A proton magnetic resonance spectroscopic study in autism spectrum disorders: Amygdala and orbito-frontal cortex

We previously reported neural dysfunction in the anterior cingulate cortex and dorsolateral prefrontal cortex in autistic patients using proton magnetic resonance spectroscopy (¹H-MRS). In this investigation, we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC), which are the main components of the social brain. We also examined the association between these metabolic findings and social abilities in subjects with autism. The study group included 77 autistic patients (3–6 years old; mean age 4.1; 57 boys and 20 girls). The control subjects were 31 children (3–6 years old; mean age 4.0; 23 boys and 8 girls). Conventional proton MR spectra were obtained using the STEAM sequence with parameters of TR = 5 sec and TE = 15 msec by a 1.5-tesla clinical MRI system. We analyzed the concentrations of N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), and choline-containing compounds (Cho) using LCModel (Ver. 6.1). The concentrations of NAA in the left amygdala and the bilateral OFC in autistic patients were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in autism. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of autism.     

Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10-53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction. The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.     

Expression of TNF-related apoptosis inducing ligand (TRAIL) on infiltrating cells and of TRAIL receptors on salivary glands in patients with Sjögren's syndrome

BACKGROUND: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis of tumor cells but not normal cells; its role in normal non-transformed tissues is unknown. OBJECTIVE: To evaluate the role of apoptosis mediated by TRAIL and TRAIL-receptor (TRAIL-R) system in lymphocytic sialadenitis in patients with Sj?gren's syndrome. METHODS: The expression of TRAIL and TRAIL-R1, 2, 3 and 4 in lymphocytic sialadenitis was examined by immunoperoxidase staining in patients with Sj?gren's syndrome and in normal subjects. To elucidate the mechanism of de novo expression of TRAIL-R1 antigen, we quantitatively investigated its induction by cytokines in human salivary duct cell line (HSG) by cell enzyme-linked immunosorbent assay. In human salivary duct cells stimulated by cytokines, we investigated the induction of apoptotic cell death by recombinant TRAIL protein. RESULTS: In patients with massive mononuclear cell infiltration, some infiltrating cells showed TRAIL. In patients with severe lymphocytic sialadenitis, TRAIL-R1, TRAIL-R2, or both were strongly expressed on the ductal epithelial cells. Neither TRAIL-R3 nor R4 were observed on ductal epithelium. In contrast, TRAIL-R1 and R2 were not found in the minor salivary glands of normal subjects or patients with mild lymphocytic sialadenitis. Unstimulated HSG cells did not express TRAIL-R1. Interferon-gamma (IFN-gamma) consistently upregulated levels of TRAIL-R1. In contrast, tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), IL-2, and IL-4 had no effect on TRAIL-R1 levels. HSG cells expressing TRAIL-R1 in response to IFN-gamma were susceptible to apoptosis by recombinant TRAIL protein. CONCLUSION: Our findings suggest that TRAIL and TRAIL-R system may play a role in the pathogenesis of lymphocytic sialadenitis in patients with Sj?gren's syndrome.     

Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society

Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of approximately 25%, and with approximately 50% of cases resulting in end‐stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely.     

Development of autoimmune hepatitis-like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator

OBJECTIVE: B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity. METHODS: We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA(-/-) mice. We also examined histopathologic changes in the organs of BTLA(-/-) mice. RESULTS: We observed that BTLA(-/-) mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti-SSA antibodies, anti-double-stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis-like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA(-/-) mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sj?gren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA(-/-) mice was significantly reduced after the age of 7 months. CONCLUSION: Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.     

Accelerating effects of basic fibroblast growth factor on wound healing of rat palatal mucosa.

PURPOSE: In this study, basic fibroblast growth factor (bFGF) was examined for its ability to accelerate tissue repair in a rat oral mucosal wound. MATERIALS AND METHODS: A 4-mm mucosal defect was surgically made to the depth of the periosteum in a rat palate. bFGF was injected along the edge of the mucosal defect immediately after surgery. A control group received only phosphate-buffered saline vehicle. RESULTS: bFGF significantly accelerated granular tissue formation and reepithelialization. From the histologic analysis, the bFGF-treated group showed relatively faster collagen maturation. Starting 3 days after surgery, fibroblast growth factor receptor 1 (FGFR1)-positive cells appeared in the granular and spinous cell layers of the reepithelializing mucosa in the bFGF-treated group, whereas almost none was observed in the intact oral mucosa. By day 5, FGFR1-positive cells were seen below the stratum corneum, even in the control group. However, the number and intensity of FGFR1-positive cells in the bFGF-treated group were greater than in the control group. Results of immunostaining against proliferating cell nuclear antigen showed that bFGF stimulated cell proliferation of the basal cell layer in the regenerating epithelium. At a higher dose of bFGF, proliferating cell nuclear antigen-positive cells were also observed in the submucosal connective tissue. CONCLUSION: By the induction of its ligand protein concomitant with direct effects such as increased granular tissue formation and reepithelialization, a single topical application of bFGF facilitated wound healing in rat oral mucosa. The results of this study support the consideration for bFGF application for patients with impaired healing of oral mucosal injury.     

Risk assessment of medically assisted reproduction and advanced maternal ages in the development of Prader–Willi syndrome due to UPD(15)mat

Recent studies have suggested that disomic oocyte‐mediated uniparental disomy 15 (UPD(15)mat) is increased in patients with Prader–Willi syndrome (PWS) born after medically assisted reproduction (MAR). However, it remains unknown whether the increase is primarily due to MAR procedure itself or advanced maternal childbearing ages as a predisposing factor for the disomic oocyte production. To examine this matter, we studied 122 naturally conceived PWS patients (PWS‐NC group) and 13 MAR‐conceived patients (PWS‐MAR group). The relative frequency of disomic oocyte‐mediated UPD(15)mat was significantly higher in PWS‐MAR group than in PWS‐NC group (7/13 vs 20/122, p = 0.0045), and the maternal childbearing ages were significantly higher in PWS‐MAR group than in PWS‐NC group [median (range), 38 (26–45) vs 30 (19–42), p = 0.0015]. However, the logistic regression analysis revealed no significant association between the occurrence of disomic oocyte‐mediated UPD(15)mat and MAR, after adjusting for childbearing age (p = 0.25). Consistent with this, while the frequency of assisted reproductive technology (ART)‐conceived livebirths was higher in the PWS patients than in the Japanese general population (6.4% vs 1.1%, p = 0.00018), the distribution of childbearing ages was significantly skewed to the increased ages in the PWS patients (p < 2.2 × 10^?16). These results argue against a positive association of MAR procedure itself with the development of UPD(15)mat.     

Radiological evaluation of dysmorphic thorax of paternal uniparental disomy 14

Background  

The “coat-hanger” sign of the ribs with a bell-shaped thorax has been known as a radiological hallmark of the paternal uniparental disomy 14 (upd(14)pat).     

Late‐onset anaphylactic reactions following i.v. cyclophosphamide pulse in a patient with systemic sclerosis and systemic lupus erythematosus overlap syndrome

Late‐onset anaphylactic reaction is a rare adverse effect of i.v. cyclophosphamide pulse (IVCY), which is caused by cyclophosphamide metabolites. We herein report a case of scleroderma and lupus overlap syndrome who developed anaphylactic reactions 3 h to 4 days after IVCY. Long time lapses between IVCY and appearance of symptoms are compatible with type I hypersensitivity to cyclophosphamide metabolites, appearing as late‐onset anaphylactic reaction. Albeit unusual, this is an important anaphylactic reaction to be aware of following IVCY.