AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells.

PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.

The role of allopurinol on oxidative stress in experimental hyperthyroidism.

AIM: During hyperthyroidism, production of free oxygen radicals derives, where xanthine oxidase may also play an important role. Allopurinol, a xanthine oxidase inhibitor, has a significant effect on thyrotoxicosis-related oxidative stress. However, the relationship between thyroid hormones, oxidative stress parameters and allopurinol remains to be explored. METHODS: Forty-two Wistar albino rats were divided into three groups. Rats in group A served as negative controls, while group B had untreated thyrotoxicosis and group C received allopurinol. Hyperthyroidism was induced by daily 0.2 mg/kg L-thyroxine intraperitoneally in groups B and C; 40 mg/kg allopurinol were given daily intraperitoneally. Efficacy of the treatment was assessed after 72 h and 21 days, by measuring serum xanthine oxidase (XO), malondialdehyde (MDA), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) and nitric oxide derivates (NO*x). RESULTS: In both time periods, serum XO, MDA, GSH and NO*x levels were significantly increased after thyroid hormone induction (p<0.05). Levels of XO, MDA and NO*x decreased with allopurinol treatment (p<0.05). There was a remarkable decrease in triiodothyronine levels in group C after 72 h (p<0.05), and in both triiodothyronine and thyroxine levels in group C after 21 days (p<0.05). There was no difference between groups B and C in means of serum GSH, GR and GPx levels (p>0.05). CONCLUSIONS: This study suggests an association between allopurinol and the biosynthesis of thyroid hormones. Allopurinol prevents the hyperthyroid state, which is mediated predominantly by triiodothyronine and not by XO. This issue has to be questioned in further studies where allopurinol is administered in control subjects.

The relationship of the apolipoprotein E gene polymorphism Turkish Type 2 diabetic patients with and without nephropathy.

OBJECTIVE: Apolipoprotein E (ApoE) genetic variation which is a major constituent of plasma lipoproteins causes diabetic nephropathy progress. Chronic kidney disease is associated with increased E2 allele and the decreased E4 allele risk. The aim of this study was to investigate the association between ApoE gene polymorphism in the development of diabetic nephropathy in Type 2 diabetes Turkish patients. RESEARCH DESIGN AND METHODS: The objective of the study is to investigate the influence of ApoE gene polymorphism in the development of diabetic nephropathy in Turkish Type 2 diabetes. The ApoE genotypes were determined retrospectively in 46 patients with nephropathy and 56 without nephropathy and a control group of 35 healthy individuals. Genomic DNA was extracted from peripheral leukocytes of the subjects using the High Pure PCR Template Preparation Kit. For the detection of the presence of the three ApoE E alleles epsilon2, epsilon3, and epsilon4 (codon 112 and 158) were analyzed by the commercial LightCycler ApoE Mutation Detection Kit. RESULTS: No differences in ApoE genotype or the allelic frequencies of epsilon2, epsilon3 or epsilon4 were found between the Type 2 diabetic patient group (with and without nephropathy) and a control group. CONCLUSIONS: We conclude that the ApoE gene polymorphism is not associated with the development of diabetic nephropathy in Turkish Type 2 diabetic patients. Lack of association between ApoE gene polymorphism and Type 2 diabetic nephropathy might be due to ethnic differences.

[Frequency of obsessive compulsive symptoms and disorder in patients with schizophrenia: importence for prognosis]. / Fréquence des symptômes et du trouble obsessionnel compulsif chez les personnes atteintes de schizophrénie et leur importance pour le pronostic.

OBJECTIVE: The objective is to study the comorbidity rate of obsessive compulsive disorder and obsessive compulsive symptoms in patients with schizophrenia and their relation with the course of this illness. DESIGN: 73 out-patients from Istanbul Medical Faculty Department of Psychiatry and 4th Unit of Bakirköy Mental Hospital who met the DSM III-R criteria for schizophrenia were recruited for this study. Other inclusion criteria were being out of acute exacerbation phase of schizophrenia. Yale-Brown Obsessive-Compulsive Scale, Yale Brown Obsessive Compulsive Symptom Screening Inventory were applied to patients. RESULTS: Comorbidity rate of obsessive-compulsive disorder in patients with schizophrenia was 9.6%, and also obsessive compulsive symptoms were detected 31% of patients. Aggressive obsessions were seen most frequently. These symptoms were also reported more frequently in the patients whose Global Assessment of Functionality score was higher than 45 points. Suicide attempts in psychiatric history were significantly higher for patients with obsessive-compulsive symptoms. CONCLUSION: Our findings indicate that obsessive-compulsive symptoms are seen more frequently than previously reported, and have no major effect upon the course of schizophrenia.

Chest injuries in civilian life and their treatment.

Between 1971 and 1980, some 1,452 patients who had injuries to their chest were hospitalized and treated in our clinic; 949 (65.4 percent) of them had blunt chest injury, and 504 (34.7 percent) had open chest injury. Conservative treatment was given in 1,327 cases. Surgical exploration was carried out in the remaining 125 patients. Twenty-nine of these patients (2 percent) were operated on immediately, and late thoracotomy was carried out in 96 (8 percent). A total of 1,272 of the patients who had conservative treatment (95.9 percent) and 118 who had surgery (94 percent) recovered. The overall mortality in patients who had conservative treatment was 4.1 percent (55 cases) and in those who had surgery was 6 percent (seven cases).

Serum prolactin levels in Behçet's Syndrome.

Since prolactin (PRL) has been implicated as playing a role in the pathogenesis of certain autoimmune diseases and since Behcet's Syndrome (BS) is a unique systemic vasculitis, we investigated serum PRL levels in patients with BS. We found that mean PRL levels in patients with clinically active BS, were not significantly higher than patients with clinically inactive BS and healthy controls. This finding may be regarded as evidence that a contribution of hyperprolactinemia to the aetiopathogenesis of BS seems unlikely.

Penetrating chest injuries in children: a review of 94 cases.

Ninety-four children with penetrating chest injuries were treated at Dicle University School of Medicine during a 6-year period. The mean age was 11.51 +/- 3.31 years, and the male:female ratio was 5.25:1. Forty-five had stab wounds, 27 had high-velocity gunshot wounds, 13 had low-velocity gunshot wounds, seven had a bomb (shrapnel) injury, one had a shotgun wound, and one had a horse bite. Sixty patients had isolated thoracic injuries, and 34 had associated injuries. The most common thoracic injury was hemothorax (28), followed by hemopneumothorax (25). Tube thoracostomy alone was sufficient in 79.8% of the patients (75 of 94). Thoracotomy was performed in 4.25% (4 of 94). In two of the five observed patients, delayed hemothorax developed. The mean duration of hospitalization was 5.13 +/- 1.93 days. The mean Injury Severity Score was 14.71 +/- 8.62. Prophylactic antibiotics were used in all patients. The morbidity rate was 8.51% (8 of 94). Only one death occurred after cervical tracheal repair. The study suggests that the majority of penetrating chest injuries in children can be treated successfully by tube thoracostomy alone or in conjunction with expectant observation.

Peripheral vascular injuries in children.

We report 94 arterial injuries in 91 children treated at the Department of Thoracic and Cardiovascular Surgery, Medical School of Dicle University, between 1978 and 1988. The average age was 10.3 (range, 3 to 14) years. Stab wounds were seen in 37 patients (40%). Gunshot wounds were seen in 21 patients (23%), and two cases were caused by iatrogenesis. Vein damage was present in 39 patients (44.4%), and nerve loss was observed in 20 patients (21.2%). Twenty-one cases (23.3%) were associated with fractures. Diagnosis of arterial injury was made by clinical findings. Arteriography was used in 15 patients (16.5%) as the diagnostic method. The surgical interventions performed for arterial repair in our series were end-to-end anastomosis in 61 (64.5%), interposition of autogenous reversed saphenous vein grafts in 22 (23.4%), lateral suture in 8 (8.3%), and ligation in 3 (3.9%) patients. Four patients (5.3%) underwent limb amputation.

Surgical treatment of pulmonary hydatidosis in children: experience in 92 patients.

Ninety-two patients with a total of 112 pulmonary hydatid cysts underwent surgical treatment in our clinic between January 1980 and January 1992. Nine patients were found to have concomitant liver and pulmonary hydatid cysts. There were 65 boys and 27 girls; the age range was 5 to 14 years. The authors performed cystotomy and capitonnage in 78 patients, lobectomy in 9, segmentectomy in 3, and wedge resection in 2. Of 9 cases with concomitant liver and pulmonary hydatid cysts, 8 were approached by right thoracophrenotomy and 1 by median sternotomy and right phrenotomy. A one-stage operation via median sternotomy was performed in 3 patients who had bilateral pulmonary hydatid cysts. To prevent the development of secondary hydatid cysts because of spillage of hydatid fluid, the authors used 10% povidone-iodine poly (1-vinyl-2-pyrrolidone)-iodine complex intraoperatively as a scolicidal agent. There was no mortality or recurrence in the series.

Is vestibular rehabilitation as effective in bilateral vestibular dysfunction as in unilateral vestibular dysfunction?

BACKGROUND: Bilateral vestibular dysfunction causes serious disabilities and handicaps. Patients with bilateral dysfunction often restrict their activities and tend to be unsocial. AIM: To compare the effects of vestibular rehabilitation on disability, balance, and postural stability in patients with unilateral and bilateral vestibular dysfunction. DESIGN: Retrospective study. SETTING: Outpatient rehabilitation center. POPULATION: Patients with unilateral (group 1, N.=42) and bilateral vestibular dysfunction (group 2, N.=19). METHODS: All patients were evaluated before and after eight weeks of customized vestibular rehabilitation for disability (Dizziness Handicap Inventory [DHI], Activities-specific Balance Confidence Scale [ABC]), dynamic balance (Timed Up and Go Test [TUG], Dynamic Gait Index [DGI]), and postural stability (static posturography). RESULTS: The differences between DHI, TUG, DGI, and falling index (as assessed by static posturography) scores before and after the exercise program were statistically significant in both groups (P<0.05). There were no significant intergroup differences in any of the parameters evaluated (P>0.05). CONCLUSION: In this study, vestibular rehabilitation was found to be equally effective in unilateral and bilateral vestibular dysfunction patients for improving disability, dynamic balance, and postural stability. CLINICAL REHABILITATION IMPACT: Patients with bilateral dysfunction, causing more disability and greater handicap may indeed regain their functions as in patients with unilateral vestibular dysfunction by receiving appropriate and adequate vestibular rehabilitation.

Clinical presentation of Von Hippel Lindau syndrome type 2B associated with VHL p.A149S mutation in a large Turkish family.

Von Hippel Lindau (VHL) syndrome is an autosomal dominant disorder characterized by benign and malignant tumors. This study presents the clinical and genetic features of VHL syndrome in a Turkish family. For the diagnosis of pheochromocytoma-related diseases, 49 family members from three generations were evaluated between March 2008 and January 2013. Family members were examined to identify components of pheochromocytoma-related genetic syndromes through physical examination, laboratory tests, and imaging methods. For the causative mutation, sequence analysis of VHL gene was performed. Nine patients were diagnosed with pheochromocytoma. Lumbal spinal hemangioblastoma and pancreatic neuroendocrine tumor without pheochromocytoma were detected in one patient. In patients with pheochromocytoma, additional tumors, such as retinal angioma, renal cell carcinoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors were detected. All patients were diagnosed as VHL syndrome type 2B. Sequence analysis of VHL gene revealed heterozygous p.A149S mutation in all symptomatic patients and in seven of the asymptomatic family members. This is the first study that identified VHL p.A149S mutation in a Turkish family with VHL syndrome. However, VHL p.A149S mutation was identified in an American family by Atuk et al. (J Clin Endocrinol Metab, 83:117-120, 14) and the family was defined as VHL type 2A. In our study, the family was identified as VHL type 2B. This variability in the phenotypic features suggests that further studies are required to beter assess the genotype-phenotype correlation in such cases.

Increased oxidative DNA damage in lean normoglycemic offspring of type 2 diabetic patients.

OBJECTIVE: Several studies have shown increased oxidative stress in patients with pre-diabetes and newly diagnosed Type 2 diabetes mellitus (T2DM). It has been proposed that oxidative stress initiates insulin resistance in genetically predisposed individuals. The aim of this study was to evaluate the markers of oxidative stress in the offspring of patients with T2DM. MATERIAL AND METHODS: We examined 60 lean normoglycemic offspring of Type 2 diabetics, and 52 age, sex and body mass index matched subjects without family history of T2DM as controls. Anthropometric, biochemical and carotid intima media thickness (IMT) measurements and oral glucose tolerance test (OGTT) were performed. Erythrocyte superoxide dismutase and glutathione peroxidase activities, serum nitric oxide, plasma total sulfhydryl (tSH) groups, plasma total antioxidant status, plasma malondialdehyde and serum 8-hydroxydeoxy-guanosine (8-OHdG) levels were compared between 2 groups. RESULTS: 2 groups were similar for the measurements of anthropometric, blood pressure, lipids, fasting glucose, HOMA-IR and carotid IMT. Glucose levels during OGTT were significantly higher in the offspring of Type 2 diabetics than controls (p=0.035). The offspring of Type 2 diabetics showed a significant increase in serum 8-OHdG level (p=0.005) and plasma tSH groups (p=0.032) when compared to the controls. Significant differences were not obtained in other oxidative stress marker levels between 2 groups. CONCLUSION: Main finding of our study was the presence of increased oxidative DNA damage in lean normoglycemic offspring of Type 2 diabetic patients. There is a need for further clinical studies in order to explain whether oxidative stress is present in genetically predisposed subjects and induces the insulin resistance.

Dehydroepiandrosterone and human adipose tissue.

OBJECTIVE: The aim of this study was to investigate whether DHEA alters the proliferation and differentiation of human sc and visceral adipose cells in primary cultures. METHOD: Sc and omental adipose tissue was obtained from 10 female donors aged 36+/-3.6 yr with a body mass index (BMI) of 33+/-3.21 kg/m2. Stromal vascular cells were isolated and cultured using modified procedures described by Entenmann and Hauner. For the proliferation assay, stromal-vascular cells from sc and visceral adipose tissue cultures were fed with proliferation media containing 0, 25 or 100 microM DHEA for 3 days. At the end of this treatment period, two type cultures were prepared for determining their metabolic activity using the sulforhodamine B staining procedure. RESULTS: The metabolic activity of proliferating human visceral adipose tissue was higher than sc adipose tissue. The activity of proliferating human visceral tissue cultures decreased more than the sc tissue as the level of DHEA in the cultures was increased. CONCLUSIONS: These data suggest that DHEA predominantly influences the proliferation and differentiation of human omental adipose tissue.

Ret proto-oncogene mutations in apparently sporadic Turkish medullary thyroid carcinoma patients: Turkmen study.

OBJECTIVE: Medullary thyroid carcinoma (MTC) frequently occurs in a sporadic form, but a substantial number of cases are hereditary and appear as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Germline mutations in ret proto-oncogene have been shown to be the underlying cause of MEN2 syndromes. DESIGN: We carried out a multi-center study that aimed to perform mutational analysis of so called sporadic MTC patients. METHODS: Fifty-six MTC patients verified by histopathologic examination were subjected to genetic analysis. Exon 10, 11, 13, 14, 15 and 16 of the ret gene were analyzed by DNA sequencing and restriction enzyme digestion method. RESULTS: Among 56 apparently sporadic MTC patients, we identified 6 (10.7%) ret germline mutation carriers. Three individuals carried mutations at codon 634 in exon 11, one at codon 618 in exon 10, and two at codon 804 in exon 14. Identification of the predisposition gene mutation has allowed DNA-based strategy for direct mutation detection in patients with apparently sporadic MTCs. A substantial number of patients with apparently sporadic MTC carried germline mutations and 50% of their first degree relatives are expected to have or to develop MTC and/or other endocrine tumors. CONCLUSIONS: These results indicate the importance of careful genetic surveillance of any patient with apparently sporadic MTCs.

Simultaneous operation for right pulmonary and liver echinococcosis.

Of 156 patients referred in 1977-1987 for pulmonary hydatid cyst, nine were found to have simultaneous affection of the right lung and the liver. The diagnosis of concomitant liver cyst was made from radiographic dumbbell elevation of the diaphragm (3 cases), by preoperative ultrasound scan and computed tomography in (5 cases), and by intraoperative palpation through the diaphragm (1 case). The hepatic cysts were removed via the thoracotomy performed for removal of the lung cyst in seven patients and via thoracolaparotomy in two. The postoperative course was satisfactory and no recurrence of cyst has been observed, although mebendazole was not given. In cases of hydatidosis of the right lung, preoperative search should be made for subdiaphragmatic concomitant liver cyst which can be removed through the same thoracotomy.

Near-total esophageal exclusion in the treatment of late-diagnosed esophageal perforation.

Two cases of late-diagnosed esophageal perforation were successfully treated with near-total esophageal exclusion, using cervical T-tube esophagostomy with circumferential suture fixation of the lower arm of the T-tube. Esophageal stricture developed at the site of catgut or dexon tie. This complication can be managed with esophageal dilation. Drainage-tube gastrostomy proved to be unnecessary.

Traumatic oesophageal perforation.

Sixteen patients were treated for traumatic oesophageal perforation (13 cervical, 3 thoracic) over a 16-year period. In 14 cases the trauma was penetrating. The median delay from injury to treatment was 32 hours and the mean period of hospitalization was 26 days. The treatment procedures were two-layer primary closure with or without drainage, drainage alone and near-total oesophageal exclusion with cervical T-tube oesophagostomy. Postoperative complications were cervical oesophageal leak in two patients and tracheo-oesophageal fistula and oesophageal stenosis, each in one case. Of the eight patients treated within 24 hours of perforation, two died, and of the eight treated later, four died (overall mortality 37.5%). The heightened mortality after delayed diagnosis illustrates the prognostic importance of a high index of suspicion. To prevent leakage, buttressing with viable tissue following primary closure can be useful, especially after delayed diagnosis. Because of the continuing controversy concerning management of late-diagnosed oesophageal perforation, individualized treatment is widely advocated.

The comparison of adenosine deaminase activity values with polymerase chain reaction results in patients with tuberculosis.

Three methods in the diagnosis and treatment of tuberculosis have been compared in this study. Serum adenosine deaminase activities of patients with tuberculosis was compared with those of control groups with (+) and (-) PPD (purified protein derivative) results and were found to be higher than the controls. Within the controls the PPD (+) group displayed higher adenosine deaminase activities in comparison to the PPD (-) group. All patients had growth of B. Tuberculosis in the culture medium and all but one had positive polymerase chain reaction (PCR) results. Control patients were negative for culture and PCR. The sensitivity of ADA (adenosine deaminase) assay was 91.7% and specificity was 94.5%, whereas PCR had a sensitivity of 95.8% and a specificity of 100%. The ADA assay may be used in adjunction with other methods in the follow-up of tuberculosis with high sensitivity, specificity, and ease in applicability and specimen collection.

Vascular injuries and amputation following limb fractures.

Sixty-seven cases treated for peripheral vascular injuries associated with fractures between the years of 1977 and 1988 in the Department of Thoracic and Cardiovascular Surgery of the Dicle University, Faculty of Medicine, were reviewed retrospectively. The cause of injury was blunt trauma in 37 cases (55%) and penetrating wounds in the others, 29 gunshot injuries and one case with a stab wound. The maintenance of vessel continuity was aimed at in all patients. The ratio of limb amputation was 13% in patients operated upon within the first 8 hours after the injury. The same ratio was 39% in cases where the surgical intervention was delayed beyond 8 hours.

Penetrating chest injuries: unusually high incidence of high-velocity gunshot wounds in civilian practice.

Penetrating chest injuries are a challenge to the thoracic or trauma surgeon. Penetrating thoracic trauma, especially that due to high-velocity gunshot wounds, is increasing at an alarming rate in our region. We report our experience with penetrating chest injuries mainly due to high-velocity gunshot wounds. During a period of 6 years we retrospectively reviewed the hospital records of 755 patients admitted to the Department of Thoracic and Cardiovascular Surgery, Dicle University School of Medicine, with the diagnosis of penetrating thoracic trauma. The mean age was 27.48 years, and 89-8% were male. The causes of penetrating injury were stab wounds in 45.3% and gunshot wounds in 54.7%. About 30% of the wounds were due to high-velocity gunshots; and among the gunshot wounds 56.2% were due to high-velocity shots. The most common thoracic injury was hemothorax (n = 190) followed by hemopneumothorax (n = 184). Isolated thoracic injuries were found in 53% of the patients. Nonoperative management was sufficient in 92% of the patients. Thoracotomy was performed in 8.1%. The mean duration of hospitalization was 11.2 days. The mean injury severity score (ISS) was 20.17 +/- 13.87. The morbidity was 23.3% and the mortality 5.6%. Fifty percent of all deaths were due to adult respiratory distress syndrome. Altogether 17% of patients with an ISS > 25 died, whereas only 0.9% of those with a score < 16 died. The mortality due to firearms was 8.95%. We concluded that in civilian practice chest tube thoracostomy remains by far the most common method of treating penetrating injury to the chest. The easy availability of high-velocity guns will continue to increase the number of civilians injured by these weapons.