Spondyloenchondrodysplasia Due to Mutations in <Emphasis Type="Italic">ACP5</Emphasis>: A Comprehensive Survey

Purpose

Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.

Methods

We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.

Results

We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.

Conclusions

Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

     

Autologous Immune Enhancement Therapy in Recurrent Ovarian Cancer with Metastases: A Case Report

Current therapeutic modalities for ovarian cancer such as chemotherapy, radiotherapy and surgery have been reported to yield only marginal success in improving survival rates of patients and have associated adverse effects. We report here a case of recurrent stage IV ovarian cancer, treated with cell-based autologous immune enhancement therapy (AIET) along with chemotherapy and followed up for 18 months. A 54-year-old female was diagnosed with a recurrence of ovarian carcinoma 1 year after initial surgical removal followed by chemotherapy for stage IIIC ovarian carcinoma. When diagnosed in 2010 with recurrence, she had liver and spleen metastases with a CA-125 level of 243 U/ml and a stage IV clinical status. Six infusions of AIET using autologous in vitro expanded and activated natural killer (NK) cells (CD3–CD56+) and activated T lymphocytes (CD3+CD56+) were administered in combination with 6 cycles of chemotherapy with carboplatin and doxorubicin. Following this treatment, CA-125 decreased to 4.7 U/ml along with regression of the metastatic lesions and an improved quality of life. No adverse reactions were reported after the AIET transfusions. Eighteen months of follow-up revealed a static nonprogressive disease. Combining AIET with chemotherapy and other conventional treatments has been found to be effective in our experience, as reported earlier, even in patients with advanced ovarian cancer, and we recommend this strategy be considered in treating similar cases.Key words: Autologous immune enhancement therapy, Recurrent ovarian carcinoma, Natural killer cells (CD3–CD56+), • Activated T lymphocytes (CD3+CD56+)     

Influence of gestational age to low-level gamma irradiation on postnatal behavior in mice

The present investigation was carried out to study the effects of in utero exposure to low-level gamma radiation (0.25, 0.35, or 0.50 Gy) on the postnatal neurophysiology and neurochemistry of the mouse. Pregnant Swiss albino mice were irradiated on days 11.5, 12.5, 14.5, or 17.5 post coitus (PC) and allowed to deliver. Locomotor and exploratory activities, learning and memory functions, and emotional activities were tested at 3 months of age using behavior tests. A representative group of animals was killed and hippocampal biogenic amines, noradrenaline, dopamine, serotonin (5-HT), and 5-HT's metabolite 5-hydroxy indoleactetic acid (5-HIAA), were measured. Exposure to 0.25 Gy at any of the gestation days did not produce any significant impairment in brain functions. However, an increase in gamma irradiation to 0.50 Gy on all the gestation days produced significant impairment in locomotor (open-field test) and anxiolytic (light and dark area test) activities, learning (hole board test), memory functions (active avoidance test), and emotional activity (rearings). The late fetal period is relatively resistant to radiation-induced impairment of brain functions. Both of the organogenesis gestation days showed a higher sensitivity than the fetal gestation days studied. Even a lower dose of 0.35 Gy when exposed on the late organogenesis days 11.5 and 12.5 PC, produced significant reduction in locomotor and exploratory activities. Day 11.5 PC showed a higher sensitivity than the other PC days studied. Biogenic amines did not show significant change after any of the exposures on any of the gestation days. The results suggest a threshold between 0.25 to 0.35 Gy for postnatal neurobehavior changes.     

Serum Mortalin Correlated with α-Synuclein as Serum Markers in Parkinson’s Disease: A Pilot Study

Mortalin, a mitochondrial chaperone, plays a crucial role in reducing toxicity of Lewy bodies. Earlier studies had reported that Mortalin level gets downregulated in astrocytes and other brain tissue samples in Parkinson’s disease (PD). This study aims to estimate the Mortalin concentration in serum and correlate with α-synuclein (α-Syn) in PD. The concentration of Mortalin and α-Syn in serum samples of 38 PD patients and 33 control group (CG) individuals was quantified by surface plasmon resonance. The receiver operating characteristic curves were plotted to develop it as blood-based protein marker. The expression of Mortalin in serum was validated by western blot. The Mortalin level was found to be declined in PD patients (1.98 ± 0.53 ng/µL) in comparison with CG individuals (3.13 ± 0.48 ng/µL), whereas α-Syn level was found to be elevated in PD patients (38.20 ± 4.22 ng/µL) than CG individuals (34.31 ± 3.23 ng/µL) in serum. The statistical analysis revealed the negative correlation between Mortalin and α-Syn. This preliminary study summarized that Mortalin plays a significant role in PD with negative correlation with α-Syn. This study provides a new paradigm for the development of Mortalin as a potent serum protein marker for diagnosis of PD.     

Oxidative requirement for degranulation of human peripheral blood eosinophils.

Eosinophils possess both oxygen-dependent and oxygen-independent mechanisms for damaging helminthic parasites such as schistosomula. We have studied the release of the granular enzymes beta-glucuronidase and arylsulfatase to evaluate the oxidative requirement for degranulation. Both ionophore-mediated and immunoglobulin G-mediated release of granular enzymes were enhanced in the presence of oxygen (P less than or equal to 0.05). Calcium ionophore-mediated degranulation under aerobic conditions was reduced by the addition of the degradative enzymes catalase and superoxide dismutase, suggesting that active oxygen products enhance degranulation. In contrast, oxygen products did not appear to contribute to degranulation induced by immunoglobulin G-coated beads.     

Expression of the Epstein–Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice

The latent membrane protein 1 (LMP1) of the Epstein–Barr virus has transforming properties in rodent fibroblasts and is expressed in most of the cancers associated with Epstein–Barr virus (EBV) infection including posttransplant lymphomas, Hodgkin’s disease, nasopharyngeal carcinoma, and AIDS-related lymphomas. In this study, three lineages of LMP1 transgenic mice were established with LMP1 expressed under the control of the Ig heavy chain promoter and enhancer. Lymphoma developed in all three lineages, and the incidence of lymphoma increased significantly with age with lymphomas developing in 42% of transgenic mice over 18 months. The expression of LMP1 was detected at high levels in the lymphoma tissues but only at trace levels in normal lymphoid tissues. Gene rearrangement of the Ig heavy chain indicated monoclonality or oligoclonality in all lymphomas, some of the lymphoid hyperplastic spleens, and some histologically normal spleens. These data reveal that LMP1, without the expression of other EBV genes, is oncogenic in vivo and indicate that LMP1 is a major contributing factor to the development of EBV-associated lymphomas.     

Evaluation of wound healing and antimicrobial potentials of Ixora coccinea root extract

ObjectiveTo evaluate the wound healing and antimicrobial activity of root extracts of Ixora coccinea (I. coccinea).MethodsTo investigate the wound healing efficacy of root extract of I. coccinea Linn, five groups of animals were divided each containing six animals. Two wound models including incision and excision wound models were used in this study. The parameters studied were tensile strength on incision wound model and in terms of wound contraction for excision wound model were compared with standard Nitrofurazone (NFZ) ointment (0.2% w/w). Six extracts (ethanol, aqueous, petroleum ether, benzene, chloroform and ethyl acetate) of I. coccinea were screened for in vitro growth inhibiting activity against different bacterial strains viz, Staphylococcus aureus, Bacillus pumilius, Enterococcus faecalis, Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa and fungi Candida albicans and Aspergillus niger were compared with the standard drugs ciprofloxacin and chloramphenicol for antibacterial and griseofulvin for antifungal screening. The serial dilution and cup (or) well plate methods were used for the antimicrobial study and MIC was determined.ResultsThe ethanolic extract showed significant (P<0.001) wound healing activity when compared to standard drug NFZ with respect to normal control group. Amongst all, ethanolic extract showed highly significant antibacterial activity against all bacterial strains used in this study when compared to standard. The aqueous extract showed moderate significant inhibition against all bacterial strains when compared to standard. All the extracts were shown negligible activity against the fungal strains used in this study.ConclusionsThe ethanolic root extract of I. coccinea showed pronounced wound healing and antibacterial activity. The probable reason to heal the wound was that the external application of the extract prevented the microbes to invade through the wound thus the protection of wound occurs against the infection of the various organisms.