Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.

BACKGROUND AND PURPOSE: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi-allelic mutations in NKX6-2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. METHODS: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6-2 mutations in a multicentre setting is described. Then, all reported NKX6-2 mutations and those identified in this study were combined and an in-depth analysis of NKX6-2-related disease spectrum was provided. RESULTS: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6-2 were identified, evidencing a high NKX6-2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6-2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. CONCLUSIONS: NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6-2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels.

Epidemiology of pertussis in adolescents and adults in Turkey.

Two hundred and fourteen patients who had a cough illness lasting at least 2 weeks were studied to investigate Bordetella pertussis as a cause of prolonged cough in adolescents and adults. Medical history and nasopharyngeal swab specimens for culture and polymerase chain reaction (PCR) were obtained at presentation. Three (1·4%) patients were B. pertussis culture-positive; 15 (7%) were B. pertussis PCR-positive (including the culture-positive patients) and 11 (5·1%) were Bordetella spp. PCR-positive. Symptom combinations were significantly high both in patients with pertussis and patients with indeterminate results (P < 0·05). We conclude that B. pertussis should be considered among differential diagnoses of prolonged cough in adolescents and adults and PCR and culture should be used to detect these cases and facilitate public health response.

Investigation of enterovirus infections, autoimmune factors and HLA genotypes in patients with T1DM.

AIM: Besides of genetic and autoimmun factors, role of viral infections have been investigated in pathogenesis of type 1 diabetes mellitus (T1DM). The aim of this study was to determine enterovirus (EV) infections, glutamic acid decarboxylase (GAD) antibody positivity and HLA genotype distribution in T1DM patients with respect to corresponding healthy subjects. This is the first study in Turkey designed to investigate enteroviral infections and autoimmune and genetic factors together in this group of patients. METHODS: EV RNA, coxsackie virus B type 4 (CV-B4) antibodies, GAD antibodies and HLA genotypes were investigated in 86 patients with T1DM and in 100 control subjects. RESULTS: EV RNA was not detected in either the patient or control group. CV-B4 type antibodies and GAD antibodies were identified in 66.3% and 47.6% patients and 55.0% and 19% control subjects, respectively (for GAD antibodies P=0.001). High-risk HLA-DQ and high-risk HLA-DR genotypes for T1DM were identified in 67.3% and 86.0% of patients, respectively, and the difference was significantly higher compared with controls (34% and 40%, respectively, P=0.001). CONCLUSION: There was no significant relation between CV-B4 neutralizing antibody, GAD antibody positivity and high-risk HLA genotypes in patients. In conclusion, no correlation was found in this study between T1DM and EV infections. In addition, there was no relation between EV infections and T1DM in patients with high-risk genotypes or in patients with autoimmunity.

Effects of folinic acid and fluorouracil chemotherapy on right ventricle func-tions as assessed with tricuspid annular plane systolic excursion.

AIM: This study aimed to investigate the effects of folinic acid and fluorouracil (bolus FUFA regimen) chemotherapy on right ventricle (RV) functions. MATERIALS AND METHODS: Thirty-four gastrointestinal (GI) cancer patients treated with antineoplastic drugs were included the study. All participants received FUFA chemotherapy protocol for colorectal, gastric and pancreatic cancer (i.e. fluorouracil 400-425 mg/m(2) intravenous day 1-5 + folinic acid 20-25 mg/m2 intravenous day 1-5 every 28 days x6 cycles) with or without radiation therapy according to the cancer and patient status. All participants have undergone complete physical and laboratory examination and complete echocardiographic evaluation including detailed right ventricle functional evaluations before the onset of chemotherapy and 6 months after the start of treatment. RESULTS: Mean RV thickness was 0.49 cm before chemotherapy and 0.62 cm at the end of the treatment (p=0.29). Mean tricuspid annular plane systolic excursion (TAPSE) values were 2.08 ± 0.3 and 2.00 ± 0.39 cm, respectively (p=0.25). RV total ejection isovolumic (Tei) index related to the chemotherapy did not change significantly (0.24 and 0.29, respectively, p=0.07). Also we did not find significant chance in the RV end diastolic diameter, RV end systolic diameter, vena cava diameter on inspiration and expiration. CONCLUSION: Bolus FUFA regimen chemotherapy does not diminish the RV functions as assessed by TAPSE and RV Tei index in GI cancer patients.

A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11.

We report a consanguineous family of three girls and one boy affected with a novel syndrome involving the lens and the basal ganglia. The phenotype is strikingly similar between affected siblings with cognitive impairment, attention deficit hyperactivity disorder (ADHD), microcephaly, growth retardation, congenital cataract, and dystonia. The magnetic resonance imaging showed unusual pattern of swelling of the caudate heads and thinning of the putamina with severe degree of hypometabolism on the [18F] deoxyglucose positron emission tomography. Furthermore, the clinical assessment provides the evidence that the neurological phenotype is very slowly progressive. We utilized the 10K single-nucleotide polymorphism (SNP) microarray genotyping for linkage analysis. Genome-wide scan indicated a 45.9-Mb region with a 4.2353 logarithm of the odds score on chromosome 11. Affymetrix genome-wide human SNP array 6.0 assay did not show any gross chromosomal abnormality. Targeted sequencing of two candidate genes within the linkage interval (PAX6 and B3GALTL) as well as mtDNA genome sequencing did not reveal any putative mutations.

Prognostic factors in patients with advanced pancreatic cancer treated with gemcitabine alone or gemcitabine plus cisplatin: retrospective analysis of a multicenter study.

PURPOSE: The majority of patients with pancreatic cancer present with advanced disease. Systemic chemotherapy for patients with pancreatic cancer has limited impact on overall survival (OS). Patients eligible for chemotherapy should be selected carefully. The aim of this study was to analyse prognostic factors for OS in advanced pancreatic cancer patients treated with first-line palliative chemotherapy with gemcitabine alone or gemcitabine plus cisplatin. METHODS: We retrospectively reviewed 343 locally advanced or metastatic pancreatic cancer patients who were treated with gemcitabine or gemcitabine plus cisplatin as first-line chemotherapy between December 2000 and June 2011. Fifteen potential prognostic variables were chosen for analysis. Univariate and multivariate analyses were conducted to identify prognostic factors associated with OS. Univariate and multivariate statistical methods were used to determine prognostic factors. RESULTS: Among the 15 variables of univariate analysis, 6 were identified to have prognostic significance: stage (p<0.001), cholestasis (p=0.02), weight loss, prior pancreatectomy, serum CEA level (p<0.001) and serum CA19-9 level (p>0.001). In addition, age, chemotherapy and liver metastasis were of borderline significance (p=0.06). Multivariate analysis (Cox proportional hazard model) included the 6 significant prognostic factors of univariate analysis and showed that stage was independent prognostic factor for OS, as were weight loss, and serum CEA level. CONCLUSION: Stage, weight loss, and serum CEA level were identified as important prognostic factors for OS in advanced pancreatic cancer patients. These findings may also facilitate pretreatment prediction of OS and can be used for selecting patients for treatment.

Gemcitabine alone versus combination of gemcitabine and cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a retrospective analysis of multicenter study.

The majority of patients with pancreatic cancer is of advanced disease. Several randomized Phase II and III trials suggest that the combination of gemcitabine and cisplatin (GemCis) response rates were higher than Gemcitabine (Gem) alone, however the trials were not enough powered to indicate a statistically significant prolongation of survival in patients with advanced pancreatic adenocarcinoma. The aim of this retrospective multicenter study is to evaluated the efficiency of Gem alone versus GemCis in patients with locally advanced and/or metastatic pancreatic adenocarcinoma .A total of 406 patients, from fourteen centers were evaluated retrospectively. All patients received Gem or GemCis as first-line treatment between September 2005 to March 2011. Primary end of this study were to evaluate the toxicity, clinical response rate, progression-free survival (PFS) and overall survival (OS) between the arms. There were 156 patients (M: 98, F: 58) in Gem arm and 250 patients (M: 175, F: 75) in the combination arm. Gemcitabin arm patients older than the combination arm ( median 63 vs 57.5, p=0.001). In patients with the combination arm had a higher dose reduction (25.2% vs 11.3%, p=0.001) and dose delay (34% vs 16.8%, p=0.001). Among patients with the combination and Gemcitabin arm gender, diabetes mellitus, performance status, cholestasis, grade, stage did not have a statistically difference (p>0.05). Clinical response rate to the combination arm was higher than the Gem arm (69.0% vs 49.7%, p=0.001). PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance (8.9 vs 6.0, p=0.08). OS was not significantly superior in the GemCis arm (12.0 vs 10.2, p>0.05). Grade III-IV hematologic and nonhematologic toxicity were higher in the combination arm. PFS was more favorable in the GemCis arm than Gem alone, but the difference did not attain statistical significance. OS was not significantly superior in the GemCis arm.

Novel mutation in GLRB in a large family with hereditary hyperekplexia.

Hereditary hyperekplexia (HH) is a disorder of the inhibitory glycinergic neurotransmitter system. Mutations in five genes have been reported to cause the disease. However, only single mutation in GLRB, the gene encoding beta-subunit of the glycine receptor, in a singleton patient with HH has been found to date. In this study, 13 patients with HH were identified through neurology and genetic clinics. Formal clinical examinations, linkage analysis, homozygosity mapping, in-mutation screening of GLRB and in silico functional analyses were carried out. A novel mutation in GLRB among nine patients was identified. This c.596 T>G perturbation results in the change of the highly conserved methionine at position 177 to arginine. Besides the classical HH phenotype, seven patients had esotropia and few of them had behavioral problems. This study presents a large family with HH as a result of homozygous mutation in GLRB and expands the clinical spectrum of HH to include eye misalignment disorder. Moreover, the report of these familial cases supports the previous evidence in a single patient of an autosomal recessive inheritance of HH because of defects in GLRB.

Gemcitabine and cisplatin combination chemotherapy in triple negative metastatic breast cancer previously treated with a taxane/anthracycline chemotherapy; multicenter experience.

This study was aimed to establish clinical efficacy and tolerability of gemcitabine and cisplatin combination in patients with metastatic triple negative breast cancer progressing after anthracycline and taxane based chemotherapies.Thirty-three patients who were given cisplatin and gemcitabine for triple negative and metastatic breast cancer were evaluated retrospectively. A total of 141 cycles were administered with a median 4 cycles per patient. Median follow-up time was 14 months (range, 2-36 months). Objective response rate was 27.3%. Total clinical benefit of the combination was 48.4%. The estimated median progression free survival and median overall survival were 5 months and 14 months, respectively. The most common Grade 3 and 4 toxicity were neutropenia and thrombocytopenia observed in 10 (27.7%) and 9 (24.9%) patients, respectively. The combination of the gemcitabine and cisplatin after taxane/anthracycline is well tolerated and seems to be effective with acceptable toxicity profile.

Posttransplant lymphoproliferative disorders in transplant recipients.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with a reported incidence between 0.8% and 32%. The incidence of PTLD mainly depends on the transplanted organ, the immunosuppressive drugs, the viral serology, and the age of the recipient. The aim of our study was to analyze our patients diagnosed with PTLD. Among 1040 transplantations, including 931 renal, 14 heart, 55 liver and 40 allogeneic peripheral blood stem cell (PBSC), 8 patients (7 male, 1 female) were diagnosed with PTLD. Five patients had undergone renal, one cardiac, one liver, and one PBSC transplantations. Four patients were diagnosed within the first year of transplantation. Six patients presented with abdominal disease, one with convulsions, and one with peripheral lymph node involvement. According to the World Health Organization classification system, six patients were diagnosed as diffuse large B-cell lymphoma, one patient Burkitt's lymphoma, and one polymorphic PTLD. At the time of diagnosis, 7 patients showed positive Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Ig G and negative Ig M; one patient, positive EBV Ig M and negative CMV Ig G and M. EBV viral load was extremely high in the plasma of two patients by polymerase chain reaction. One of these patient's pathologic tissue revealed positive EBV DNA, which was not detected in six of the other eight patients. This patient was an 8-year-old boy diagnosed with Burkitt's lymphoma at 31 months after liver transplantation. Seven patients died of disease or complications of chemotherapy. Only one patient survived after the diagnosis of PTLD. In conclusion, even with treatment the mortality rate was high among our patients with PTLD. To decrease the incidence of PTLD and related mortality, risk factors must be evaluated in multicenter studies.

Serological evidence of West Nile Virus (WNV) in mammalian species in Turkey.

In this study, the sera collected from a variety of mammalian species (ass-mules, cat, cattle, dog, horse, human and sheep) in 10 representative provinces of Turkey, were surveyed for the presence of neutralizing antibodies to West Nile virus (WNV). Overall, 1 of 40 (2.5%) ass-mules, 4 of 100 (4%) cattle, 43 of 114 (37.7%) dogs, 35 of 259 (13.5%) horses, 18 of 88 (20.4%) humans and 1 of 100 (1%) sheep, tested positive for WNV-neutralizing antibodies. The results indicate that a wide range of mammals are exposed to a West Nile-related virus and this could contribute to the long-term survival of this virus in the absence of overt disease.

A rare case of HSV-2 encephalitis.

Herpes simplex viruses (HSV), and especially HSV-1, are the most common cause of acute, sporadic viral encephalitis. HSV-2 is an uncommon cause of encephalitis. We report a rare case of HSV-2 encephalitis that was free of genital lesions. In terms of the patient's case history, she had a Cesarean section four months before, herpes labialis 30 days before, varicella zoster 20 days before. We discuss the possibility that postpartum stress may be one of the factors in this case.

Seroprevalence of antibodies to legionella pneumophila in hemodialysis patients.

Patients with chronic renal failure are at increased risk for infections because of impaired cellular immunity. This study was designed to determine the prevalence of antibodies to Legionella pneumophila serogroups 1 to 6 and to evaluate the possible risk factors for Legionnaires' disease in hemodialysis patients. Serum samples to be screened for antibodies against L pneumophila and risk factor data were collected from 252 hemodialysis patients. The overall prevalence of L pneumophila antibodies in hemodialysis patients was found to be 5.16% There was no statistically significant difference between L pneumophila seropositivity and potential risk factors. Further studies are needed to determine possible risk factors for Legionnaires' disease in hemodialysis patients.

First confirmed case of vancomycin-resistant Enterococcus faecium meningitis in Turkey: case report and literature review.

Vancomycin-resistant enterococci are unusual etiologic agents of bacterial meningitis and pose significant therapeutic difficulties. We report the first confirmed case of nosocomial vancomycin-resistant Enterococcus faecium meningitis in Turkey. The patient was treated with chloramphenicol and cerebrospinal fluid cultures became negative, but clinical success was not achieved. We also review the previously reported cases of vancomycin-resistant Enterococcus faecium meningitis.

Seroprevalence of antibodies to hepatitis A and E viruses in pediatric age groups in Turkey.

Hepatitis A and hepatitis E are enteric transmitted viral diseases occurring in epidemic and sporadic forms especially in developing countries. Previous studies in Turkey showed that most residents are infected with HAV by the second decade of life. Since HEV is generally transmitted by the same route as HAV we conducted a community-based seroprevalence study for HAV and HEV infection in Ahatli area in Antalya, Turkey where socioeconomic conditions are low. Anti-HAV total immunoglobulin was tested by using a microparticle EIA (Axsym-Abbott Lab). Anti-HEV IgG was assayed by a micro ELISA method (Genelabs-Singapore). Of the 338 sera tested, 112 (33.1%) were positive for anti-HAV total antibody. Anti-HEV IgG was detected in three (0.89%) of the serum samples. Seropositivity rates of HAV in preschool and school children were 19.9% and 43.9% respectively (p < 0.001). No antibody to HEV was detected in preschool children, while the prevalence of anti-HEV IgG was 1.6% in children attending school. Our data showed that seroprevalence of anti-HAV is high among children samples but HEV infection appears to be relatively rare in pediatric age groups.

Hepatitis C virus association with non-Hodgkin's lymphoma.

Infectious etiology has been confirmed only in a few lymphoproliferative disorders such as human T-cell lymphotropic virus in adult T-cell leukemia lymphoma, Epstein-Barr virus in African-type Burkitt's lymphoma and Hodgkin's disease, and Helicobacter pylori infection in primary gastric B-cell lymphoma. In recent years, Ferri and colleagues have found hepatitis C virus (HCV) association with non-Hodgkin's lymphoma (NHL) in Italy. The aim of our study was to determine the HCV association in NHL patients in Antalya. Forty-eight patients (22 women and 26 men, with a median age of 52 years) with NHL were included in the study. The control group consisted of 28 patients with various hematological disorders (11 women and 17 men with a median age of 50 years). Anti-HCV antibodies were investigated in 48 patients, and HCV RNA was assessed in 35 of them. Anti-HCV antibodies were found to be negative in the NHL group, but HCV RNA was positive in the serum of three patients (8.6%), who were diagnosed with diffuse small cell lymphoma (19%). Anti-HCV antibodies and HCV RNA were negative in the control group. Since HCV association with NHL has previously been reported in Italy, it is likely that both genetic and environmental factors in the Mediterranean sea-region may be involved in the oncogenesis in HCV RNA-positive patients. Multicenter studies with large patient groups will disclose the true association of HCV with NHL in Turkey.