Anemia is the most common hematologic condition encountered in outpatient clinics. It is often overlooked because it is common among patients; however, anemia is one of the leading indicators of cancer. This study examined the prevalence and characteristics of cancer among anemia patients who visited an outpatient clinic.
The data were collected by reviewing the records of an outpatient clinic from January 2007 to December 2011.
In total, 502 patients (52 males, 450 females) were diagnosed with anemia. Cancer prevalence among anemia patients was 5.57% (25.0%, men; 3.3%, women); further, the most frequently diagnosed cancer was colorectal cancer (22.5%), followed by advanced gastric cancer (16.1%), breast cancer (9.6%), myelodysplastic syndrome (9.6%), cervical cancer (6.4%), renal-cell carcinoma (6.4%), and thyroid cancer (6.4%). The prevalence of cancer was 4.1% in those aged 40-49 years, 4.2% in the subjects in their fifties, 8.0% in those in their sixties, 21.6% in those in their seventies, and 55.6% in those aged over 80 years. The cancer prevalence among iron deficiency anemia (IDA) patients was 6.18% (28.8%, men; 3.5%, women). The cancer prevalence in postmenopausal and premenopausal female IDA patients was 16.0% and 1.6%, respectively.
Among anemia patients, male patients aged over 40 years and female patients aged over 60 years, along with postmenopausal female patients, were more likely to be diagnosed with cancer. Consequently, male IDA patients, and female patients aged over 60 years must be carefully evaluated for the possibility of malignancy.
Anemia; Prevalence; Cancer; Outpatient clinic
Typhlitis is a necrotizing colitis that usually occurs in neutropenic patients and develops most often in patients with hematologic malignancies such as leukemia and lymphoma. Typhlitis may proceed to bowel perforation, peritonitis and sepsis, which requires immediate treatment. Irinotecan is a semisynthetic analogue of the natural alkaloid camptothecin which prevents DNA from unwinding by inhibition of topoisomerase I. It is mainly used in colon cancer and small cell lung carcinoma (SCLC), of which the most common adverse effects are gastrointestinal toxicities. To the best of our knowledge, no case of typhlitis after chemotherapy with a standard dose of irinotecan in a solid tumor has been reported in the literature. We, herein, report the first case of typhlitis developed after chemotherapy combining irinotecan and cisplatin in a patient with SCLC.
Typhlitis; Irinotecan; Small Cell Lung Carcinoma
Invasive aspergillosis (IA) is a leading cause of infectious mortality in patients who have undergone a hematopoietic stem cell transplant (HSCT); the mortality due to IA ranges from 70% to 93% in HSCT patients. Early diagnosis and treatment are the cornerstones for the good prognosis of IA. Primary renal aspergillosis is an extremely rare presentation in patients who have undergone HSCT, and the risk factor for this uncommon presentation is not well known. We report a patient who developed primary renal aspergillosis and renal stones in both the kidneys after HSCT. Invasive renal aspergillosis was diagnosed after a nephrectomy, which was performed to treat massive renal hematoma.
Primary renal aspergillosis; Hematopoietic stem cell transplant; Renal stones
AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, is activated in response to cellular stress when intracellular levels of AMP increase. We investigated the neuroprotective effects of AMPK against scopolamine-induced memory impairment in vivo and glutamate-induced cytotoxicity in vitro. An adenovirus expressing AMPK wild type alpha subunit (WT) or a dominant negative form (DN) was injected into the hippocampus of rats using a stereotaxic apparatus. The AMPK WT-injected rats showed significant reversal of the scopolamine induced cognitive deficit as evaluated by escape latency in the Morris water maze. In addition, they showed enhanced acetylcholinesterase (AChE)-reactive neurons in the hippocampus, implying increased cholinergic activity in response to AMPK. We also studied the cellular mechanism by which AMPK protects against glutamate-induced cell death in primary cultured rat hippocampal neurons. We further demonstrated that AMPK WT-infected cells increased cell viability and reduced Annexin V positive hippocampal neurons. Western blot analysis indicated that AMPK WT-infected cells reduced the expression of Bax and had no effects on Bcl-2, which resulted in a decreased Bax/Bcl-2 ratio. These data suggest that AMPK is a useful cognitive impairment treatment target, and that its beneficial effects are mediated via the protective capacity of hippocampal neurons.
Adenovirus; AMPK; Apoptosis; Learning and memory; Scopolamine
Prader–Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1–BP3 and BP2–BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n=5) or larger (n=2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in ∼8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.
Prader–Willi syndrome; 15q11.2-q13; MS-MLPA; array CGH; genotype–phenotype; seizures
Purpose: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are complex neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region depending on the parent of origin. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) kits from MRC-Holland (Amsterdam, The Netherlands) were used to detect PWS and AS deletion subtypes. We report our experience with two versions of the MS-MLPA-PWS/AS kit (original A1 and newer B1) in determining methylation status and deletion subtypes in individuals with PWS. Methods: MS-MLPA analysis was performed on DNA isolated from a large cohort of PWS subjects with the MS-MLPA-PWS/AS-A1 and -B1 probe sets. Results: Both MS-MLPA kits will identify deletions in the 15q11-q13 region but the original MS-MLPA-A1 kit has a higher density of probes at the telomeric end of the 15q11-q13 region, which is more useful for identifying individuals with atypical deletions. The newer B1 kit contains more probes in the imprinting center (IC) and adjoining small noncoding RNAs useful in identifying small microdeletions. Conclusion: The A1 kit identified the typical deletions and smaller atypical deletions, whereas the B1 kit was more informative for identifying microdeletions including the IC and SNORD116 regions. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions.
Only a few patients who experience AML relapse derive lasting benefit from re-induction therapy. The utility of reassessing the disease karyotype at relapse is unclear. The main goals of this study were to identify prognostic factors for AML relapse and to determine the prognostic utility of karyotypic change between diagnosis and relapse as a variable for predicting response to salvage therapy for relapsed AML.
This retrospective study included 58 patients with relapsed AML treated at the Yonsei University College of Medicine between 2005 and 2010. Karyotypes at both diagnosis and relapse were available for 45 patients (77%). A change in karyotype at relapse was observed in 17 of 45 cases (37%), and no change was noted in 28 of 45 cases (62%).
Karyotypic changes between diagnosis and relapse were associated with the response rate (RR) to salvage therapy (P=0.016). Overall survival (OS) and event-free survival (EFS) in the group with karyotypic changes between diagnosis and relapse were significantly different from those with no karyotypic changes (P=0.004 and P=0.010, respectively). We applied multiple multivariate Cox regression analyses to identify independent prognostic factors for overall response (OR), OS, and EFS. A change in karyotype between diagnosis and relapse was significantly associated with OS (P=0.023; RR=2.655) and EFS (P=0.033; RR=2.831).
Karyotypic changes between the diagnosis and relapse of AML could be used to predict outcomes and tailor clinical and biological therapeutic strategies for relapsed AML patients.
Karyotype; Prognosis; Salvage therapy; Acute myeloid leukemia
The purpose of the present study was to examine the effect of Lycii Radicis Cortex (LRC) and betaine (BT) on immobility and neurochemical change in the forced swimming test (FST) in the rat. LRC, BT or fluoxentine was administered intraperitoneally to Sprague-Dawley rats three times (1, 5 and 23.5 h) before the FST. To investigate antidepressant-like effect, serotonin (5-HT) and norepinephrine (NE) were examined in the hippocampus and hypothalamus of rats. LRC (100 mg/kg) and BT (30, 100 mg/kg) significantly decreased the immobility time in the FST. LRC (100 mg/kg) significantly increased both 5-HT and NE levels in the hypothalamus of rats exposed to FST. BT (100 mg/kg) significantly increased 5-HT levels in the hypothalamus and hippocampus of rats. Taken together, these results demonstrated that improvement in the behavioral changes after LRC and BT administration may be mediated by elevation of 5-HT level in the hypothalamus and hippocampus, indicating a possible antidepressant-like activity. The present results suggest that the efficacy of LRC and BT in an animal model of depression may provide anti-depressant effects in human, which remains to be determined.
Lycii Radicis Cortex; Betaine; Depression; Norepinephrine; Serotonin
The overexpression of Aurora A kinase (AurA) has been reported in various malignancies, including acute myeloid leukemia (AML). However, the expression of AurA and the effects of AurA inhibition in cancer stem cells are not yet fully understood. We investigated the expression and inhibition of AurA in AML stem cells (CD34+/CD38-).
Expression of AurA was investigated in cell lines (NB4 and KG1) that express high levels of CD34 and low levels of CD38. Primary AML cells were harvested from 8 patients. The expression of AurA and cell death induced by inhibition of AurA were analyzed in CD34+/CD38- cells.
AurA was shown to be overexpressed in both primary AML cells and leukemia stem cells (LSCs) compared to normal hematopoietic stem cells. Inhibition of AurA plus cytarabine treatment in LSCs resulted in increased cytotoxicity compared to cytarabine treatment alone. Additional stimulation with granulocyte-colony stimulating factor (G-CSF) increased the cell death caused by AurA inhibition plus cytarabine treatment.
To our knowledge, this is the first report describing increased expression of AurA in LSCs. Our results suggest that selective AurA inhibition may be used to reduce LSCs, and this reduction may be enhanced by stimulation with G-CSF. Further exploration of relationship between nuclear factor kappa-B and AurA inhibition and the potential of AurA inhibition for use in leukemia treatment is needed.
Acute myeloid leukemia; Leukemia stem cell; Aurora kinase
Stress has been shown to suppress immune function and increase susceptibility to inflammatory disease and psychiatric disease. CD4+CD25+ regulatory T (Treg) cells are prominent in immune regulation. This study was conducted to determine if anti-CD25 antibody (Ab) mediated depletion of Treg cells in mice susceptibility to stress-induced development of depression-like behaviors, as well as immunological and neurochemical activity. To accomplish this, an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST) were used to examine depression-like behaviors upon chronic immobilization stress. Immune imbalance status was observed based on analysis of serum cytokines using a mouse cytometric bead array in conjunction with flow cytometry and changes in the levels of serotonin (5-HT) and dopamine (DA) in the brain were measured by high performance liquid chromatography (HPLC). The time spent in the open arms of the EPM decreased significantly and the immobility time in the FST increased significantly in the anti-CD25 Ab-treated group when compared with the non stressed wild-type group. In addition, interlukin-6 (IL-6), tumor necrosis factor-á (TNF-á), interlukin-2 (IL-2), interferon-gamma (IFN-γ), interlukin-4 (IL-4) and interlukin-17A (IL-17A) concentrations were significantly upregulated in the stressed anti-CD25 Ab-treated group when compared with the non stressed wild-type group. Furthermore, the non stressed anti-CD25 Ab-treated group displayed decreased 5-HT levels within the hippocampus when compared with the non stressed wild-type group. These results suggest that CD4+CD25+ Treg cell depletion modulated alterations in depressive behavior, cytokine and monoaminergic activity. Therefore, controlling CD4+CD25+ Treg cell function during stress may be a potent therapeutic strategy for the treatment of depression-like symptoms.
Despite extensive study, the use of allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (AML) vary considerably. The decision of which of these options to choose is complex and depends on both clinical and molecular variables as well as the availability and histocompatability of donor stem cells. So far there is no clear explanation on whether the expression of myeloperoxidase (MPO) relates to the prognosis of AML.
Materials and Methods
We retrospectively analyzed the prognostic significance of the MPO expression in the 140 patients with diagnosed AML treated at a single institution.
In our study, MPO expression was associated with disease-free survival (DFS) and transplant was beneficial to overcome a negative prognostic effect of MPO-negative at diagnosis based upon the result that the DFS in patients received transplants are not significant between the MPO-positive group and MPO-negative group although DFS in all patients was different according to MPO expression.
MPO expression at diagnosis helps to choose therapy for each AML patient and can differentiate AML patients who need transplantation.
Myeloperoxidase; acute myeloid leukemia; prognostic factor; transplant
Chronic use of alcohol is considered to be a potential risk factor for the incidence of type 2 diabetes mellitus (T2DM), which causes insulin resistance and pancreatic β-cell dysfunction that is a prerequisite for the development of diabetes. However, alcohol consumption in diabetes has been controversial and more detailed information on the diabetogenic impact of alcohol seems warranted. Diabetes, especially T2DM, causes dysregulation of various metabolic processes, which includes a defect in the insulin-mediated glucose function of adipocytes, and an impaired insulin action in the liver. In addition, neurobiological profiles of alcoholism are linked to the effects of a disruption of glucose homeostasis and of insulin resistance, which are affected by altered appetite that regulates the peptides and neurotrophic factors. Since conditions, which precede the onset of diabetes that are associated with alcoholism is one of the crucial public problems, researches in efforts to prevent and treat diabetes with alcohol dependence, receives special clinical interest. Therefore, the purpose of this mini-review is to provide the recent progress and current theories in the interplay between alcoholism and diabetes. Further, the purpose of this study also includes summarizing the pathophysiological mechanisms in the neurobiology of alcoholism.
Alcohol; Diabetes mellitus; Glucose; Insulin
This study was conducted to evaluate the efficacy of the herbal formula PM012 on an Alzheimer's disease model, human presenilin 2 mutant transgenic mice (hPS2m), and also to evaluate the toxicity of PM012 in Sprague-Dawely rats after 4 or 26 weeks treatment with repeated oral administration.
Spatial learning and memory capacities of hPS2m transgenic mice were evaluated using the Morris Water Maze. Simultaneously, PM012 was repeatedly administered orally to male and female SD rats (15/sex/group) at doses of 0 (vehicle control), 500, 1,000 and 2,000 mg/kg/day for 4 or 26 weeks. To evaluate the recovery potential, 5 animals of each sex were assigned to vehicle control and 2,000 mg/kg/day groups during the 4-week recovery period.
The results showed that PM012-treated hPS2m transgenic mice showed significantly reduced escape latency when compared with the hPS2m transgenic mice. The repeated oral administration of PM012 over 26 weeks in male and female rats induced an increase and increasing trend in thymus weight in the female treatment groups (main and recovery groups), but the change was judged to be toxicologically insignificant. In addition, the oral administration of the herbal medicine PM012 did not cause adverse effects as assessed by clinical signs, mortality, body weight, food and water consumption, ophthalmology, urinalysis, hematology, serum biochemistry, blood clotting time, organ weights and histopathology. The No Observed Adverse Effects Levels of PM012 was determined to be 2,000 mg/kg/day for both sexes, and the target organ was not identified.
These results suggest that PM012 has potential for use in the treatment of the Alzheimer's disease without serious adverse effects.
PM012; Repeated oral toxicity; Presenilin 2; NOAEL; Morris water maze; Spatial memory
Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader–Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score <15. Despite the highly heterogeneous nature, the three ASD samples (UIC, UF and Lam’s) showed a similar pattern of the RBS-R endorsements, and the mean RBS-R scores were not different between the UIC and UF samples. However, higher RRB was noted in the ASD sample compared with the PWS sample, as well as in the PWS subgroup with a SCQ score ≥15 compared with the PWS subgroup with a SCQ score <15. Study limitations include a small sample size, a wide age range of our participants, and not controlling for potential covariates. A future replication study using a larger sample and further investigation into the genetic bases of overlapping ASD and RRB phenomenology are needed, given the higher RRB in the PWS subgroup with a SCQ score ≥15.
RRB; ASD; PWS; RBS-R
This study aimed to estimate the prevalence of metabolic syndrome (MetS) in adolescents and adults and to compare the impact of body mass index (BMI) on MetS between adolescents and adults in Korea.
Materials and Methods
Data were used from 6,186 subjects aged 10 years or more who representatively participated in the Third Korean National Health and Nutrition Examination Survey. Body composition, blood test, and health behavioral factors were measured. We used the definition of MetS from the modified the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) for adolescents and the NCEP-ATP III for adults.
The prevalence of MetS was 6.4 (95% CI 4.5-8.4) and 22.3 (95% CI 20.8-23.8) in adolescents and adults, respectively. The prevalence of MetS among normal, overweight and obese body types for both adolescents and adults differed significantly (p<0.001). After adjustment for covariates, the odds ratios (ORs) of obese and overweight body types on MetS compared with normal BMI in adolescents were 28.1 (95% CI 11.4-69.1) and 8.7 (95% CI 2.3-33.1), respectively. The ORs of obesity on MetS were 32.0 (95% CI 7.5-136.9), 32.2 (95% CI 12.8-80.8), 16.2 (95% CI 9.4-27.9), 7.6 (95% CI 4.7-12.2) and 9.9 (95% CI 6.8-14.6) for subjects in their 20's, 30's, 40's, 50's and older than 60, in order.
We found that the prevalence of MetS increased with age and was more prevalent in males. Moreover, the group younger than 39 years of age had a higher chance of having MetS than the group older than 40 years of age. Weight control is more vital in the earlier stages of life for the prevention and management of MetS.
Obesity; metabolic syndrome X; prevalence; adolescents; adults
BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) are members of the tumor necrosis factor family and promote B cell survival and proliferation. We evaluated the correlation between serum concentration of BAFF or APRIL and severity of acute graft-versus-host disease (GVHD).
Fifteen patients who received allogeneic hematopoietic stem transplantation for leukemia and developed acute GVHD were enrolled. We determined serum concentrations of BAFF and APRIL at the onset of the first clinical manifestation of GVHD by enzyme-linked immunosorbent assay.
Nine patients had grade 2 acute GVHD, and 6 had grade 3-4 acute GVHD. The BAFF serum concentration was higher in patients with grade 3-4 acute GVHD (1,093.42 in grade 2 vs. 2,171.99 pg/mL in grade 3-4), although the difference was not significant (P=0.077). However, the ratio of BAFF serum concentration to absolute lymphocyte count (ALC) (BAFF/ALC) was significantly higher in patients with grade 3-4 acute GVHD (P=0.045). The APRIL serum concentration and APRIL/ALC ratio showed similar results (P=0.077 and P=0.013, respectively).
Patients with grade 3-4 acute GVHD had higher BAFF/ALC and APRIL/ALC ratios than patients with grade 2 acute GVHD. These findings suggest that B cells might play an important role in the development of acute GVHD, and that the BAFF and APRIL concentrations in serum might be significant predictive factors for estimating the severity of acute GVHD. Their clinical significance should be further evaluated in a larger patient population.
B cell-activating factor (BAFF); A proliferation-inducing ligand (APRIL); Acute graft-versus-host disease; Allogeneic hematopoietic stem cell transplantation
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of aggressive T-cell lymphomas with poor treatment outcomes. The aim of this study was to evaluate whether lymphopenia at diagnosis would have an adverse effect on survival in patients with PTCL-NOS treated with anthracycline-containing chemotherapy.
A total of 118 patients with PTCL-NOS treated with anthracycline-containing chemotherapy from 4 Korean institutions were included.
Thirty-six patients (30.5%) had a low absolute lymphocyte count (ALC, < 1.0 × 109/L) at diagnosis. Patients with lymphopenia had shorter overall survival (OS) and progression-free survival (PFS) rates compared with patients with high ALCs (P = 0.003, P = 0.012, respectively). In multivariate analysis, high-intermediate/high-risk International Prognostic Index (IPI) scores and lymphopenia were both associated with shorter OS and PFS. Treatment-related mortality was 25.0% in the low ALC group and 4.8% in the high ALC group (P = 0.003). In patients considered high-intermediate/high-risk based on IPI scores, lymphopenia was also associated with shorter OS and PFS (P = 0.002, P = 0.001, respectively).
This study suggests that lymphopenia could be an independent prognostic marker to predict unfavorable OS and PFS in patients with PTCL-NOS treated with anthracycline-containing chemotherapy and can be used to further stratify high-risk patients using IPI scores.
peripheral T-cell lymphoma; not otherwise specified; lymphopenia; international prognostic index; prognostic factor
SLC25A12 was previously identified by a linkage-directed association analysis in autism. In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R).
We used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). We examined associations in our University of Illinois at Chicago-University of Florida (UIC-UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families).
In the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025-0.040). The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202-rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset.
This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies.
Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and postmortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson's disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism.
Autism; Neurodevelopmental disorders; Stereotypy; Compulsions; Rituals; Cortical-basal ganglia circuitry
The aim of this study was to investigate the effect of changes in cardiovascular disease (CVD) risk factors on progression from prehypertension (PreHTN) to hypertension (HTN) using an 8-yr prospective Korean Cancer Prevention Study (KCPS) by the National Health Insurance Corporation (NHIC) in Korea.
A total of 16,229 subjects, aged 30 to 54, with new onset preHTN at baseline (1994-1996) in a biennial national medical exam were selected and followed up till 2004 at 2-yr intervals. All subjects underwent a biennial health examination including biochemical measurements and behavior. The log-rank test was performed to assess the relationship between changes in CVD risk factors and progression to HTN. The Cox proportional hazard model was used to identify factors influencing progression to HTN.
With regards the progression rate in men, ex-smokers (42.9%), abstainers (37.5%), and regular exercisers (37.6%) showed a slower progression rate than continuous smokers (49.5%) and continuous drinkers (50.9%). In women, those who participated in regular exercise (22.6%) had a lower rate of progression than continuous non-exercisers (36.1%). According to the results of the Cox proportional hazard model, improvements in smoking (hazard ratio [HR], 0.756), drinking (HR, 0.669), regular exercise (HR, 0.653), body mass index (HR, 0.715), and total cholesterol (HR, 0.788) played a protective role in progression to HTN in men, while in women, participating in regular exercise (HR, 0.534) was beneficial.
Improvements in CVD-related behaviors diminished the progression rate of HTN. This study suggests that individuals with PreHTN should be targeted for specific health behavioral intervention to prevent the progression of HTN.
Hypertension; Progression; Cardiovascular disease; Health behavior; Prospective study
Elevated platelet serotonin (5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood serotonin (5-HT), 5-HT binding affinity for the serotonin transporter (Km), 5-HT uptake (Vmax), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in twenty-four first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (Km, p = 0.005) and 5-HT uptake rate (Vmax, p = 0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p = 0.046). These initial studies of indices of the 5-HT system with several SNPs at loci in this system generate hypotheses for testing in other samples.
Autism; serotonin; binding; platelet; genetic; association
Reports identified the neuronal glutamate transporter gene, SLC1A1 (OMIM 133550, chromosome 9p24), as a positional and functional candidate gene for obsessive–compulsive disorder (OCD). The presence of obsessions and compulsions similar to OCD in autism, the identification of this region in a genome-wide linkage analysis of individuals with autism spectrum disorders (ASDs), and the hypothesized role of glutamate in ASDs make SLC1A1 a candidate gene for ASD as well. To test for association between SLC1A1 and autism, we typed three single nucleotide polymorphisms (SNPs, rs301430, rs301979, rs301434) previously associated with OCD in 86 strictly defined trios with autism. Family-Based Association Tests (FBAT) with additive and recessive models were used to check for association. Additionally, an rs301430–rs301979 haplotype identified for OCD was investigated. FBAT revealed nominally significant association between autism and one SNP under a recessive model. The G allele of rs301979 was undertransmitted (equivalent to overtransmission of the C allele under a dominant model) to individuals with autism (Z = −2.47, P = 0.01). The G allele was also undertransmitted in the T–G haplotype under the recessive model (Z = −2.41, P = 0.02). Both findings were also observed in the male-only sample. However, they did not withstand correction for multiple comparisons.
autism; SLC1A1; OCD; association
Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson’s disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism.
Autism; Neurodevelopmental disorders; Stereotypy; Compulsions; Rituals; Cortical-basal ganglia circuitry
The prognosis for patients with primary central nervous system (CNS) lymphoma (PCNSL) who relapse after the initial response is usually poor. A standard treatment for relapsed PCNSL has not yet been identified because of the heterogeneity of the therapies employed and the lack of large, prospective clinical trials. We describe a 46-year-old relapsed PCNSL patient who was successfully treated with intraventricular applications of rituximab to minimize neurotoxicity, 2 cycles of salvage chemotherapy with etoposide, ifosfamide, and cytarabine (VIA) regimen and high-dose chemotherapy with autologous stem cell rescue. The high-dose chemotherapy consisted of bischloroethylnitrosourea, etoposide, cytarabine, and melphalan (BEAM) regimen. Partial remission was detected after intraventricular rituximab therapy and the patient has been in complete remission without evidence of neurotoxicity for 28 months after high-dose chemotherapy with autologous stem cell rescue. This case indicates a new appropriate treatment guideline in relapsed PCNSL patient after initial intensive chemo-radiotherapy.
Primary central nervous system lymphoma; salvage therapy; rituximab; high-dose chemotherapy with autologous stem cell rescue