Biological heterogeneity and length-biased sampling in asymptomatic neurosurgical patients.

Increased numbers of asymptomatic intracranial lesions are being identified because of recent advances in imaging technology. Understanding of the natural history of these diseases, together with length bias is highly important in refining treatment strategy. Two sample models of hypothetical healthy cohorts were constructed, in which diseases showed either dual-type or multiple-type heterogeneity. Relative preclinical interval (PCI) of asymptomatic lesions including length-biased sampling was calculated, confirming that relative PCI increased according to heterogeneity of the disease. Length-biased sampling in asymptomatic lesions results from biological heterogeneity of the disease. Because lesions of longer PCI always are over-represented in a healthy population, conventional frequency analysis will tend to over-estimate risks in these patients.

Assessment of hemorrhage in pituitary macroadenoma by T2*-weighted gradient-echo MR imaging.

BACKGROUND AND PURPOSE: Intratumoral hemorrhage occurs frequently in pituitary macroadenoma and manifests as pituitary apoplexy and recent or old silent hemorrhage. T2*-weighted gradient-echo (GE) MR imaging is the most sensitive sequence for the detection of acute and old intracranial hemorrhage. T2*-weighted GE MR imaging was used to investigate intratumoral hemorrhage in pituitary macroadenomas. MATERIALS AND METHODS: Twenty-five consecutive patients who underwent total or subtotal resection of pituitary macroadenoma with heights from 17 to 53 mm, including 1 patient with classic pituitary apoplexy, underwent MR imaging before surgery, including T2*-weighted GE MR imaging. For histologic assessment of the hemorrhage in whole surgical specimens, we used hematoxylin-eosin staining. RESULTS: T2*-weighted GE MR imaging detected various types of dark lesions, such as "rim," "mass," "spot," and "diffuse" and combinations, indicating clinical and subclinical intratumoral hemorrhage in 12 of the 25 patients. The presence of intratumoral dark lesions on T2*-weighted GE MR imaging correlated significantly with the hemorrhagic findings on T1- and T2-weighted MR imaging (P < .02 and <.01, respectively), and the surgical and histologic hemorrhagic findings (P < .001 and <.001, respectively). CONCLUSION: T2*-weighted GE MR imaging could detect intratumoral hemorrhage in pituitary adenomas as various dark appearances. Therefore, this technique might be useful for the assessment of recent and old intratumoral hemorrhagic events in patients with pituitary macroadenomas.

Publication bias in neurosurgery: lessons from series of unruptured aneurysms.

BACKGROUND: Bias favouring publication of research with "positive" results over studies with "negative" results is widely suspected. The present investigation addressed this problem in the field of neurosurgery through a review of recent literature concerning outcome of surgery for unruptured intracranial aneurysms. METHODS AND FINDINGS: A Medline search was performed seeking case series of surgical treatment for unruptured intracranial aneurysms that analyzed 50 or more patients. Ten type I studies (retrospective studies from a single institution; 1457 patients) met these entry criteria. In general, type I studies reported excellent surgical outcome, with mean combined mortality and morbidity of 7.8% (95% confidence interval (CI), 6.4% to 9.2%). We found 4 multicenter or community-based studies (type II studies; 5401 patients). Mean combined mortality and morbidity in the type II studies was 20.3% (95% CI, 19.2% to 21.4%), much higher than in type I studies. Relative risk was 2.6 (95% CI, 2.2 to 3.1) for patients in type II studies compared with those in type I studies. Two meta-analyses (type III studies) described combined mortality and morbidity of 5.0% and 12.7%, essentially corresponding to results of type I studies. INTERPRETATION: Publication bias is present in the neurosurgical literature. Studies with an excellent surgical outcome are more likely to be published than those with an average outcome. Conclusions of literature reviews or meta-analyses based on published work therefore may be misleading. The solution to the problem would be community-based prospective registration of all patients who underwent surgery, providing a sampling frame free from publication bias.

[Reversible posterior leukoencephalopathy syndrome accompanied by HELLP syndrome and eclampsia: a case report].

We report a case of reversible posterior leukoencephalopathy syndrome accompanied by HELLP syndrome and eclampsia. A 30-year-old woman complained of diminution of visual acuity and eclampsia. Laboratory data revealed hemolysis, elevated liver enzyme and low platelets. CT showed low density areas in the bilateral occipital cortex. T1-weighted images showed a low signal intensity and T2-weighted images showed a high signal intensity in the occipital cortex bilaterally. Magnetic resonance angiography showed stenotic change in the intracranial artery. An operation was performed and significant improvement was seen in her visual function and MRI and MRA returned to normal on a month after operation. The mechanism of a reversible posterior leukoencephalopathy syndrome was discussed.

Hormonal regulation of the human ghrelin receptor gene transcription.

The aim of this study is to clarify the hormonal regulation of the human ghrelin receptor gene expression in GH(3) cells transfected with our previously cloned 5'-flanking region inserted into a luciferase reporter vector. Phorbor 12-tetradecanoate 13-acetate (TPA) with simultaneous addition of Bay K8644 mimicking ghrelin action caused a significant inhibition of the luciferase activity through the ghrelin receptor gene upstream proximal to -669 but not to -608 base pairs (bp). Glucocorticoid caused a weak but significant inhibition of the luciferase activity through the ghrelin receptor gene upstream proximal to -531 but not to -475 bp. Electrophoretic mobility shift assay resulted in binding of oligonucleotides between -669 and -640 bp, and between -520 and -491 bp to GH(3) cell nuclear proteins unlike AP(2) or glucocorticoid receptor. These results suggest that both TPA/Bay K8644 and glucocorticoid downregulate human ghrelin receptor gene expression through the transcriptional mechanism involving some nuclear factors.

Malignant struma ovarii with Graves' disease.

BACKGROUND: Malignant struma ovarii is a rare tumor, consisting of a struma ovarii with malignant change. Because of the rarity of the tumor, only a few reports with detailed data of thyroid function of the patient have been published. CASE: Medical and surgical treatments were performed in a case of malignant struma ovarii with Graves' disease and data from thyroid function tests were analyzed. After removal of the tumor, rapid improvement of thyroid function was observed and thyroglobulin level decreased. CONCLUSION: This case demonstrates the possible, if not dominant, contribution from the malignant struma ovarii to the hyperthyroidism of the patient.

MK800-62F1, a new inhibitor of apoptotic cell death, from Streptomyces diastatochromogenes MK800-62F1. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

A new compound, MK800-62F1, was isolated from a cultured broth of Streptomyces diastatochromogenes MK800-62F1. It inhibited H2O2-induced apoptosis in human small cell lung carcinoma Ms-1 cells as well as in human T-cell leukemia Jurkat cells. In addition, MK800-62F1 also inhibited camptothecin-induced apoptosis in Jurkat cells, which was mediated by intracellular H2O2 generation. MK800-62F1 did not exhibit antioxidative activity in vitro, suggesting that inhibition of apoptosis by MK800-62F1 was not due to the scavenging of H2O2, rather it was due to the modulation of the downstream event of H2O2 generation.

The expression of three types of CINCs by lipopolysaccharide-stimulated rat macrophages is inhibited similarly by anti-inflammatory steroids.

OBJECTIVE: Expression of CINCs was regulated differentially in lipopolysaccharide-stimulated rat macrophages. We examined whether the expression of CINCs in lipopolysaccharide-stimulated rat macrophages is similarly inhibited by anti-inflammatory drugs. MATERIALS AND METHODS: Rat peritoneal macrophages were stimulated by lipopolysaccharide in the presence of anti-inflammatory steroids (dexamethasone, prednisolone and hydrocortisone) or non-steroidal anti-inflammatory drugs (indomethacin and piroxicam). The production and mRNA expression of three types of CINCs were measured using enzyme-linked immunosorbent assay and northern hybridization. RESULTS: Anti-inflammatory steroids; dexamethasone, prednisolone and hydrocortisone, dose-dependently inhibited the production of CINC-1, -2 and -3, whose inhibitory patterns were similar to each other. Furthermore mRNA expression of each CINC was inhibited by dexamethasone in a dose-dependent manner. In contrast, non-steroidal anti-inflammatory drugs, indomethacin and piroxicam were without effect. Expression of each CINC was regulated differently; the production of CINC-1 reached a maximum at 12 h and then slightly decreased after lipopolysaccharide stimulation, whereas that of CINC-2 and CINC-3 increased up to 24 h. Dexamethasone inhibited the CINCs production and mRNA expression at 9 h after lipopolysaccharide stimulation. CONCLUSIONS: These results indicate no difference among CINC-1, -2 and -3 in the inhibition of production and mRNA expression of CINCs by anti-inflammatory steroids, although lipopolysaccharide differentially induces expression of each CINC expression in culture of rat macrophages.

8-bromo-cyclicAMP stimulates glucose transporter-1 expression in a human choriocarcinoma cell line.

Facilitative glucose transporter-1 (GLUT1) is abundant in trophoblast cells and is responsible for glucose transport in the placenta. However, the change in GLUT expression in human placenta upon trophoblast differentiation remains to be clarified. Therefore, we first examined the localization of GLUT1 and GLUT3 using human first-trimester chorionic villi. We found that GLUT1 and GLUT3 were mainly localized to syncytiotrophoblast and cytotrophoblast cells respectively. We analyzed whether placental GLUT1 and GLUT3 expression changes during differentiation using a human choriocarcinoma (BeWo) cell line which is known to show functional and morphological differentiation in response to cAMP in culture. Treatment of BeWo cells with 8-bromo-cyclicAMP (8-bromo-cAMP) increased the level of hCG secretion and induced cell fusion leading to the formation of large syncytia. Treatment of BeWo cells with 8-bromo-cAMP also resulted in a significant increase in glucose uptake on days 2-3 of culture. The stimulating effect of 8-bromo-cAMP on glucose uptake was concentration dependent. Northern and immunoblot analyses revealed that the levels of mRNA and protein of GLUT1, but not of GLUT3, were significantly increased by 8-bromo-cAMP. These findings suggest that 8-bromo-cAMP stimulates GLUT1 expression with differentiation in BeWo cells.

Lymph node metastases identified with mediastinoscopy in a patient with superficial carcinoma of the esophagus.

Superficial esophageal cancers limited to the lamina propria are not associated with lymph node metastases. Mediastinoscopic transhiatal esophagectomy was planned in a patient with widespread superficial cancer of the midthoracic esophagus. Sampling of the upper mediastinal lymph nodes revealed metastases. The operation was converted to a transthoracic esophagectomy with radical lymphadenectomy. Histopathologic examination of the resection specimen showed three metastatic lymph nodes, despite local invasion limited to the lamina propria. This is the first report of a patient with superficial esophageal cancer and lymph node metastases.

Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp. MK929-43F1. Taxonomy, fermentation, isolation and biological activities.

A new compound, migrastatin, was isolated from a cultured broth of Streptomyces sp. MK929-43F1, as an inhibitor of tumor cell migration. It was purified by column chromatographies on silica gel and Sephadex LH-20 and HPLC. Migrastatin has the molecular formula of C27H39NO7 consisting of 14-membered macrolide and glutarimide moiety. It inhibited spontaneous migration of human esophageal cancer EC17 cells. Migration inhibitory activity of migrastatin was not dependent on cytotoxicity or inhibition of protein synthesis.

Intraparenchymal and intrasylvian haematomas secondary to ruptured middle cerebral artery aneurysms: prognostic factors and therapeutic considerations.

The aim of this study was to investigate prognostic factors and the most appropriate treatment for patients with ruptured middle cerebral artery (MCA) aneurysms in relation to haematoma distribution. Ninety-two patients with ruptured MCA aneurysms, who underwent surgery during the last 11 years from 1986 to 1996, were assigned to one of the three groups according to the haematoma distribution. Group A comprised 17 patients who had an intraparenchymal haematoma (IPH) larger than 30 mm (maximum diameter) with or without subarachnoid haemorrhage (SAH), group B comprised 24 patients having a dense intra-Sylvian fissure haematoma (ISH) larger than 30 mm (maximum diameter) and group C consisted of 52 patients having only diffuse SAH without a localized dense haematoma. The clinical course and factors affecting the outcome of the patients in each group were investigated. Patients in groups A and B had a more severe clinical grade on admission than those in group C. As a result, patients in these two groups had a poorer outcome. In group C, independent life was achieved for 98% of the patients. In group A, the clinical grade on admission and the diameter of the haematoma were significantly correlated with outcome. Initial brain damage due to IPHs seemed to be the main cause of disability, while only 7% developed delayed ischaemic neurological deficits (DIND). In group B, 54% of patients suffered from subsequent brain oedema and DIND occurred in 50%. These factors were related to a poor outcome. The MCA aneurysms tend to have localized dense haematomas, as well as diffuse SAH; the former seems to affect more on the course and outcome of the patients. Accurate assessment of the bleeding patterns in patients with ruptured MCA aneurysms will be useful in helping us predict the clinical course and the most appropriate treatment for these individuals.

Cost-effectiveness analysis of screening for asymptomatic, unruptured intracranial aneurysms. A mathematical model.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) due to aneurysmal rupture is a major cause of cerebrovascular disease-related death. This problem could be eliminated by diagnosis and successful treatment of aneurysms before rupture. Recent developments in high-resolution imaging technology have made screening for unruptured aneurysms possible in the general population. Such screening has become widespread in Japan ("No Dokku, " or brain checkup). As a result, unruptured aneurysms are being identified with increasing frequency. However, the economic implications of treatment decisions for unruptured aneurysms have not been analyzed. Therefore, we performed such an analysis. METHODS: We used a Markov model to evaluate the cost-effectiveness of screening for asymptomatic, unruptured intracranial aneurysms. The model involved a set of variables describing discrete health states. Each state was assigned a quality of life score and an associated medical cost. A comparison of the expected outcomes was then made between 2 hypothetical cohorts, one receiving screening and the other no screening. A sensitivity analysis was performed by altering the input values within clinically reasonable ranges to reflect uncertainty in the baseline analysis and then assessing the effects on outcomes. RESULTS: Combining the incremental cost and effectiveness data revealed a cost per quality-adjusted life-year of $7760 for an annual rate of subarachnoid hemorrhage due to unruptured aneurysms (rupture rate) of 0.02; this cost was $39 450 for a rupture rate of 0.01. There was no benefit (negative quality-adjusted life-year benefit) for a rupture rate of 0.005, the rupture rate found in a recently published international cooperative study. The risks of surgery for unruptured aneurysms and the discounting ratio used to assess the impact of timing of costs and benefits on future outcomes also had significant effects on the results. Other variables had little impact on cost-effectiveness. CONCLUSIONS: The cost-effectiveness of screening for an unruptured aneurysm is highly sensitive to the annual rate of subarachnoid hemorrhage due to unruptured aneurysms. The low annual rupture rate seen in the recent large international cooperative study implies that screening asymptomatic populations to identify and treat unruptured aneurysms would not be cost cost-effective.

A pooled analysis of case-control studies of thyroid cancer. II. Menstrual and reproductive factors.

OBJECTIVE: It has been suggested that female hormones, and hence menstrual and reproductive factors, play a role in thyroid cancer etiology. Epidemiological data, however, are limited and inconsistent, partly because of the small number of cases included in each study. To clarify the etiology of thyroid cancer, we conducted a pooled analysis of original data from 14 case-control studies, 4 from the United States, 2 from Asia, and 8 from Europe. METHODS: This analysis included a total of 2,247 female cases of thyroid cancer (80% papillary) and 3,699 control women. Pooled odds ratios (OR) were estimated using logistic regression, conditioning on study and (i) matching sets for individually matched studies, or (ii) quinquennia of age for the other studies. Additional terms for age and history of radiation exposure were included in the regression equations. RESULTS: The OR per year of later menarche was 1.04 (95% confidence interval (CI) 1.0-1.1). Compared to premenopausal women, the OR was 1.3 for women with natural menopause, and 1.8 for those with artificial menopause, but the studies were heterogeneous and the association may be due, at least in part, to diagnostic or ascertainment bias. Parity, spontaneous or induced abortions and history of infertility were not associated with thyroid cancer risk. The OR was above unity in women reporting later age at first birth (OR = 1.1, 95% CI 1.0-1.3 for 5-year delay) and higher in the first years after a birth. CONCLUSIONS: The associations of menstrual and reproductive factors with thyroid cancer risk were generally weak, but appeared stronger among women diagnosed with thyroid cancer at younger ages.

Cancer mortality among radiological technologists in Japan: updated analysis of follow-up data from 1969 to 1993.

A retrospective cohort study was conducted for 12,195 male radiological technologists who received the occupational exposure to low dose radiation over a long term. A total of 1,097 deaths including 435 from cancer were ascertained by Koseki and death certificates from 1969 to 1993. Cancer mortality among the study population was basically compared with that of whole Japanese men. The significant low SMRs were obtained for all cancers, stomach and lung cancer partly due to Healthy Worker Effect, unlike the results of the early reports with some inappropriateness in the methods. Apparent high risks of lymphatic and hematopoietic cancers were observed, although none of site-specific cancers revealed the statistically significant increase. For these cancers, the SMRs among old sub-cohort were somewhat higher than those of young sub-cohort, whereas similar SMRs for solid cancer were obtained between the two sub-cohorts. The SMR for leukemia reached statistically significant level of 1.75 (95% CI: 1.07-2.71) when using whole professional and technical workers as a standard population. The study results might suggest that the chronic exposure to low-dose radiation enhanced the risk of lymphatic and hematopoietic cancers.

A prospective study on the effects of early surgery on vasospasm after subarachnoid hemorrhage.

BACKGROUND: To test the hypothesis that early surgery prevents vasospasm, a prospective analysis used strictly selected cases of anterior communicating artery aneurysms with symmetric distribution of subarachnoid hemorrhage. METHODS: Seven patients underwent early surgery (9-29 hours after ictus) through a standard pterional approach. Subarachnoid blood clots surrounding the ipsilateral major cerebral arteries were meticulously irrigated and suctioned. Comparison was made between the hemispheres with surgical intervention and those without, in terms of incidence of delayed ischemic neurologic deficits and cerebral infarction on computed tomographic scans, degree of angiographic vasospasm, and cerebral blood flow (CBF). RESULT: The degree of angiographic vasospasm, quantified by measuring the alterations in the ratio of the diameters of the intracranial arteries (C1, M1) to the extracranial internal carotid artery (C5), did not differ significantly between the surgical and nonsurgical sides. The mean CBF was also comparable between both sides in the chronic spasm phase (Day 6-9) as well as in the early postoperative period (Day 1-3). A significant reduction of CBF was observed during the early postoperative period in the basal frontal lobe of the surgical side. This CBF reduction seems to correspond to brain retraction. CONCLUSIONS: The results suggest that the effect of clot removal may be offset by the negative aspect of early surgery, and early surgery per se seems to have little effect on the course of the chronic vasospasm.

Secretagogue-induced exocytosis recruits G protein-gated K+ channels to plasma membrane in endocrine cells.

Stimulation-regulated fusion of vesicles to the plasma membrane is an essential step for hormone secretion but may also serve for the recruitment of functional proteins to the plasma membrane. While studying the distribution of G protein-gated K+ (KG) channels in the anterior pituitary lobe, we found KG channel subunits Kir3.1 and Kir3.4 localized on the membranes of intracellular dense core vesicles that contained thyrotropin. Stimulation of these thyrotroph cells with thyrotropin-releasing hormone provoked fusion of vesicles to the plasma membrane, increased expression of Kir3.1 and Kir3.4 subunits in the plasma membrane, and markedly enhanced KG currents stimulated by dopamine and somatostatin. These data indicate a novel mechanism for the rapid insertion of functional ion channels into the plasma membrane, which could form a new type of negative feedback control loop for hormone secretion in the endocrine system.