure drug. The solubility and lipophilicity of ACaa exhibited higher values at all pH range when compared to AC. The micromeritic properties also evaluated in terms of particle shape and size, IQCS and kurtosis. Resulting IQCS value approached zero thus suggesting reducing in the degree of skewness.