A Deletion Mutation of the Connexin 26 (Gjb2) Gene in a Turkish Patient with Vohwinkel Syndrome .

Vohwinkel syndrome (VS), also known as keratoderma hereditaria mutilans, is a rare keratinization genetic disorder characterized by palmoplantar keratoderma, skeletal dysmorphisms and varying degrees of sensorineural deafness. Its mode of inheritance is autosomal-dominant, with mutations in loricrin and connexin 26 (GJB2) genes that manifest during infancy and boceme more evident during adulthood. We herein report a case of VS in a 23-year-old female exhibiting sensorineural hearing loss, palmar keratoderma and homozygous deletion mutation delE120 (c.358-360delGAG) in the GJB2 gene. VS, is a rare genetic disorder, should be considered in patients with palmoplantar keratoderma and hearing loss and should be investigated connexin 26 (GJB2) gene mutation.

TWO DIFFERENT MUTATIONS OF GL13 GENE IN TWO DIFFERENT SYNDROMES.

Polydactyly is among comnion extremity abnormalities. Mutations of GLI3 gene have been reported commonly in Greig Cephalopolysyndactyly Syndrome (GCPS) and Pallister-Hall Syndrome (PHS). We have determined two different mutations of GLI3 gene in two different cases, one of which is with GCPS and the other one is with PHS. A deletion mutation was detected in the proband with GCPS and his mother. Otherwise, we found that, unlike the previously reported, the mutation c.2437C>T, p.Q813X which was detected in the GLI3 gene caused typical PHS. We are in thought of that our cases will contribute to understanding of phenotypic variability leading to GLI3 mutations.

Effects of MMP-1 and MMP-3 gene polymorphisms on gene expression and protein level in lumbar disc herniation.

The aim of this study was to identify the possible correlation between polymorphisms in matrix metalloproteinase (MMP)-1 and MMP-3 and their corresponding protein levels in disc tissues obtained from patients with lumbar disc herniation (LDH) using biochemical and immunohistochemical analyses. Blood and disc samples were obtained from 100 patients with LDH who underwent a lumbar microdiscectomy. Based on the radiological degeneration, the patients were diagnosed with grade 2, 3, or 4 LDH. MMP-1 -1607 1G/2G and MMP-3 -1171 5A/6A were analyzed by real-time polymerase chain reaction. The expressions of MMP-1 and MMP- 3 were detected by biochemical and immunohistochemical analyses. We found no association between the MMP-1 polymorphism and disc degeneration and MMP-1 expression. However, patients expressing the 6A/6A and 5A/6A alleles of MMP-3 -11715A/6A showed higher MMP-3 expression, compared to those expressing the 5A/5A genotype. Additionally, the radiological degeneration grades were correlated with the histological degeneration scoring. Protein levels and immunopositive cell rates of MMP-1 and MMP-3 were associated with disc degeneration grades. Moreover, the MMP-1 and MMP-3 expression and the histological and radiological scores were positively correlated and the MMP-3 -11715A/6A polymorphism was associated with MMP-3 expression in herniated disc tissues. This study is the first to investigate polymorphisms in MMP-1 and MMP-3, as well as their corresponding protein expressions. We also quantified an association between the radiological degeneration grades and MMP-1 and MMP- 3 expression. Further genomic studies on MMPs could focus on the utilization of MMP-1 and MMP-3 as markers for the prevention and treatment of this disease.

Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group.

The etiology underlying neural tube defects (NTDs) is not fully understood and is believed to involve a complex milieu of genetic and environmental factors. The A1298C polymorphism in the methylenetetrahydropholate reductase gene (MTHFR) has been associated with mild risk for NTDs. In this study, the genotype distribution of the MTHFR gene A1298C polymorphism and the levels of serum homocysteine, vitamin B12, and folate were evaluated in 33 children with NTDs, their mothers, and 46 healthy controls. Genotyping of the A1298C polymorphism was performed by real-time polymerase chain reaction. The A and C allele frequencies in children with NTDs and their mothers were similar to controls (P = 0.160). The 1298AA and 1298CC genotype frequencies (P = 0.551 and 0.062, respectively) in children with NTDs and their mothers did not differ from controls. On the other hand, the 1298AC genotype frequencies in children with NTDs and their mothers were significantly different from controls (P = 0.025). The genotype frequency of 1298AC was lower in children with NTDs than in controls. There was no significant association between clinical distribution of NTDs and 1298AA/AC/CC genotypes (P > 0.05). Serum vitamin B12 levels were higher in children with NTDs than their mothers and controls (P = 0.001). There were no differences among serum homocysteine and folate levels in all groups (P = 0.494 and 0.141, respectively). Both genetic and nutritional factors are important in the etiology of NTDs. Thus, the A1298C polymorphism cannot be regarded as a major risk factor for NTDs.

Pretransplant serum ferritin level may be a predictive marker for outcomes in patients having undergone allogeneic hematopoietic stem cell transplantation.

Iron overload increases the risk of infections, veno-occlusive disease and hepatic dysfunction in post-transplant period. Our objective was to investigate the association of pre-transplant ferritin levels with complications and survival after allogeneic hematopoietic stem cell transplantation (alloHSCT).We retrospectively analysed 84 patients' data who had undergone allogeneic HSCT into two groups: patients with a serum ferritin level ≥ 1000 ng/ml, and patients with <1000 ng/ml at the time of HSCT.Cox-regression analysis showed that pre-transplant serum ferritin levels were significantly higher in patients who had at least one infectious event compared with those who had no any infectious event in the post-transplant 100 days (p<0.023). Overall survival (OS) and disease-free survival (DFS) rates were significantly higher in patients with a time-to-tx interval 12 months (p=0.002 and p=0.008 respectively). A higher risk of death was observed in high-ferritin group (hazard ratio=2.27, CI:1.01-5.09, p=0.023 for OS and hazard ratio=2.49, CI:1.12-5.53 p=0.039 for DFS). No significant effect on OS and DFS among groups was observed for variables conditioning regimen, gender and diagnosis. Acute GVHD was more common in patients with a ferritin level ≥ 1000 ng /mL, but this was not statistically significant (p>0.05). There was no statistical significance in both groups (ferritin ≥ 1000 ng /mL and ferritin <1000 ng/mL) for relapse rates (p>0.05). Platelet and neutrophil engaftment day was not found statistically significant compared with both groups (p=0.273 and p=0.882, respectively). Pre-transplant ferritin levels may predict poor outcomes in patients who had undergone allogeneic hematopoietic stem cell transplantation.

Research on and clinical importance of duplications in various chromosomal regions in addition to Philadelphia chromosome in chronic myeloid leukemia.

PURPOSE: To investigate the chromosomal aberrations in chronic myelogenous leukemia (CML), particularly in chromosomal regions which carried 67 genes pertaining to oncogenes, transcription factors, signal transduction, tumor suppressors, apoptosis etc, in addition to Philadelphia (Ph+) chromosome by multiplex ligation-dependent probe amplification (MLPA) method and to compare them with clinical parameters. METHODS: The aberrations were investigated in 48 CML patients receiving imatinib therapy and a group of 15 healthy controls, by using the MLPA method between 2000 and 2009. The obtained results were compared both between patient and control groups and with clinical parameters. RESULTS: Duplication was detected in the fibroblast growth factor receptor 1 (FGFR1) gene of 2 patients, inosine 5' monophosphate dehydrogenase 1 (IMPDH1) gene of 4, postmeiotic segregation increased S. Cerevisiae 2 (PMS2) gene of 1, nuclear factor kappa beta (NFKB) of 5 and T-cell translocation 2 (LMO2) gene of 1 patient. Univariate analysis showed that splenomegaly, advanced age, Sokal risk score (SRS) and the duplications in IMPDH1 and FGFR1 genes significantly shortened 7-year event-free survival (EFS); multivariate analysis showed that only the duplications in IMPDH1 and FGFR1 genes were the factors that significantly affected EFS. No statistically significant correlations were detected between duplications and other clinical parameters. CONCLUSION: Duplications in 4 genes (FGFR1, IMPDH1, PMS2, LMO2) in addition to Ph+ chromosome in CML patients were detected for the first time. This study indicates that chromosomes 7 and 8 should be particularly investigated in more detail in addition to the Ph+ chromosome for better determination of disease prognosis and selection of alternative treatments.

The clinicopathological features and survival of Castleman disease: a multicenter Turkish study.

OBJECTIVE: In this study, we aimed to investigate the clinicopathological features and survival of CD, which is quite rare and has many unknowns. PATIENTS AND METHODS: This study was conducted by retrospectively evaluating patients diagnosed with CD in six different centers in Turkey. RESULTS: The median age of 33 patients included in the study was 49 and 51.5% (n = 17) of these patients were women. 18 (54.5%) patients were in the hyaline vascular subtype and most of the patients were UCD (n = 20, 60.6%). The most common involvement region was head and neck (n = 19, 57.5%). The UCD group was younger than the MCD group (p=0.027). Visceral lymph node involvement was higher in MCD than in UCD (p=0.001). Similarly, it was observed that there was more hepatomegaly (p=0.035) and splenomegaly (p=0.013) in the MCD group. During the median 19.5 months follow-up period, there were no patients who died. CONCLUSIONS: It was observed that UCD and MCD are different clinical entities. Promising survival times can be achieved with surgical and systemic treatments in both subtypes of this extremely rare disease. However, this result should be supported by well-designed prospective comprehensive studies.

Association of estrogen receptor alpha and collagen type I alpha 1 gene polymorphisms with bone mineral density in postmenopausal women.

UNLABELLED: In this study, ERα gene PvuII and XbaI polymorphisms and COL1A1 gene Sp1 polymorphisms in postmenopausal women were compared with lumbar vertebra and femoral neck BMD values. In conclusion, it was designated that PvuII polymorphism was effective on average lumbar vertebra BMD value in postmenopausal women of our study group. INTRODUCTION: Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. Several candidate gene polymorphisms have been implicated in the regulation of this process. In this study, the relationship among BMD values of lumbar vertebra and femoral neck and ERα gene PvuII and XbaI polymorphisms and COL1A1 gene Sp1 polymorphism in 126 postmenopausal women (30 normal, 46 osteopenic, and 50 osteoporotic in terms of bone mineral density) was researched. METHODS: The ERα gene PvuII and XbaI genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) whereas the COL1A1 gene Sp1 genotype was determined by real-time PCR. BMDs at the lumbar spine (vertebrae L1-L4) and hip (femur neck) were measured by dual-energy X-ray absorptiometry. RESULTS: According to our study results, the significant difference was found in women with normal, osteopenic, and osteoporotic bone mass in terms of ERα gene PvuII polymorphism "pp" genotype frequency. The "pp" genotype frequency was significantly lower in women with normal bone mass. Average lumbar vertebra BMD value of women with "PP" genotype was significantly higher than that with "pp" genotype. On the other hand, in the evaluations on ERα gene XbaI polymorphism and COL1A1 gene Sp1 polymorphism, it was noted that there was no difference in terms of average BMD values, genotype, and allele frequencies among groups. CONCLUSION: In conclusion, it was designated that ERα gene PvuII polymorphism was effective on average lumbar vertebra BMD value in postmenopausal women of our study group.

Short aggrecan gene repetitive alleles associated with lumbar degenerative disc disease in Turkish patients.

We investigated a possible association between aggrecan gene polymorphism and lumbar degenerative disc disease in Turkish patients. One hundred 20-30-year-old patients with or without low back pain were selected for the study. Lumbar magnetic resonance imaging was performed on all patients. The patient group had low back pain clinically and degenerative disc disease radiographically. The control group included patients with and without low back pain: all were negative radiographically for degenerative disc disease. Genomic DNA was extracted from all participants. A PCR assay were used to evaluate variable number of tandem repeat polymorphism of aggrecan gene alleles to determine if there was any correlation with degenerative disc disease. Significant associations were found between short repeated alleles of the aggrecan gene and severe disc degeneration. A significant association was also found between short repeated alleles of the aggrecan gene and multilevel disc herniation as well as extrusion and sequestration types of disc herniation. In Turkish population, short repeated alleles of the aggrecan gene are associated with increased disc degeneration and disc herniation.

C677T polymorphism of the methylenetetrahydrofolate reductase gene does not affect folic acid, vitamin B12, and homocysteine serum levels in Turkish children with neural tube defects.

Association between neural tube defects (NTDs) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was suspected, because the MTHFR gene codes for a key enzyme in folate metabolism. Its deficiency usually leads to significant reductions in plasma concentrations of folate, vitamin B(12) and methionine, whereas homocysteine levels are increased. We examined folate, vitamin B(12) and homocysteine serum concentrations and polymorphism of the C677T MTHFR gene in Turkish children with neural tube defects. Thirty-three children with NTDs, 26 mothers and 48 healthy individuals were studied. C677T MTHFR polymorphism was determined by melting curve analyses (LightCycler). The levels of folate, vitamin B(12) and homocysteine serum concentrations in NTDs were evaluated and compared, along with information concerning alleles of the MTHFR gene. C677T allele frequencies in NTD children and their mothers were similar to those found in controls. Serum folate and vitamin B(12) concentrations were significantly higher in NTD children than that of controls. Serum homocysteine concentrations were not significantly higher in NTD children and mothers. We concluded that C677T MTHFR gene polymorphism does not affect folic acid, vitamin B(12) and homocysteine metabolism in Turkish children with NTDs. C677T polymorphism of the MTHFR gene cannot be regarded as a major risk factor for NTDs in Turkish children.

Familial nodular lymphocyte predominant Hodgkin lymphoma: Successful treatment with CHOP plus rituximab.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare tumor type distinct from classical Hodgkin lymphoma and its familial form is unusual. The two cases (mother at age 48 and son at age 30 years) of NLPHL in advanced clinical stage are described. The patients were successfully treated with an immunochemotherapy schedule consisting CHOP plus rituximab (CHOP-R). This chemotherapy was well tolerated and the patients reached complete remission. These remissions were for 34 and 40 months for mother and son, respectively. In patients with NLPHL, CHOP-R regimen should be used as an alternative treatment regimen to obtain a good long-lasting response without any adverse events.

Solitary plasmacytoma: experiences from Central Anatolia.

BACKGROUND: Solitary plasmacytoma localised to bone or soft tissue without myeloma. AIM: Clinical features and survival was analysed in patients from Central Anatolia. METHODS: Twenty-three solitary plasmacytoma (18 male, 5 female) were evaluated retrospectively. Median age was 58 years (46-72). The major localisation was vertebral column. RESULTS: All patients but one (larynx) had surgical resection and 21 patients received radiotherapy postoperatively. Multiple myeloma developed in eight patients (35%) and local relapse was detected in one patient. Eight patients died, causes of death were multiple myeloma progression in six patients, local relapse of intracranial plasmacytoma in one patient and cranial trauma in one patient who was in complete remission. Three and 5 years progression free survival were 45.6% and 22.8% respectively and overall survivals were 54.4% and 27.2% respectively. CONCLUSION: Solitary plasmacytoma cases should be followed carefully regarding local relapse and progression to myeloma.

A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor type but most patients ultimately experience disease progression. SCLC is associated with alterations in the coagulation system. The present randomized clinical trial (RCT) was designed to determine whether addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) would improve SCLC outcome compared with CT alone. METHODS: Combination CT consisted of cyclophosphamide, epirubicine and vincristine (CEV) given at 3-weekly intervals for six cycles. Eighty-four patients were randomized to receive either CT alone (n = 42) or CT plus LMWH (n = 42). LMWH consisted of dalteparin given at a dose of 5000 U once daily during the 18 weeks of CT. Results Overall tumor response rates were 42.5% with CT alone and 69.2% with CT plus LMWH (P = 0.07). Median progression-free survival was 6.0 months with CT alone and 10.0 months with CT plus LMWH (P = 0.01). Median overall survival was 8.0 months with CT alone and 13.0 months with CT plus LMWH (P = 0.01). Similar improvement in survival with LMWH treatment occurred in patients with both limited and extensive disease stages. The risk of death in the CT + LMWH group relative to that in the CT group was 0.56 (95% confidence interval 0.30, 0.86) (P = 0.012 by log rank test). Toxicity from the experimental treatment was minimal and there were no treatment-related deaths. CONCLUSIONS: These results support the concept that anticoagulants, and particularly LMWH, may improve clinical outcomes in SCLC. Further clinical trials of this relatively non-toxic treatment approach are indicated.

Effects of DMSO on platelet functions and P-selectin expression during storage.

Recent studies suggested that the expression of P-Selectin on stored platelets is related to in vitro activation and loss of viability. We examined the effects of dimethylsulfoxide (DMSO) on in vitro function and P-Selectin expression of platelet concentrates. Fresh random-donor platelet units (n = 60) were divided into four equal groups. A DMSO-free group was chosen as a control. DMSO (0.5%, 1.0%, and 3.0%) was added to the other three groups. The samples were stored on a horizontal shaker at room temperature. Biochemical, morphological and platelet function tests and P-Selectin expression were monitored during storage. In all groups, P-Selectin expression, lactate and LDH levels, mean platelet volumes and PO2 increased but the aggregation response to agonist, the recovery response to hypotonic shock, platelet count, glucose level, pCO2, and HCO3 decreased during storage. In DMSO-containing groups, the P-Selectin expression which is a predictor of in vitro activation, was found significantly less often than in the DMSO-free group.

Meropenem +/- granulocyte colony stimulating factor in the treatment of febrile neutropenic patients with cancer: prospective randomized study.

The purpose of this study was to evaluate the impact of granulocyte-colony stimulating factor (G-CSF) on the therapy for febrile neutropenia (FN). Our patient population differed significantly from those of previous studies as no patients received antimicrobial or CSF prophylaxis before randomization and all were solid tumor patients. When the diagnosis of FN was established, patients were started on intravenous meropenem 1 g every 8 hours and randomly assigned to receive G-CSF (5 microg/kg body weight per day subcutaneously) or not. Twenty-eight patients with 30 FN episodes received G-CSF and 25 patients with 30 FN episodes did not receive G-CSF according to randomization. The time to resolution of fever, recovery of neutrophil count over 1000/mm3, duration of hospitalization, need for erythrocyte and platelet transfusion and mortality rate were similar in both study groups. Side effects of therapy were mild. These results provide preliminary evidence that G-CSF administration, in addition to effective antibiotic therapy as treatment of febrile neutropenic patients with solid tumor, does not help improve infection-related morbidity and mortality.

Unusual Cause of Back Pain in a Multiple Myeloma Patient: Infectious Discitis.

A 58 year old patient, followed up for diabetes mellitus and multiple myeloma for ten years and six months, respectively, presented with persistent back pain, weakness at his lower extremity and intermittent fever. Activation markers of myeloma were in normal limits except high erythrocyte sedimentation rate and elevated C-reactive protein. Magnetic resonance imaging revealed increased T1 spinal intensity at the suspected disc level. Discitis was suspected on the basis of MRl and high fever. An intraoperative examination of specimens revealed Staphylococcus aureus. Detailed laboratory and radiological investigations should be performed to diagnose unusual causes of persistent back pain, such as discitis in patients with myeloma.

Hodgkin's Disease: Results of a Single Center in Central Anatolia.

Hodgkin's Disease (HD) accounts for about 1% of newly diagnosed malignant diseases. In this study 119 HD cases followed in Erciyes University Hospital were evaluated. 67.2% of the patients was male, 32.8% female. The patients' age ranged from 15 to 72 years with a median of 41.5 years. Of the patients 10.1% was stage I, 29.4% stage II, 39.5% stage III, and 21.0% stage IV. According to Rye classification frequency of histologic subtypes was as follows; 21.0% lymphocyte predominant, 25.2% nodular sclerosis, 43.7% mixed cellularity, and 10.1% lymphocyte depletion. Combination chemotherapy consisting cyclophosphamide, vincristine, procarbazine and prednisolone (COPP) was used as first line treatment in 59.7% of patients. Complete remission was achieved in 84.9% of patients and partial remission in 5.0% of patients; response could not be obtained in remaining 10.1% of patients. Disease progression or recurrence was observed in 30.2% of patients. Five year survival rate was found as 70.8% of all patients, 90.1% for stage I-II, 55.3% for stage III-IV patients (p= 0.03).

The impact of pretransplant hypoalbuminemia on survival in patients with leukemia who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT): a nutritional problem?

OBJECTIVE: Serum albumin level is considered to be a marker reflecting the nutritional status in both healthy subjects and patients with malignancies. In this study we sought to investigate the association between pretransplantation serum albumin levels and prognosis among patients with leukemia who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). METHODS: We retrospectively analyzed the data of 102 patients who underwent alloHSCT from 2004 to 2010. Pretransplant serum albumin, D-dimer, creatinine, and fibrinogen levels drawn within 10 days before transplantation were obtained from patient files. All parameters were divided into 2 groups: normal levels (group 1) versus abnormal levels (group 2). Our normal range of serum albumin is 3.2-5.2 g/dL; patients with pretransplantation albumin level ≥3.2 g/dL were included in group 1 versus group 2 with <3.2 g/dL. RESULTS: The patients included 42 (41.1%) female and 60 (58.9%) male patients. The diagnoses were acute myeloblastic leukemia in 65 (63.7%) and acute lymphoblastic leukemia in 37 (36.3%). The median age was 26.0 years (range, 13-57). Univariate and multivariate analysis showed that patients with serum albumin levels <3.2 g/dL experienced significantly lower overall survival (OS) compared with ≥3.2 g/dL (hazard ratio [HR] 2.32 [range, 1.23-4.54] and HR 2.70 [range 1.38-5.26], respectively; P = .009). The median (range) OS in group 2 was 230.0 (184.0-544.0) days versus 570.5 (249.5-1,101.0) days in group 1 (P = .007). For disease free survival (DFS) evaluation, univariate and multivariate analysis showed that patients with serum albumin levels <3.2 g/dL had significantly lower values compared with patients with serum albumin ≥3.2 g/dL. (HR 2.17 [range 0.98-4.76] and HR 2.85 [range, 1.25-6.66], respectively; P = .046). The median (range) DFS in group 2 was 184.0 (61.0-524.0) days versus 445.0 (199.0-917.5) days in group 1 (P = .045). Among the patient characteristics the presence of infection was a significant independent variable for worse OS (HR 2.12 [range, 0.98-4.36], P = .036). The other parameters-age, sex, donor status, time to transplant interval, conditioning regimens, HLA status, and number of total infused CD34(+) cells-showed no significant effect on OS and DFS (P = .05). CONCLUSIONS: Pretransplantation decreased serum albumin levels were associated with poor survival in patients with leukemia who underwent alloHSCT.

Successful kidney transplantation from a cadaveric donor unsuitable for other centers due to acute renal failure: a case report.

The demand for kidney transplantation due to improved recipient outcomes has stimulated surgeons to expand the criteria for usable donors, but still the use of organs from deceased donors with terminal acute renal failure is uncommon. We report 2 kidney transplant recipients from a cadaveric donor who was not accepted by other centers because of acute renal failure. The donor, a 24-year-old man with an intracerebral hemorrhage, displayed a serum creatinine (SCr) value of 0.6 mg/dL on hospital admission, which increased to 7.3 mg/dL on the fourth hospital day. After the diagnosis of brain death and refusal of the kidneys by other regional centers, we decided to transplant the 2 kidneys. Recipient 1, a 31-year-old man on an 11-year dialysis program, discontinued hemodialysis after 7 days of delayed graft function. The SCr level decreased gradually and was stable at 1.08 mg/dL on postoperative day (POD) 45. The contralateral graft was transplanted into a 30-year-old man (recipient 2) undergoing dialysis treatment for 7 years. After 10 days of delayed graft function, the SCr decreased gradually with continued hemodialysis until POD 24. The SCr level has been stable at 1.34 mg/dL on POD 52. At the end of the third month the SCr levels in recipients 1 and 2 were 1.1 mg/dL and 1.4 mg/dL, respectively. In conclusion, one may safely expand the donor pool with kidneys from deceased donors with acute renal failure (ARF) with good short-term outcomes.