Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations

Purpose

This study was designed to investigate the characteristics of Korean patients with calpainopathy.

Materials and Methods

Thirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed.

Results

Nine different mutations, including four novel mutations ({"type":"entrez-nucleotide","attrs":{"text":"NM_000070","term_id":"27765081","term_text":"NM_000070"}}NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology.

Conclusion

We identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.     

Clinical Characteristics and Treatment Outcomes of Mycobacterium kansasii Lung Disease in Korea

Purpose

While Mycobacterium kansasii is a common cause of nontuberculous mycobacterial (NTM) lung disease in many developed countries, M. kansasii is infrequently isolated in Korea. We investigated the clinical and radiological features and treatment outcomes of M. kansasii lung disease in Korea retrospectively.

Materials and Methods

We identified 41 patients with M. kansasii lung disease who met the diagnostic criteria for NTM lung disease in two tertiary referral hospitals in Seoul, Korea, between January 1998 and December 2007.

Results

Their median age was 63 years [interquartile range (IQR) 51-75 years] and 33 (81%) were men. Twenty-three patients (56%) were smokers and 13 patients (32%) had previous pulmonary tuberculosis. The most common radiographic findings were nodules (n = 22, 54%) and consolidation (n = 22, 54%). Cavitation was present in 13 patients (32%). Thirty-one patients (76%) were treated with isoniazid, rifampin, and ethambutol. The median treatment duration was 16 months (IQR 9-18 months). The negative conversion rate after 12 months of treatment was 95%.

Conclusion

Clinicians should be aware of the various radiographic manifestations of M. kansasii lung disease. With appropriate treatment, these patients have a good prognosis.     

Clinical and Genetic Aspects in Twelve Korean Patients with Adrenomyeloneuropathy

Purpose

This study was designed to investigate the characteristics of Korean adrenomyeloneuropathy (AMN) patients.

Materials and Methods

We retrospectively selected 12 Korean AMN patients diagnosed by clinical analysis and increased plasma content of very long chain fatty acids.

Results

All 12 patients were men. Patient ages at symptom onset ranged from 18 to 55 years. Family history was positive in two patients. The phenotype distributions consisted of AMN without cerebral involvement in seven patients, AMN with cerebral involvement in two patients, and the spinocerebellar phenotype in three patients. Nerve conduction studies revealed abnormalities in four patients and visual evoked tests revealed abnormalities in three patients. Somatosensory evoked potential tests revealed central conduction defects in all of the tested patients. Spinal MRI showed diffuse cord atrophy or subtle signal changes in all 12 patients. Brain MRI findings were abnormal in six of the nine tested patients. These brain abnormalities reflected the clinical phenotypes. Mutational analysis identified nine different ABCD1 mutations in 10 of 11 tested patients. Among them, nine have been previously reported and shown to be associated with various phenotypes; one was a novel mutation.

Conclusion

In conclusion, the present study is the first to report on the clinical and mutational spectrum of Korean AMN patients, and confirms various clinical presentations and the usefulness of brain MRI scan.     

Standardized combination antibiotic treatment of Mycobacterium avium complex lung disease

Purpose

The optimal treatment regimen for Mycobacterium avium complex (MAC) lung disease has not yet been fully established. We evaluated the efficacy of standardized combination antibiotic therapy and the factors that might affect unfavorable microbiologic responses in patients with MAC pulmonary disease.

Materials and Methods

This retrospective study reviewed data from 96 patients (56 females; median age 59 years) treated with newly diagnosed MAC lung disease between January 2003 and December 2006.

Results

All patients received standardized combination antibiotic therapy, consisting of clarithromycin, rifampicin, and ethambutol. Streptomycin was additionally given in 72 patients (75%) for a median duration of 4.5 months. The overall favorable microbiologic response rate was 79% (76/96); 20 patients (21%) had unfavorable microbiologic responses, including failure to sputum conversion (n = 13), relapse (n = 3), and MAC-related death (n = 4). A positive sputum acid-fast bacillus smear at the start of treatment was an independent predictor of an unfavorable microbiologic response.

Conclusion

Standardized combination antibiotic therapy consisting of clarithromycin, rifampicin, and ethambutol with or without initial use of streptomycin is effective in treating patients with newly diagnosed MAC lung disease.     

Homozygous SMN2 deletion is a major risk factor among twenty-five Korean sporadic amyotrophic lateral sclerosis patients

Purpose

The association between survivor motor neuron (SMN) gene deletion and spinal muscular atrophy suggests that sporadic amyotrophic lateral sclerosis (sALS) may be related to SMN deletion. We examined the association between the SMN genotype and susceptibility to and severity of sALS.

Materials and Methods

We genotyped the copy number of SMN1 and SMN2 in 25 patients diagnosed with sporadic ALS and 100 healthy subjects in a Korean population. Onset age and medical research council (MRC) scale were compared among patients according to SMN1 : SMN2 genotypes.

Results

There was a significantly higher incidence of homozygous deletion of SMN2 (SMN1 : SMN2 genotype, 2 : 0) in sALS patients (20%) than in the normal controls (2%) (p<0.001). The onset age for patients with homozygous deletion of SMN2 (2 : 0) was significantly younger (34±15.38 years) than that of patients with 2 : 1, 2 : 2 and 2 : 3 of the SMN1 : SMN2 genotype (59.5±5.09; 52.69±16.46 and 50±0.00 years) (p=0.049). The ratio of patients with an MRC scale above G4- was smaller in the 2 : 0 genotype (40%) than in the 2 : 1, 2 : 2 and 2 : 3 genotypes (83.3%, 100% and 100%) (p=0.02).

Conclusion

The homozygous SMN2 deletion (2 : 0) was statistically more frequent and associated with earlier onset age and lower MRC scale in Korean sALS patients. These suggest that SMN2 deletion may be one of the factors associated with susceptibility to and severity of sALS in a Korean population.     

Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study

Objective

To obtain penetrance data for Huntington''s disease when DNA results are in the range of 36–39 CAG repeats and assess the consistency of reporting the upper allele from two reference centres.

Method

Data were collected anonymously on age of onset or age last known to be unaffected from a cohort of individuals with results in this range. DNA samples were re‐analysed in two reference centres. Kaplan‐Meier analysis was used to construct an age of onset curve and penetrance figures.

Results

Clinical data and concordant DNA results from both reference centres were available for 176 samples; penetrance figures (and 95% confidence intervals) for this cohort, at age 65 and 75 years, were 63.9% (55.5% to 73.2%) and 74.2% (64.2% to 84.2%), respectively. Inclusion of 28 additional subjects for whom repeat DNA results were unavailable, obtained from only one reference centre, or discrepant by one repeat within this range, gave penetrance data (including 95% confidence intervals) at ages 65 and 75 years of 62.4% (54.4% to 70.4%) and 72.7.% (63.3% to 82.1%), respectively. 238 duplicate results were available from the reference centres; 10 (4.2%) differed by one CAG repeat in the reporting of the upper allele and in two (0.84%) of these cases the discrepancy was between 39 and 40 repeats.

Conclusion

When DNA results are in this range, a conservative approach is to say that there is at least a 40% chance the person will be asymptomatic at age 65 years and at least a 30% chance the person will be asymptomatic at age 75 years.     

Association Analysis Between FILIP1 Polymorphisms and Aspirin Hypersensitivity in Korean Asthmatics

Purpose

Aspirin exacerbated respiratory disease (AERD) results in a severe asthma attack after aspirin ingestion in asthmatics. The filamin A interacting protein 1 (FILIP1) may play a crucial role in AERD pathogenesis by mediating T cell activation and membrane rearrangement. We investigated the association of FILIP1 variations with AERD and the fall rate of forced expiratory volume in one second (FEV1).

Methods

A total of 34 common FILIP1 single nucleotide polymorphisms (SNPs) were genotyped in 592 Korean asthmatic subjects that included 163 AERD patients and 429 aspirin-tolerant asthma (ATA) controls.

Results

This study found that 5 SNPs (P=0.006-0.01) and 2 haplotypes (P=0.01-0.03) of FILIP1 showed nominal signals; however, corrections for the multiple testing revealed no significant associations with the development of AERD (P_corr>0.05). In addition, association analysis of the genetic variants with the fall rate of FEV1, an important diagnostic marker of AERD, revealed no significant evidence (P_corr>0.05).

Conclusions

Although further replications and functional evaluations are needed, our preliminary findings suggest that genetic variants of FILIP1 might be not associated with the onset of AERD.     

Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy's disease)

OBJECTIVE:

To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy''s disease.

METHODS:

Ten patients (from 7 families) with a genetic diagnosis of Kennedy''s disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene.

RESULTS:

Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53). Tremor was present in 8 (80%) patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88%) patients with tremor, who all responded well to treatment with a β-blocker (propranolol).

CONCLUSION:

Tremor is a common feature in patients with Kennedy''s disease and has characteristics similar to those of essential tremor.     

Molecular and Epidemiological Characterization of Carbapenem-Resistant Acinetobacter baumannii in Non-Tertiary Korean Hospitals

Purpose

The increasing prevalence and global spread of carbapenem-resistant Acinetobacter baumannii (A. baumannii) has become a serious problem. The aim of this study was to investigate molecular and epidemiological characteristics of carbapenem-resistant A. baumannii isolates collected from Korean non-tertiary hospitals.

Materials and Methods

Thirty six non-duplicated carbapenem-resistant A. baumannii isolates were collected from 17 non-tertiary hospitals in Korea between 2004 and 2006. Isolates were typed by multilocus sequence typing and repetitive-sequence-based PCR (rep-PCR). Detection of genes encoding OXA carbapenemase and their relationship with ISAba1 was performed by PCR.

Results

Two clones were prevalent among 36 isolates: ST69 (17 isolates, 47.2%) and ST92 (19 isolates, 52.8%). Rep-PCR patterns were diverse and revealed that all isolates were clustered into eight band patterns. The ISAba1-activated blaOXA-23-like and ISAba1-activated blaOXA-51-like genes were prevalent among the carbapenem-resistant A. baumannii isolates.

Conclusion

The class D β-lactamase genes of A. baumannii were distributed nationwide in non-tertiary Korean hospitals.     

Nodding syndrome: origins and natural history of a longstanding epileptic disorder in sub-Saharan Africa

Background

Repetitive involuntary head nodding was first reported in the 1960s in the Wapogoro tribe of Tanzania.

Objectives

We describe the natural history of head nodding in the Wapogoro tribe, with special reference to the earliest reported dates of onset.

Methods

We analyzed clinical data from 150 historical patients seen between 1960 and 1971.

Results

Head nodding with or without grand mal convulsions was present in 33/150 (∼20%) cases, was mostly familial and equally distributed by gender. Age at onset of head nodding ranged from 2–22 years (mean: ∼10 years) in the period 1934–1962. Head nodding preceded onset of grand mal convulsions by up to 12 months, and motor and psychomotor deficits indicative of brain damage developed with time. Fourteen of the 33 cases died at 13–39 years of age (mean: ∼20 years) while nineteen aged 16–28 years (mean: ∼16 years) were still alive.

Conclusion

Historical accounts of head nodding (amesinzia kichwa, Swahili) among the Wapogoro tribe fit the August 2012 World Health Organization (WHO) case definition of probable Nodding Syndrome. Reported to have existed in this population for at least 80 years, Nodding Syndrome is a progressive seizure disorder that leads to generalized convulsions (kifafa), brain damage and death.     

Association of the adiponectin gene variations with risk of ischemic stroke in a Korean population

Purpose

Stroke is the second leading cause of death and a major cause of morbidity and mortality worldwide. Evidence of variations in adiponectin(AdipoQ) genes that are associated with ischemic stroke has not been consistent, and it is unclear whether the same loci contribute to these associations in the Korean population. Using a Korean population, we tested ischemic stroke-associated AdipoQ markers.

Materials and Methods

In a preliminary genome-wide association study using 320 250 k Affymetrix NSP chips, AdipoQ was found to be associated with ischemic stroke in Koreans. To study of AdipoQ, a further 673 ischemic stroke patients and 267 unrelated individuals without a history of stroke or transient ischemic attack were examined in a case-control study.

Results

Six polymorphisms (rs182052G > A, rs16861205G > A, rs822391T > C, rs822396A > G, rs12495941G > T and rs3774261A > G) that had a minor allele frequency of over 1% were strongly associated with stroke (p < 0.05). Two of these, rs822391T > C and rs822396A > G showed this association on both dominant and additive logistic regression analysis after adjusting for age and sex. The haplotypes ht 1 (AGGCGG and AAGTAG) were significantly associated with susceptibility to stroke.

Conclusion

Our findings show that polymorphisms in AdipoQ are associated with risk for ischemic stroke in the Korean population. This study lends further support to the putative role of AdipoQ in stroke.     

The Impact of Cigarette Smoking on the Frequency of and Qualitative Differences in KRAS Mutations in Korean Patients with Lung Adenocarcinoma

Purpose

This study was designed to determine the relationship of cigarette smoking to the frequency and qualitative differences among KRAS mutations in lung adenocarcinomas from Korean patients.

Materials and Methods

Detailed smoking histories were obtained from 200 consecutively enrolled patients with lung adenocarcinoma according to a standard protocol. EGFR (exons 18 to 21) and KRAS (codons 12/13) mutations were determined via direct-sequencing.

Results

The incidence of KRAS mutations was 8% (16 of 200) in patients with lung adenocarcinoma. KRAS mutations were found in 5.8% (7 of 120) of tumors from never-smokers, 15% (6 of 40) from former-smokers, and 7.5% (3 of 40) from current-smokers. The frequency of KRAS mutations did not differ significantly according to smoking history (p=0.435). Never-smokers were significantly more likely than former or current smokers to have a transition mutation (G→A or C→T) rather than a transversion mutation (G→T or G→C) that is known to be smoking-related (p=0.011). In a Cox regression model, the adjusted hazard ratios for the risk of progression with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were 0.24 (95% CI, 0.14-0.42; p<0.001) for the EGFR mutation and 1.27 (95% CI, 0.58-2.79; p=0.537) for the KRAS mutation.

Conclusion

Cigarette smoking did not influence the frequency of KRAS mutations in lung adenocarcinomas in Korean patients, but influenced qualitative differences in the KRAS mutations.     

Clinical review of endogenous endophthalmitis in Korea: a 14-year review of culture positive cases of two large hospitals

Purpose

To identify the clinical features and outcomes of endogenous endophthalmitis in Korea.

Materials and Methods

We reviewed 18 patients with endogenous endophthalmitis at 2 Korean hospitals, treated over a 14 year period between January 1993 and December 2006.

Results

The comorbidities observed in these cases were diabetes mellitus and liver cirrhosis. The most common pathogens, which were found in 7 patients each (38.9%), were Klebsiella pneumonia and Pseudomonas aeruginosa. All patients were treated with systemic antibiotics and fortified topical antibiotics. A surgical approach including vitrectomy was performed in 9 cases (50.0%). The prognosis was generally poor, and visual acuity improved slightly in 6 patients (33.3%).

Conclusion

In this study, diabetes mellitus and Klebsiella pneumonia showed a close relationship with endogenous endophthalmitis, respectively. Endogenous endophthalmitis is a serious risk to sight and careful attention to establishing the diagnosis and management may decrease the ocular morbidity.     

Acute toxicity effects of the methanolic extract of Fagara zanthoxyloides (Lam.) root-bark

Background

Fagara zanthoxyloides is a well known medicinal plant in Uganda. It is used extensively in malaria and other infections. However nothing is known about its toxicity.

Objective

The objective of the study was to evaluate the acute toxicity of the methanolic extract of the root-bark of F. zanthoxyloides, in mice.

Methods

Methanolic extract of the root-bark of the plant was administered orally to mice at various dose levels to determine the acute toxic effects and the median lethal dose (LD₅₀) in mice.

Results

The LD50 of the methanolic extract was found to be 5.0 g/Kg body weight within 95 % confidence limits. The mice showed signs of cerebral irritation before dying. Histopathological examinations of the viscera showed congestion and focal necrosis of the liver and renal tubules.

Conclusion

It was concluded that the extract of F. zanthoxyloides is safe, however the cerebral mechanism that lead to the death of the mice need to be investigated further.     

Factors associated with HD CAG repeat instability in Huntington disease

Background

The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene.

Results

In this study, we used a collection of 112 sperm DNAs from male HD gene‐positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat‐length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father–offspring and 311 mother–offspring pairs in this Venezuelan pedigree. Repeat‐length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat‐length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring.

Conclusion

Significant sibling–sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.     

Association Between Serum IgE Levels and the CTLA4 +49A/G and FCER1B -654C/T Polymorphisms in Korean Children With Asthma

Purpose

T cells play a central role in cell-mediated immunity, atopic disease, and asthma. The balance of CD28/cytotoxic T-lymphocyte antigen 4 (CTLA4)-derived signal transduction plays an important role in the activation of T cells and an increased immunoglobulin E (IgE) response. The aim of the current study was to investigate the association between polymorphisms in the genes encoding both CTLA4 and the high-affinity IgE receptor 1B (FCER1B) and serum IgE levels in Korean children with asthma.

Methods

We enrolled 238 controls and 742 children with asthma. The CTLA4 +49A/G and FCER1B -654C/T polymorphisms were genotyped by PCR-restriction fragment length polymorphism analysis.

Results

We observed no difference in the distribution of CTLA4 +49A/G among controls, children with asthma, and those with atopic asthma. In contrast, the GA genotype of CTLA4 +49A/G in children with atopic asthma was significantly higher compared to that in those with non-atopic asthma. Moreover, significantly higher log Dp/Df-specific IgE levels were found in children with asthma and those with atopic asthma carrying one or two copies of the CTLA4 +49A versus those homozygous for +49G. Gene-gene interactions between CTLA4 and FCER1B with the heterozygote and homozygote of variant genotypes were associated with the log Dp/Df-specific IgE levels, but not asthma development. In addition, children with Dp/Df (+) asthma carried an elevated combined genotype of risk allele compared to those with Dp/Df (-) asthma.

Conclusions

The CTLA4 +49A/G polymorphism may contribute to the production of IgE in Korean children with asthma, especially in Dp/Df-specific IgE levels, but not in the direct development of asthma. In addition, Dp/Df-specific IgE levels with a FCER1B -654C/T polymorphism may involve additive effects.     

Antibiogram of E. coli serotypes isolated from children aged under five with acute diarrhea in Bahir Dar town

Background

Diarrheal disease and its complications remain a major cause of morbidity and mortality in children. The prevalence and antibiogram of E. coli as causative agents of diarrhea vary from region to region, and even within countries in the same geographical area.

Objectives

To determine the serotype and antimicrobial susceptibility of E. coli in children under-five years of age.

Methods

A cross-sectional study was conducted among 422 children with diarrhea from December 2011 to February 2012. Identification of E. coli and antimicrobial susceptibility testing were done following standard procedures.

Results

The overall isolation rate of E. coli was 48.3%. Poly 2 sero-groups, poly 3 sero-groups, poly 4 sero-groups and E. coli O157:H7 accounted for 80 (39.2%), 40 (19.6%), 25 (12.3%), and 59 (28.9%) of the isolates, respectively. Poly 2 sero-groups, constituting isolates belonging to enteropathogenic E. coli were the most commonly isolated serotypes. E. coli exhibited high levels of antimicrobial resistance to ampicillin (86.8%), tetracycline (76%) and cotrimoxazole (76%). Low levels of resistance to ciprofloxacin (6.9%) and norfloxacin (9.3%) were documented.

Conclusion

High prevalence of diarrheagenic E. coli compounded by alarming antimicrobial resistances is a serious public health problem. Regular determination of antibiogram and public education are recommended.     

Surveillance of Stool Samples for the Presence of Enterobacter sakazakii among Korean People

Purpose

Enterobacter sakazakii (E. sakazakii) infections are an important cause of life-threatening meningitis, septicemia, and necrotizing enterocolitis in infants. Dried infant formula milk is an important vehicle for E. sakazakii infection. E. sakazakii was isolated in Korea from dried infant formula milk. Although E. sakazakii infection of infants may occur in Korea, its prevalence has not yet been documented. Therefore, we determined the prevalence of E. sakazakii and documented symptoms.

Materials and Methods

Between March and October 2006, 1,146 stool samples were collected from patients at Uijeongbu St. Mary''s Hospital. Each fecal swab was dissolved in 10 mL of buffered peptone solution, and enriched culture was streaked onto Druggan-Forsythe-Iversen (DFI) agar. Presumptive E. sakazakii colonies that exhibited a blue-green color during culture on DFI medium were selected. The identity of colonies that developed yellow pigment during culture on TSA was determined using the Vitek system and PCR.

Results

We isolated 4 E. sakazakii strains whose 16S rRNA sequence alignments had a similarity of 99% with those of 3 E. sakazakii ATCC strains.

Conclusion

This is the first report on isolation of E. sakazakii from stool samples and to document the symptoms of Korean patients.     

Teicoplanin dosing strategy for treatment of Staphylococcus aureus in Korean patients with neutropenic fever

Purpose

The present study was conducted to determine and compare the target attainment rate (TAR) between microorganism-nonspecific (C_trough) and microorganism-specific (AUC₂₄/MIC) targets over two weeks of teicoplanin administration according to several dose regimens for the treatment of Staphylococcus aureus in Korean patients with neutropenic fever.

Materials and Methods

One thousand virtual concentrations were obtained for each dose using the population pharmacokinetic parameters of teicoplanin adopted from a published study. Simulation of 1,000 virtual MICs was performed using the MICs of 78 clinical isolates of S. aureus collected from a hospital in Korea. Thereafter, these simulated MICs were randomly allocated to 1,000 virtual patients in whom the TARs for AUC₂₄/MIC >125 [or 345] and C_trough >10 [or 20] mg/L were determined. The relationship of the maintenance dose with the steady-state TAR was predicted with respect to the AUC₂₄/MIC >125 [or 345] using logistic analysis.

Results

The standard dose regimen of teicoplanin showed TARs of about 70% [or 33%] and 70% [or 20%] at steady-state in cases with AUC₂₄/MIC >125 [or 345] and C_trough >10 [or 20] mg/L, respectively.

Conclusion

The current standard dose regimen was predicted to be insufficient to adequately treat S. aureus in Korean patients with neutropenic fever. To assure at least an 80% TAR in this population, dose adjustment of teicoplanin should be considered.