Flavopiridol Suppresses Cell Proliferation and Migration and Induces Apoptotic Cell Death by Inhibiting Oncogenic FOXM1 Signaling in IDH Wild-Type and IDH-Mutant GBM Cells.

Glioblastoma multiforme (GBM) remains one of the most challenging solid cancers to treat due to its highly aggressive and drug-resistant nature. Flavopiridol is synthetic flavone that was recently approved by the FDA for the treatment of acute myeloid leukemia. Flavopiridol exhibits antiproliferative activity in several solid cancer cells and currently evaluated in clinical trials in several solid and hematological cancers. In this study, we investigated the molecular mechanisms underlying antiproliferative effects of flavopiridol in GBM cell lines with wild-type and mutant encoding isocitrate dehydrogenase 1 (IDH1). We found that flavopiridol inhibits proliferation, colony formation, and migration and induces apoptosis in IDH1 wild-type and IDH-mutant cells through inhibition of FOXM1 oncogenic signaling. Furthermore, flavopiridol treatment also inhibits of NF-KB, mediators unfolded protein response (UPR), including, GRP78, PERK and IRE1α, and DNA repair enzyme PARP, which have been shown to be potential therapeutic targets by downregulating FOXM1 in GBM cells. Our findings suggest for the first time that flavopiridol suppresses proliferation, survival, and migration and induces apoptosis in IDH1 wild-type and IDH1-mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-KB, PARP, and UPR response in GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1 wild-type and IDH1-mutant GBM.

Alterations in Serum miR-126-3p Levels over Time: A Marker of Pituitary Insufficiency following Head Trauma.

INTRODUCTION: Traumatic brain injuries (TBIs) pose a high risk of pituitary insufficiency development in patients. We have previously reported alterations in miR-126-3p levels in sera from patients with TBI-induced pituitary deficiency. METHODS: To investigate why TBI-induced pituitary deficiency develops only in some patients and to reveal the relationship between miR-126-3p with hormone axes, we used mice that were epigenetically modified with miR-126-3p at the embryonic stage. These modified mice were subjected to mild TBI (mTBI) according to the Marmarou's weight-drop model at 2 months of age. The levels of miR-126-3p were assessed at 1 and 30 days in serum after mTBI. Changes in miR-126-3p levels after mTBI of wild-type and miR-126-3p* modified mouse lines validated our human results. Additionally, hypothalamus, pituitary, and adrenal tissues were analyzed for transcripts and associated serum hormone levels. RESULTS: We report that miR-126-3p directly affects hypothalamus-pituitary-adrenal (HPA) axis upregulation and ACTH secretion in the acute phase after mTBI. We also demonstrated that miR-126-3p suppresses Gnrh transcripts in the hypothalamus and pituitary, but this is not reflected in serum FSH/LH levels. The increase in ACTH levels in the acute phase may indicate that upregulation of miR-126-3p at the embryonic stage has a protective effect on the HPA axis after TBI. Notably, the most prominent transcriptional response is found in the adrenals, highlighting their role in the pathophysiology of TBI. CONCLUSION: Our study revealed the role of miR-126-3p in TBI and pituitary deficiency developing after TBI, and the obtained data will significantly contribute to elucidating the mechanism of pituitary deficiency development after TBI and development of new diagnostic and treatment strategies.

The Role of Apoptosis and Autophagy in the Hypothalamic-Pituitary-Adrenal (HPA) Axis after Traumatic Brain Injury (TBI).

Traumatic brain injury (TBI) is a major health problem affecting millions of people worldwide and leading to death or permanent damage. TBI affects the hypothalamic-pituitary-adrenal (HPA) axis either by primary injury to the hypothalamic-hypophyseal region or by secondary vascular damage, brain, and/or pituitary edema, vasospasm, and inflammation. Neuroendocrine dysfunctions after TBI have been clinically described in all hypothalamic-pituitary axes. We established a mild TBI (mTBI) in rats by using the controlled cortical impact (CCI) model. The hypothalamus, pituitary, and adrenals were collected in the acute (24 h) and chronic (30 days) groups after TBI, and we investigated transcripts and protein-related autophagy (Lc3, Bcln1, P150, Ulk, and Atg5) and apoptosis (pro-caspase-3, cleaved caspase-3). Transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI, however, this was not reflected in autophagy-related protein levels. In contrast, protein markers related to apoptosis increased in the adrenals during the acute phase and in the pituitary during the chronic phase. TBI stresses induce a variation of autophagy-related transcripts without modifying the levels of their proteins in the HPA axis. In contrast, protein markers related to apoptosis are increased in the acute phase in the adrenals, which could lead to impaired communication via the hypothalamus, pituitary, and adrenals. This may then explain the permanent pituitary damage with increased apoptosis and inflammation in the chronic phase. These results contribute to the elucidation of the mechanisms underlying endocrine dysfunctions such as pituitary and adrenal insufficiency that occur after TBI. Although the adrenals are not directly affected by TBI, we suggest that the role of the adrenals along with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.

Vertebral Artery Mobilization and Cervical Tumor Resection.

BACKGROUND: To emphasize the importance of vertebral artery (VA) mobilization by reviewing the anatomy and variations of the VA while performing total resection of VA-associated tumors that develop from different tissues. METHODS: VA mobilization and mass resection were performed after the evaluation and preoperative imaging of 22 patients with VA-related tumors. Anterior, posterior, or both approaches were conducted on the patients and stabilization was also applied to the patients in need. Radiotherapy and/or chemotherapy were planned for patients with malignant tumors as shown by histopathology. RESULTS: Overall, 17 patients with benign and 5 patients with malignant tumors underwent tumor resection with VA mobilizing. There were 13 male and 9 female patients with a mean age of 29.3 years. The average follow-up duration was 53 months. All the patients received gross total tumor resection and had a good postoperative neurological recovery. No complications were observed; local recurrence was observed only in 2 patients. CONCLUSIONS: VA mobilization reduces the need for instrumentation in VA-related cases, especially nerve tumors, and increases the possibility of the surgical resection of vertebral tumors.

Hemilaminectomy and Bilateral Decompression for Thoracic Spinal Stenosis.

AIM: To assess the effectiveness and reliability of hemilaminectomy and bilateral decompression (HLBD) for the treatment of thoracic spinal stenosis (TSS) in selected patients. MATERIAL AND METHODS: Clinical data of 21 consecutive adult patients who underwent HLBD were investigated. Patients diagnosed with TSS by computed tomography or magnetic resonance imaging, with stenosis secondary to posterior element hypertrophy, and who underwent HLBD for the treatment of narrow spinal canal were included in this study. Patients were evaluated based on their pre- and postoperative modified Japanese Orthopedic Association (JOA) scores using their medical records. Recovery rates were evaluated using the Hirabayashi?s method. RESULTS: The mean follow-up period, age, and preoperative JOA score were 37.6 months, 61.6 years, and 5.0 (range: 1?10), respectively. The mean JOA score improved postoperatively, i.e., 10.0 (range: 7?11), during follow-up. The recovery rate was 83.3%. Operation-related transfusion, neurological deterioration, and postoperative instability did not occur during the follow-up examination. CONCLUSION: HLBD is a suitable surgical technique for patients with stenosis primarily caused by posterior element hypertrophy, such as ligamentum flavum (LF) and facet joints because it has a relatively less complication ratio, protects the posterior anatomical structures, prevents post-laminectomy kyphosis and postoperative instability, and promotes successful clinical improvement.

Pediatric central nervous system tumors in the first 3 years of life: pre-operative mean platelet volume, neutrophil/lymphocyte count ratio, and white blood cell count correlate with the presence of a central nervous system tumor.

PURPOSE: The aim of this study is to describe the relationship of pre-operative complete blood count parameters [mean platelet volume (MPV), neutrophil/lymphocyte count ratio (NLCR), and white blood cell count (WBC)], with the clinical, radiological, and histopathological features and the management options for patients under 3 years of age with a newly diagnosed central nervous system tumors. METHODS: Children with central nervous system (CNS) tumors in the first 3 years of life admitted in the Erciyes University Hospital between April 2004 and April 2014 were enrolled in this study. The CBC parameters were compared with those of an age- and sex-matched normal control group. RESULTS: In the study group, the means of MPV and WBC were 8.00 ± 1.24 fl, and 10,855 ± 3642/mm3 respectively; the median (25-75%) of NLCR was 0.98 (0.66-1.46). For the control group, the means of MPV and WBC were 6.8 ± 0.73 fl and 8565 ± 2522/mm3; the median (25-75%) of NLCR was 0.52 (0.36-0.70). The MPV, WBC, and NLCR were higher in the study group. The median overall survival (OS) of the patients was 60 months (range 0-81.6 months); and median event free survival (EFS) was 24 months (range 0-70.1 months). The formulation of MPV, NLCR, and WBC was found to be predictive for the diagnosis of CNS tumor in children with nonspecific symptoms. The univariate and multiple binary regression analyses showed a positive association of MPV, NLCR, and WBC and the risk of a diagnosis of CNS tumor. There was no relationship between MPV, WBC, NLCR, and histological subgroups. However, there were no associations between CBC parameters and OS or EFS of the patients. CONCLUSIONS: By causing suspicion, MPV, NLCR, and WBC may provide both an earlier radiological investigation decision and thereby an early diagnosis of CNS tumor in children with nonspecific symptoms in the first 3 years of life.

Surgical Strategies for Spondylodiscitis due to Lumbar Disc Surgery.

AIM: Despite different surgical treatment protocols at different centers for spondylodiscitis due to lumbar surgery, there is no consensus on its surgical indications. In this study, we aimed to clarify the steps to be followed in the management and treatment of postoperative spondylodiscitis. MATERIAL AND METHODS: The data of 20 cases with postoperative spondylodiscitis were evaluated. C-reactive protein (CRP) was used for diagnosis and follow-up. According to culture results of the infected material obtained from the operated cases, appropriate antibiotic treatment was initiated. In non-operated cases, parenteral empirical antibiotic treatment was implemented. Surgical treatment was planned for cases with clinical and radiological instability, abscess on imaging and those who were nonrespondent to empirical antibiotic treatment. For the cases that clinically recovered and had normal CRP levels, oral antibiotic treatment was continued after parenteral antibiotic treatment. RESULTS: Of the cases; 13 were male (65%) and 7 were femals (35%). The mean age was 56.3 years (32-74). The most prevalent complaints in referral were waist and leg pain. Except one, all cases had increased CRP levels. All patients had spondylodiscitis on magnetic resonance imaging. Seven had radiological and clinical instability and 3 had epidural abscess. The most commonly growing microorganism in culture was Staphylococcus aureus. Surgical treatment was applied to seven cases and medical treatment to 13 cases. CONCLUSION: In cases with waist pain in the postoperative period, the first potential diagnosis to be considered is spondylodiscitis. Surgical treatment should be implemented for cases resistant to empirical antibiotic treatment, with abscess on imaging, or with lumbar instability.

The Comparison of Hemilaminectomy and Laminoplasty Procedures in the Surgical Treatment of Cervical Spondylotic Myelopathy.

AIM: To compare cervical hemilaminectomy with cervical laminoplasty to determine the prognostic significance of both methods in cervical spondylotic myelopathy (CSM). This study is first in the literature to compare the hemilaminectomy and laminoplasty procedures MATERIAL and METHODS: A total of 42 patients who underwent surgery due to CSM and followed for at least 24 months were included in the study. Thirty-four out of 42 patients were males, while 8 were females; the mean age of the patients was 63.6 years (range 41-80). The visual analog scale (VAS) was used in the evaluation of postoperative axial neck pain. Factors known to affect prognosis of CSM such as patients" age, gender, duration of symptoms, pressure level, and T2-hyperintense appearance on magnetic resonance imaging (MRI) were evaluated. Patients were compared in terms of sagittal alignment of the vertebrae (instability), anterior-posterior diameter of the spinal canal, transsectional spinal canal area, axial neck pain, and recovery rate based on the preoperative and postoperative Japanase Orthopaedic Association (JOA) scores. RESULTS: The recovery rate in patients who underwent hemilaminectomy was 60.8%±18.8, while in patients that underwent laminoplasty it was 52.8%±11.9. The comparison of both surgical techniques in terms of postoperative recovery rates did not show any significant difference between the techniques (p > 0.05). CONCLUSION: There were no significant differences in terms of recovery rate, preoperative and postoperative canal diameter, preoperative and postoperative spinal canal area, and postoperative sagittal alignment (p > 0.05). The VAS evaluating axial neck pain was significantly lower in patients from the hemilaminectomy group compared to patients from the laminoplasty group.

Does antimicrobial usage before meningitis lead to a higher risk of adult postsurgical Acinetobacter baumannii meningitis than that of Enterobacteriaceae meningitis?

Acinetobacter baumannii and Enterobacteriaceae are two pathogens responsible for postneurosurgical meningitis. The aim of this retrospective study was to evaluate the factors that influenced the outcomes in patients with postneurosurgical meningitis caused by A. baumannii and Enterobacteriaceae. Patients with post-surgical meningitis were identified from infection control committee charts between 2007 and 2015. Subjects over 16 years old who had positive cerebral spinal fluid cultures for A. baumannii or Enterobacteriaceae were enrolled in the study. Clinical and laboratory data for 30 patients with A. baumannii meningitis were compared with those of 12 patients with Enterobacteriaceae meningitis. The mean age of patients was 51.9 years and 57.1% were male. Eleven patients had comorbidities, the most common being diabetes mellitus. Most patients were due to intracranial haemorrhage (78.6%). The rate of the patients who received an appropriate antimicrobial therapy was 35.7%, and the crude mortality rate was 64.3%. In univariate analysis, previous antibiotic use, an infection before meningitis and mechanical ventilation had an increased risk of A. baumannii meningitis. Moreover, intrathecal antimicrobial use, inappropriate empirical antimicrobial use, antimicrobial resistance and alanine aminotransferase elevation were significantly higher in patients with A. baumannii meningitis than in those with Enterobacteriaceae meningitis. Antimicrobial use before meningitis (8.84 times) and mechanical ventilation (7.28 times) resulted in an increased risk of A. baumannii meningitis. None of the results affected 30-day mortality. Avoidance of unnecessarily prolonged antimicrobial usage may help to prevent a selection of A. baumannii.

Pencil in the pharynx: Case report of a penetrating foreign body.

Pharyngeal foreign bodies are commonly encountered in otolaryngological practice. However, in certain instances, particularly in cases of penetrating injuries, major vascular damage leads to severe morbidity and mortality. Management of these cases includes airway protection, bleeding control, imaging of major vascular injury, and prophylactic antibiotics. The case of a 2-year-old patient with penetrating pharyngeal foreign body is described in the present report.

The Results of the Surgical Treatment of Spontaneous Rhinorrhea via Craniotomy and the Contribution of CT Cisternography to the Detection of Exact Leakage Side of CSF.

AIM: To share the results of conventional surgery in rhinorrhea and the contribution of computerized tomography (CT) cisternography to determination of the site of cerebrospinal fluid (CSF) leak. MATERIAL AND METHODS: Twelve cases treated for spontaneous rhinorrhea were included in this study. All the cases underwent cranial CT and magnetic resonance imaging (MRI). CT cisternography was performed in four patients whose bone defect or leakage site could not be detected by CT and MRI. In order to repair the defect, either the galea or galea together with collagen matrix was used and the procedure was supported with fibrin glue. RESULTS: In the cases, postoperative rhinorrhea was seen in neither the early nor the late follow up period. We observed no complications related to CT cisternography or craniotomy. The leakage area was successfully detected with CT cisternography when the other methods failed. CONCLUSION: Bone defect can usually be shown by means of CT. However, when bone-defect cannot be shown or the dura in the defective area is intact, CT cisternography is useful to show the CSF leak. Conventional surgery was very succesful in the treatment of spontaneous rhinorrhea but it was cosmetically problematic. In the patients both treated with galea and galea together with collagen matrix, the repair of the defect was successful.

Short Segment Stabilization by Protecting the Alar Ligaments in a Case of Eosinophilic Granuloma Involving the C2 Spine.

BACKGROUND: The craniocervical junction is a complex anatomic location that contains the occipital bone, atlas, axis, and important complex ligamentous structures. The stability of this region is ensured only with the help of ligaments. CASE DESCRIPTION: A 6-year-old boy was admitted to our clinic for neck pain. Computed tomography and magnetic resonance imaging revealed a lytic bone lesion involving the C2 vertebral body and pedicle without odontoid tip. The tumor was resected using an anterior retropharyngeal approach and a wide marginal resection method. The odontoid tip and alar ligaments were protected, and the costal autografts were located between the C1-odontoid tip and the C3 body. The costal graft was stabilized in the C3 body with a miniplate. Then, C1-C3 posterior fixation with fusion was performed. The craniocervical junction was not considered unstable because the occipital bone was not involved in the fusion. Histologic examination confirmed the diagnosis of eosinophilic granuloma. Fusion was detected on a 1-year postoperative cervical computed tomography scan. CONCLUSIONS: The occiput should not be involved in the fusion area when the alar ligaments are preserved during surgery for a C2 lesion.

Circulating MicroRNAs as Potential Biomarkers for Traumatic Brain Injury-Induced Hypopituitarism.

Traumatic brain injury (TBI), a worldwide public health problem, has recently been recognized as a common cause of pituitary dysfunction. Circulating microRNAs (miRNAs) present in the sera are characteristically altered in many pathological conditions and have been used as diagnostic markers for specific diseases. It is with this goal that we planned to study miRNA expression in patients with TBI-induced hypopituitarism. Thirty-eight patients (27 male, 11 female; mean age, 43 ± 18 years) who had been admitted to the neurosurgery intensive care unit due to TBI were included in the acute phase of the study. In the chronic phase, miRNA expression profile blood samples were drawn from 25 patients who had suffered TBI 5 years ago. In the acute phase (on Days 1, 7, and 28), a substantial amount of patients (26%, 40%, and 53%; respectively) had hypopituitarism (acute adrenocorticotropic hormone deficiency). In the chronic phase eight of 25 patients (32%) had TBI-induced-hypopituitarism. Forty-seven age-gender-similar healthy controls (25 male, 22 female, mean age: 41 ± 14 years) were included in the study. In order to identify potential candidate miRNA/miRNAs whose levels had been altered in response to TBI-induced hypopituitarism, 740 miRNA expression analyses were performed in the sera of TBI patients by high throughput real-time polymerase chain reaction. Statistical analyses showed that miRNA-126-3p (miR-126-3p) and miRNA-3610 (miR-3610) were detected in the sera of patients who developed hypopituitarism on the 1st, 7th, and 28th days, and in the 5th year following TBI. In addition, miRNA-3907 showed statistically significant and constant dynamic changes on the 1st, 7th, and 28th days, and in the 5th year in the patients with TBI. Our results indicated that altered expression of miR-126-3p and miR-3610 may play an important role in the development of TBI-induced hypopituitarism.

The effects of erythropoietin, dextran and saline on brain edema and lipid peroxidation in experimental head trauma.

BACKGROUND: The aim of this study was to investigate the protective effects of erythropoietin, dextran/saline and erythropoietin in combination with dextran/saline on brain edema and lipid peroxidation following traumatic brain injury in rats. METHODS: In the study, 40 male 3-month-old albino Wistar rats, weighing 250-340 g, were divided into four groups, each consisting of ten rats. Traumatic brain injury was induced in all rats by the weight-drop method, and erythropoietin (5,000 U/kg) and/or dextran and saline (8 ml/kg) solutions were injected intraperitoneally ten minutes after trauma. Control animals received an equal volume of serum physiologic. All rats were sacrificed 24 hours later. Glutathione peroxidase activity and malondialdehyde levels were measured in the left hemisphere, and edema was quantitated by the wet-dry method. RESULTS: Brain edema and the levels of malondialdehyde, the last product of lipid peroxidation in tissues, were decreased variably, and the activity of glutathione peroxidase, an antioxidant enzyme, was increased in others compared with the control group. CONCLUSION: In this study, it was concluded that the brain edema that developed in rats on which head trauma was induced and the secondary brain damage caused by oxidative stress could be deceased using a combination of erythropoietin, dextran, and saline.

Comparison of subgaleal and subdural closed drainage system in the surgical treatment of chronic subdural hematoma.

OBJECTIVE: One or two burr-hole craniostomies with subgaleal or subdural drainage system and irrigation are the most common methods for surgical treatment of CSDH. The aim of this study is to compare the advantages or disadvantages of these techniques used for CSDH. METHODS: Seventy patients were treated by burr-hole subdural drainage or subgaleal drainage system with irrigation. Our patients were classified into two groups according to the operative procedure as follows: Group I, one or two burr-hole craniostomy with subgaleal closed system drainage and irrigation (n=36), Group II, one or two burr-hole craniostomies with subdural closed drainage system and irrigation (n=38). We compared male and female ratios, complication rates, and age distribution between groups. RESULTS: There was no remarkable difference between recurrence rates of the two groups. Recurrence rate was 6.25% in Group I and 7.8% in Group II. Subdural empyema occurred in one of the patients in Group II. Symptomatic pneumocephalus did not develop in patients. Four patients were reoperated for recurrence at an average of 12-20 days after the operation with the same methods. CONCLUSION: Both of the techniques have a higher cure rate and a lower risk of recurrence. However, subgaleal drainage system is relatively less invasive, safe, and technically easy. So it is applicable for aged and higher risk patients.

Prospective investigation of anterior pituitary function in the acute phase and 12 months after pediatric traumatic brain injury.

PURPOSE: Although head trauma is common in childhood, there is no enough prospective study investigating both acute phase and 12 months after injury. Therefore, a prospective clinical trial was planned to evaluate the pituitary function in childhood in the acute and chronic phase after traumatic brain injury (TBI). METHODS: Forty-one children (27 boys and 14 girls, mean age 7 ± 4.3), who were admitted to neurosurgery intensive care unit due to head trauma, were included. Twenty-one (51.2 %) patients had mild, 10 (24.4 %) had moderate, and 10 (24.4 %) had severe TBI. Twenty-two of them were reevaluated 12 months after TBI. Basal pituitary hormone levels were measured during acute (first 24 h) and chronic phase of TBI. Additionally, in the chronic phase, GHRH-arginine test was used for the diagnosis of growth hormone (GH) deficiency. RESULTS: In the acute phase, 10 patients (24.4 %) had ACTH deficiency, and the overall 44.3 % of patients had at least one pituitary hormone dysfunction. All the pituitary hormone deficiencies during the acute phase were recovered after 12 months. Two patients (9.1 %) had new-onset GH deficiency in the chronic phase, and in one of them, ACTH deficiency was also present. CONCLUSIONS: Present prospective data clearly demonstrated that most of the hormonal changes in the early acute phase were transient, suggesting an adaptive response, and these changes did not predict the hormone deficiencies after 1 year. In the chronic phase, although GH deficiency was present, the frequency of TBI-induced hypopituitarism was clearly lower than the adult patients.

A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?

Traumatic brain injury (TBI) has been recently recognized as a common cause of pituitary dysfunction. However, there are not sufficient numbers of prospective studies to understand the natural history of TBI induced hypopituitarism. The aim was to report the results of five years' prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI. Moreover, we have prospectively investigated the associations between TBI induced hypopituitarism and presence of anti-hypothalamus antibodies (AHA) and anti-pituitary antibodies (APA). Twenty five patients (20 men, five women) were included who were prospectively evaluated 12 months and five years after TBI, and 17 of them also had a third-year evaluation. Growth hormone (GH) deficiency is the most common pituitary hormone deficit at one, three, and five years after TBI. Although most of the pituitary hormone deficiencies improve over time, there were substantial percentages of pituitary hormone deficiencies at the fifth year (28% GH, 4% adrenocorticotropic hormone [ACTH], and 4% gonadotropin deficiencies). Pituitary dysfunction was significantly higher in strongly AHA- and APA-positive (titers ≥1/16) patients at the fifth year. In patients with mild and moderate TBI, ACTH and GH deficiencies may improve over time in a considerable number of patients but, although rarely, may also worsen over the five-year period. However in severe TBI, ACTH and GH status of the patients at the first year evaluation persisted at the fifth year. Therefore, screening pituitary function after TBI for five years is important, especially in patients with mild TBI. Moreover, close strong associations between the presence of high titers of APA and/or AHA and hypopituitarism at the fifth year were shown for the first time.

Apolipoprotein E3/E3 genotype decreases the risk of pituitary dysfunction after traumatic brain injury due to various causes: preliminary data.

Traumatic brain injury (TBI) is a devastating public health problem which may result in hypopituitarism. However, the mechanisms and the risk factors responsible for hypothalamo-pituitary dysfunction due to TBI are still unclear. Although APO E is one of the most abundant protein in hypothalamo-pituitary region, there is no study investigating the relation between APO E polymorphism and TBI-induced hypopituitarism. This study was undertaken to determine whether APO E genotypes modulate the pituitary dysfunction risk after TBI due to various causes, including traffic accident, boxing, and kickboxing. Ninety-three patients with TBI (mean age, 30.61 +/- 1.25 years) and 27 healthy controls (mean age, 29.03 +/- 1.70 years) were included in the study. Pituitary functions were evaluated, and APO E genotypes (E2/E2; E3/E3; E4/E4; E2/E3; E2/E4; E3/E4) were screened. Twenty-four of 93 subjects (25.8%) had pituitary dysfunction after TBI. The ratio of pituitary dysfunction was significantly lower in subjects with APO E3/E3 (17.7%) than the subjects without APO E3/E3 genotype (41.9%; p = 0.01), and the corresponding odds ratio was 0.29 (95% confidence interval [CI], 0.11-0.78). In conclusion, this study provides strong evidence for the first time that APO E polymorphism is associated with the development of TBI-induced pituitary dysfunction. Present data demonstrated that APO E3/E3 genotype decreases the risk of hypopituitarism after TBI. The demonstration of the association between the APO E polymorphism and TBI may provide a new point of view in this field and promote further studies.

Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study.

OBJECTIVE: It has been recently demonstrated that traumatic brain injury (TBI)-mediated hypopituitarism could be more frequent than previously known. However, most of the previous data were obtained from retrospective studies, and the natural history of the hypopituitarism due to TBI is still unclear. So far no study has been reported in which the pituitary function of the same patients has been investigated more than 1 year after TBI. Therefore, we report the results of 3 years prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI. PATIENTS AND DESIGN: Thirty patients (25 males, 5 females; age 37.2 +/- 2.4 years) with TBI were included in the study. Pituitary function was evaluated at 1 and 3 years after TBI. RESULTS: After individual evaluation of GH deficiency from 1 year to 3 years after TBI, 7 of 13 (53.8%) GH-deficient patients at 1st year recovered after 3 years of TBI, and GH deficiency detected at 3 years in one patient was new onset. Additionally, five of six (83.3%) ACTH-deficient patients at 1st year recovered after 3 years of TBI, and ACTH deficiency detected at 3 years in one patient was new onset. CONCLUSIONS: GH deficiency is the most common pituitary deficit 1 and 3 years after TBI. In patients with mild and moderate TBI, pituitary function improves over time in a considerable number of patients, but it may also worsen rarely over the 3-year period. In patients with severe TBI, ACTH and GH deficiencies at 1st year evaluation persist at 3rd year.