Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ) gene. There is no information on AIRE mutations in Indians. In a cross-sectional study, nine patients (eight families), from four referral hospitals in India, were studied for AIRE mutations by direct sequencing. We screened for new mutations in 150 controls by allele-specific PCR. The patients had 1–7 known components of APECED. Three patients had unusual manifestations: presentation with type 1 diabetes; chronic sinusitis and otitis media; and facial dysmorphism. All patients carried homozygous, probably recessive, AIRE mutations. Two unrelated patients from a small in-bred community (Vanika Vaisya) in south India carried an unreported missense mutation, p.V80G, in the N-terminal caspase recruitment domain. Another unique mutation, p.C302X, resulting in a truncated protein with deletion of both zinc-finger domains, was detected in a patient from Gujarat. Neither mutation was detected in controls. Other mutations, previously described in Caucasians, were: 13 base pair deletion (p.C322fsX372) in 4 (38%), and Finn-major (p.R257X) and p.R139X (Sardinian) mutation in one subject each. In conclusion, in this first series of APECED in Indians, we detected AIRE mutations previously reported in Caucasians, as well as unique mutations. Of these, p.V80G is possibly an ancestral mutation in an in-bred community.     

The Skeletal Subsystem as an Integrative Physiology Paradigm

Homeostatic bone remodeling depends on precise regulation of osteoblast-osteoclast coupling through intricate endocrine, immune, neuronal, and mechanical factors. The osteoblast-osteoclast model of bone physiology with layers of regulatory complexity can be investigated as a component of a local skeletal subsystem or as a part of a complete whole-body system. In this review, we flip the traditional investigative paradigm of scientific experimentation (“bottom–top research”) to a “top–bottom” approach using systems biology. We first establish the intricacies of the two-cell model at the molecular signaling level. We then provide, on a systems level, an integrative physiologic approach involving many recognized organ-level subsystems having direct and/or indirect effects on bone remodeling. Lastly, a hypothetical model of bone remodeling based on frequency and amplitude regulatory mechanisms is presented. It is hoped that by providing a thorough model of skeletal homeostasis, future progress can be made in researching and treating skeletal morbidities.     

Denosumab for the Treatment of Osteoporosis

Being a connective tissue, bone can increase or decrease its mass through the process of remodeling. Using a discovery in the mid-1980s—that tumor necrosis factor (TNF) could dramatically increase formation of osteoclasts (the cells that break down bone)—researchers at Amgen (Thousand Oaks, CA) discovered a TNF-like molecule that regulated bone resorption. Elevations in the expression of this molecule, receptor activator of nuclear factor-κB ligand (RANKL), can cause excessive bone destruction. A blocking antibody to RANKL named denosumab inhibits osteoclast formation and bone degradation. In a large multicenter clinical trial, known as the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), the effects of denosumab were tested in 60- to 90-year-old women over 3 years. Statistically significant reductions in fracture risk at the vertebral column, hip, and nonvertebral sites were associated with increases in bone mineral density (BMD) and reciprocal decreases in markers of bone resorption. However, the FREEDOM trial did not test the most beneficial use of a resorption blocking drug—to target the rapid bone loss that occurs in late perimenopause and early postmenopause. One adverse effect from denosumab is cellulitis, and research in animals suggests that RANKL/RANK interaction is needed for Langerhans cell (LC) survival in the skin. Further mechanistic and clinical studies on the role of RANKL in the skin are needed.     

Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5

Microtubule-associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in Alzheimer's disease (AD). We recently found that the aberrant tau glycosylation precedes tau hyperphosphorylation in AD brain. In the present study, we developed assays to determine phosphorylation and dephosphorylation of tau at specific phosphorylation sites by using glycosylated tau purified from AD brain as a substrate. We then studied the effects of the aberrant glycosylation on phosphorylation and dephosphorylation of tau at each specific phosphorylation site. We found that deglycosylation of the aberrantly glycosylated tau decreased the subsequent phosphorylation of tau at Ser214, Ser262, and Ser356 in vitro by protein kinase A. On the other hand, deglycosylation of tau positively modulated the subsequent dephosphorylation by protein phosphatase 2A and protein phosphatase 5 in vitro at the phosphorylation sites Ser198, Ser199, and Ser202.Our results suggest that the aberrant glycosylation may modulate tau protein at a substrate level so that it is easier to be phosphorylated and more difficult to be dephosphorylated at some phosphorylation sites in AD brain. The combined impact of this modulation may be to make tau more susceptible to becoming abnormally hyperphosphorylated.     

HLA PROFILE OF ETHNIC PAKISTANI POPULATION GROUPS

Acute rejection is a major determinant of chronic allograft dysfunction and graft survival. This study evaluated the effect of basiliximab (Simulect^®), a 156-kDa chimeric monoclonal antibody (human and murine) directed against the alpha chain of the interleukin (IL)-2 receptor of human lymphocytes, on acute rejection in pediatric renal transplantation. Data were collected from two pediatric renal transplantation centers. Forty transplantations (22 males and 18 females; mean age 14.8±3.6 years) were performed between 1996 and 2001. Twelve of the grafts came from cadaveric donors and 28 from living-related donors. Twenty-four of the patients were on hemodialysis, 15 were on peritoneal dialysis, and one case was a pre-emptive transplantation. All patients were placed on triple-drug immunosuppression [prednisolone + (azathioprine or mycophenolate mofetil) +(cyclosporine or tacrolimus)]. Basiliximab was also administered in 17 cases. The respective rates of biopsy-proven acute rejection in the basiliximab group and the standard-regimen group were 0% vs. 17.4% ( P >0.05) at 1 month post-transplantation; 0% vs. 26.1% ( P <0.05) at 3 months; and 0% vs. 26.1% ( P <0.05) at 6 months. Thirty and 16 patients had completed 1- and 3-year follow ups, respectively, at the time of writing; the 1- and 3-year graft survival rates were 96% (29/30) and 81% (13/16), respectively.
Basiliximab significantly reduced the rates of acute rejection at 3- and 6 months post-pediatric renal transplantation. It was well tolerated by all patients, and caused no significant adverse effects. The effect of basiliximab on long-term graft survival and chronic allograft dysfunction deserves further investigation.     

A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury

Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (～ 50% reduction, P = 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.     

Treatment of earlobe keloids using the cobalt 60 teletherapy unit

The purpose of this study was to develop an easily accessible technique for the delivery of postoperative radiotherapy for the treatment of earlobe keloids. Forty-seven earlobe keloids were given postoperative radiation using the smallest achievable half field Telecobalt technique. Results showed 41 (87.2%) of treated patients' postoperative scars remained free from recurrent keloid formation. Acute reactions were minimal and patient compliance was excellent. In conclusion, the technique described in this study for the delivery of postoperative radiation to earlobe keloids should be readily available in areas of high prevalence. Results are comparable to previously used radiotherapy techniques.     

Blood flow changes in the ovarian and uterine arteries in women with normal and polycystic ovaries

This review summarizes the haemodynamic changes in the ovarian and uterine arteries, as revealed by transvaginal colour Doppler ultrasonography, (i) in women with normal ovaries (group 1), (ii) in women with the polycystic ovary syndrome who ovulate in response to clomiphene citrate (group 2) and (iii) in women with polycystic ovaries who have a regular ovulatory menstrual cycle (group 3). In each group blood flow velocities in the intraovarian arteries increased during the menstrual cycle in the dominant ovary and remained high in the mid-luteal phase. There was no significant change in pulsatility index. In group 2, the longitudinal haemodynamic changes in the intraovarian arteries were similar to those seen in women with normal ovaries. However, the follicular and ovarian stromal blood flow velocities were greater in group 2 compared with the normal group. There was a significant increase in the pulsatility index of the uterine artery during the follicular phase of the menstrual cycle and a subsequent decrease into the midluteal phase. Uterine artery pulsatility index was also significantly greater at the baseline ultrasound scan in group 2. In group 3, the longitudinal haemodynamic changes in the intraovarian arteries were similar to those in group 1. Furthermore, the intraovarian vascular changes were similar to those in group 2, but velocities were significantly greater than in group 1. There was an increase in uterine artery pulsatility index during the follicular phase of the menstrual cycle and a subsequent decrease into the mid-luteal phase. The uterine artery Doppler changes were similar to those seen in group 2. In conclusion, women with polycystic ovaries have significant differences in ovarian and uterine artery haemodynamics. Increased ovarian stromal blood flow within the polycystic ovary may help to explain the increased ovarian responsiveness that women with polycystic ovaries show after administration of gonadotrophins.