Supplementation with omega-3 fish oil has no effect on bone mineral density in adults with knee osteoarthritis: a 2-year randomized controlled trial.

UNLABELLED: This study aimed to determine the effect of fish oil on bone mineral density (BMD). There were no differences in the 2-year BMD measures between high and low dose groups after adjusting for baseline BMD. This randomized controlled trial did not demonstrate any efficacy of omega-3 fatty acids on bone loss in adults. INTRODUCTION: The purpose of this study is to investigate whether supplementation with high dose omega-3 fish oil could have an impact on BMD. METHODS: In a multicentre, double-blind randomized controlled trial (RCT) (ACTRN 12607000415404), 202 Australian participants aged ≥40 with knee osteoarthritis (mean age, 61.0 ± 10.0 years; 49 % female) were randomized to receive either high dose (4.5 g eicosapentaenoic acid and docosahexaenoic acid daily) or low dose (0.45 g/day) omega-3 fish oil for 2 years. BMD was assessed at baseline and 2 years by dual energy X-ray absorptiometry. RESULTS: In subjects with baseline and 2-year assessments, mean standardized BMD at baseline for low or high dose group was 1198 ± 198 and 1157 ± 169 mg/cm(2), respectively, for the lumbar spine and was 1035 ± 165 and 1017 ± 174 mg/cm(2), respectively, for the femoral neck. There were no differences in the 2-year BMD measures between high and low dose groups after adjusting for baseline BMD in the complete case regression analyses (lumbar spine 3.7, 95 % confidence interval (CI) -7.9 to 15.3 mg/cm(2) and femoral neck -5.5, 95 % CI -14.9 to 3.9 mg/cm(2)). The findings did not change with additional adjustments of age, gender, study centre and uses of bone-related drugs during the study period as well as using the intention-to-treat analysis or limiting to older participants (≥55 years at the baseline) (all P ≥ 0.25). Mild adverse events such as headache and gastrointestinal intolerance were common but did not occur more frequently in either group. There were no serious adverse events related to the intervention. CONCLUSION: A 2-year supplementation with high-dose omega-3 fish oil did not alter bone loss among men and women with knee osteoarthritis.

Extruded aneurysm coils found at craniotomy: report of two cases.

The operative findings are presented in two patients following inadequate coil embolization. At craniotomy, part of the coil mass had extruded through the fundus of both aneurysms. It is unclear if this phenomenon is confined to aneurysms that demonstrate significant regrowth and if there is an increased risk of rebleeding.

Correlation of VEGF production with IL1 alpha and IL6 secretion by human pituitary adenoma cells.

OBJECTIVES: Vascular endothelial growth factor (VEGF) is considered to be the most important angiogenic factor involved in the neovascularisation of solid tumours. Regulatory molecules include cytokines and growth factors. Interleukin (IL)1 and IL6 have both been shown to regulate VEGF levels in a variety of tissues. The role of cytokines in the pathogenesis of pituitary tumours remains unclear. We have examined the expression of VEGF and its relationships with IL1 and IL6 in the human pituitary tumour cell line HP75 and a series of human pituitary tumours. We have also looked at the relationship of tumour volume and invasive status to VEGF secretion. METHODS: Surgically resected tumours were routinely cultured in single-cell suspension at 200 K/well (standard unit for culture of dispersed primary pituitary adenoma cells). We measured VEGF, IL1 alpha and IL6 levels by ELISA. Tumour volume and invasion grade were assessed by preoperative magnetic resonance imaging. RESULTS: VEGF was detected in conditioned medium of HP75 cells (900+/-52 pg/ml) and in 82% of tumours tested (range 26-16 464 pg/ml). Tumour volume and secretion of VEGF were significantly associated with levels of IL6 (volume, P = 0.056; VEGF, P < 0.001 (P values based on Spearman's test)) and IL1 alpha produced (volume, P < 0.005; VEGF, P < 0.001). Invasive tumours showed a higher basal secretion of VEGF that that of the non-invasive type; however, this difference was not significant. Addition of exogenous IL1 alpha, but not IL6, significantly increased VEGF production. CONCLUSIONS: The significant associations between VEGF and the levels of IL6 and IL1 alpha suggest an important role for these cytokines in the development of these tumours.

Aneurysmal SAH: cognitive outcome and structural damage after clipping or coiling.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) and surgical clipping of intracranial aneurysms are associated with substantial morbidity and mortality. OBJECTIVE: To compare cognitive outcome and structural damage in patients with aneurysmal SAH treated with surgical clipping or endovascular coiling. METHODS: Forty case-matched pairs of patients with aneurysmal SAH treated by surgical clipping or endovascular coiling were prospectively assessed by use of a battery of cognitive tests. Twenty-three case-matched pairs underwent MRI 1 year after the procedure. Matching was based on grade of SAH on admission, location of aneurysm, age, and premorbid IQ. RESULTS: Both groups were impaired in all cognitive domains when compared with age-matched healthy control subjects. Comparison of cognitive outcome between the two groups indicated an overall trend toward a poorer cognitive outcome in the surgical group, which achieved significance in four tests. MRI showed focal encephalomalacia exclusively in the surgical group. This group also had a significantly higher incidence of single or multiple small infarcts within the vascular territory of the aneurysm, but both groups had similar incidence of large infarcts and global ischemic damage. CONCLUSION: Endovascular treatment may cause less structural brain damage than surgery and have a more favorable cognitive outcome. However, cognitive outcome appears to be dictated primarily by the complications of SAH.

Mdm2 and the p53 pathway in human pituitary adenomas.

OBJECTIVE: Studies on pituitary tumours have failed to identify mutations in the tumour suppressor gene p53 suggesting that the protein identified is wild type. p21(WAF--1) is a downstream effector of p53 which promotes growth arrest. Mdm2 (mouse double minute) is a protein induced by wild type p53 and forms an autoregulatory feedback loop suppressing wild type p53 activity. The purpose of this study was to examine a group of pituitary tumours for expression of p53 and its two downstream effector proteins p21(WAF--1) and mdm2 and to compare this with their radiological invasive status and proliferative potential as assessed by Ki-67 expression. SUBJECTS AND METHODS: Sixty-nine tumours removed at transsphenoidal surgery were examined by immunocytochemistry using antibodies against p53, p21(WAF--1), mdm2 and Ki-67 (MIB-1). The invasive status of the tumours was determined from the preoperative CT/MRI scans. RESULTS: p53 was expressed in 42 of 69 (61%) pituitary adenomas but there was no relationship with either pituitary tumour invasive status (P = 0.71) or volume (P = 0.33). p53 expression correlated, however, with the proliferative state of the tumours as assessed by the MIB-1 labelling index (P = 0.0065). Invasive tumours had a higher growth fraction than non-invasive ones (P = 0.027). p21(WAF--1) was expressed in the nuclei of 58/69 (84%) pituitary adenomas and its expression correlated with that of p53 (r = 0.26, P = 0.03). Mdm2 was expressed in the cytoplasm of 46/69 (67%) tumours and this correlated with the nuclear staining for p53 (P = 0.022) while nuclear staining was seen in 32/69 (46%) tumours but this did not correlate significantly with nuclear p53 staining (P = 0.096). CONCLUSIONS: These results suggest that p53, p21(WAF--1) and mdm2 are all expressed in pituitary tumours suggesting that the p53 protein detected by immunocytochemistry is wild type. Expression of p53 is associated with tumours which have a higher proliferative status. The p53 activity is probably the result of upstream signals of local stresses mediated through either genetic change, cytokines, hypoxia or hormonal factors. Our results suggest, however, that the downstream pathway mediated through the activities of p21(WAF--1) and mdm2 may be dysfunctional in these tumours.

Elevated p53 expression in benign meningiomas protects against recurrence and may be indicative of senescence.

Prediction of recurrence after resection of benign meningiomas represents a significant clinical problem. A prospective study commenced in 1984 aimed to elucidate the molecular mechanisms involved in the development of abnormal karyotype and tumour recurrence in meningiomas. Expression of key cell cycle regulators p53, p21, mdm2 and proliferating cell nuclear antigen (PCNA) were studied by immunohistochemistry in 85 tumours for which follow-up data was available. It was found that most tumours expressed p53, p21 and PCNA, with significant correlations between expression of p53 and both p21 and PCNA. As PCNA fulfils a multifunctional role its expression may be an unreliable indicator of proliferation in benign tumours. The degree of tumour excision remains the best prognostic indicator while p53 is the main predictor of abnormal karyotype. Karyotype is not however, related to prognosis. Incompletely excised tumours which expressed high levels of p53 and p21 did not recur. It is suggested that this is indicative of a fully functional p53-mediated DNA damage response mechanism. Rather than contributing to tumour progression, p53 is fulfilling its role as guardian of the genome in benign meningiomas. This study shows that induction of senescence may be an important tumour suppressor mechanism in benign tumours.

Long-term follow up of progesterone receptor status in benign meningioma: a prognostic indicator of recurrence?

OBJECT: A long-term prospective analysis of patients with benign meningioma was undertaken to determine whether progesterone receptor (PR) status of the excised tumor has any influence on recurrence. METHODS: Between 1983 and 1985, a total of 62 meningiomas in 53 patients (age range 19-79 years, mean age 55.6 years) were studied for clinical, histological, and pathological characteristics, including hormone receptor status and DNA features. Progesterone receptor status was quantified by cryostat section assay, and then factors affecting recurrence were analyzed. During 1997 all case records were reviewed to determine whether tumor had recurred in any patient, and PR status was correlated with tumor recurrence. Of the 62 tumors, 60 were benign, and of the benign tumors 29 (48%) were PR positive. Patients harboring 14 of the 60 benign tumors were lost to follow up. Of the 46 tumors included in the final analysis, 13 were recurrent (all within 5 years) and 33 were nonrecurrent. Of the 33 nonrecurrent tumors, 14 had not recurred 5 to 10 years postresection and 19 had not recurred after more than 10 years. Chi-square analysis of the results did not show an association between recurrence and patient's sex, extent of resection, histological subtype, or tumor site but did show an association between recurrence and PR negativity (p = 0.013). CONCLUSIONS: The results indicate that benign meningiomas that are PR positive are less likely to recur, a finding that has prognostic and therapeutic implications.

Long-term treatment of acromegaly with the somatostatin analogue SR-lanreotide.

OBJECTIVE: To assess the efficacy and tolerability of SR-lanreotide in the treatment of active acromegaly. PATIENTS AND DESIGN: 30 patients (17 men and 13 women) were treated in whom active acromegaly was confirmed by clinical features, a mean GH level of >5 mlU/l and failure to suppress GH to <2 mlU/l after a 75 g glucose load. Patients were treated for a median period of 60 weeks (range 12-168) with im injections of SR-lanreotide 30 mg given every 7-14 days. MEASUREMENTS: Mean GH and IGF-I levels were measured at baseline and every 12-weeks together with symptom score assessment. MRI of the pituitary gland was performed at baseline and if an adenoma was identified at yearly intervals. Gall bladder ultrasound scans were performed at baseline and then every 24-weeks. RESULTS: Twenty-three patients were treated for at least 48-weeks and, in these, GH levels fell from 10.5 mlU/l (7.6-17.6) (median and interquartile range) at baseline to 3.2 mlU/l (2.4-3.9) (p<0.0001) and IGF-I levels ftom 88.9 nmol/L (71.4-137.1) to 56.8 nmol/l (39.3-75.4) (p=0.0002). GH response to treatment was better in elderly patients (age> or =65 years) compared to younger patients but neither sex, pre-treatment GH levels, previous surgery nor previous radiotherapy influenced the response. Treatment resulted in a significant improvement in the symptoms of active acromegaly in the majority of patients. A significant reduction in the size of the pituitary adenoma was documented in 6 of 10 patients who had a repeat MRI scan after one year. Treatment was well-tolerated by the majority of patients; side effects were mainly transient gastrointestinal symptoms. These were severe in only 2 patients necessitating discontinuation of the drug. Two patients developed new gall stones and 4 female patients had temporal hair loss necessitating stopping treatment in one of them. There were minor effects on glucose tolerance which were not of clinical importance. CONCLUSION: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients.

Sigmoidoscopic neurosurgery? Treatment of an unusual complication of ventriculoperitoneal shunting.

A 16-year-old male with acute hydrocephalus due to bilateral acoustic neuromata was treated successfully with a ventriculoperitoneal shunt before formal neuroma resection. However, 2 years postoperatively, he noticed the distal shunt per rectum while defaecating. Subsequent removal was successfully performed using a flexible sigmoidoscope.

Cognitive outcome after aneurysm rupture: relationship to aneurysm site and perioperative complications.

We evaluated cognitive outcome in a group of 37 patients who had undergone surgery for rupture and repair of a single intracranial aneurysm at least 6 months previously. We compared outcome--assessed by tests of intelligence, attention, executive functions sensitive to frontal lobe lesions, memory, neglect, and mood, as well as by a specially devised questionnaire--between a group of 20 patients who had aneurysms of the anterior communicating artery and 17 patients who had aneurysms located on other branches of the internal carotid artery. There were no differences in cognitive outcome between patients with anterior communicating artery aneurysms and those with aneurysms on other branches of the internal carotid artery. The patient group as a whole, however, showed impairment in executive functions and some aspects of memory in comparison with normative data. Overall, 65% of the patients were impaired in at least one cognitive domain, with 19% showing executive impairments alone, 14% showing memory impairments alone, and 32% showing deficits in both domains. Cognitive outcome was most strongly predicted by postoperative neurologic events, although clipping of an anterior cerebral artery was associated with a higher impairment rating on a symptom profile completed by patients' relatives, and although preoperative rebleeding of aneurysms predicted impairment of executive function.

Do we need variable pressure shunts?

We describe our experience using a variable pressure cerebrospinal fluid shunting system, over a period of 5 years. These valves appear to be reliable and have the advantage of allowing pressure setting adjustments to be made in the out-patient clinic. An analysis of the cost-effectiveness of this system, allowing for materials, theatre time and hospital stay, suggests that over pounds 21,000 was saved, by avoiding shunt revision procedures, over this period.

Intraoperative ultrasound-guided biopsy of intracranial lesions: comparison with freehand biopsy.

Achieving the required accuracy during such relatively straightforward procedures as tumour biopsy or abscess aspiration remains a challenge especially for the more junior neurosurgeon. A study comparing freehand biopsy with ultrasound-guided biopsy is presented. The use of intraoperative ultrasound increases the accuracy at the expense of a slightly longer operating time. Diagnostic tissue was always obtained using this technique.

Exploratory burr holes.

The ability to enter the cranial cavity rapidly and effectively is a mandatory skill for those managing the head-injured patient. It may be increasingly required now that earlier computed tomography diagnosis of non-traumatic intracranial lesions is made in centres without the immediate assistance of a neurosurgeon.

The prediction of recurrence in meningiomas. A flow cytometric study of paraffin-embedded archival material.

Despite the complete macroscopic excision of meningiomas, there is a significant rate of recurrence approaching 20% at 20 years. The prediction of recurrence by clinical and histopathological means is inadequate. Flow cytometric analysis of deoxyribonucleic acid (DNA) in meningiomas has shown a correlation between a high proliferative index based on tumor cell-cycle stage (%S + %G2/M) and clinically aggressive behavior. Accordingly, the DNA analysis of meningioma tissue may be of value in predicting recurrence of these tumors. To test this hypothesis, the DNA of paraffin-embedded archival tissue from known recurrent meningiomas was compared with an age- and sex-matched nonrecurrent group. Both groups had comparable follow-up periods. Forty patients with total macroscopic removal at the time of surgery were analyzed. The paraffin blocks of these tumors were retrieved and reclassified histologically according to the World Health Organization system. Sections were then taken for flow cytometric study. The DNA analysis showed that the proliferative index of the recurrent group was significantly higher than that of the nonrecurrent group (p less than 0.002), although the histological subtyping of the two groups was similar. These results support the suggestion that flow cytometry may be of value in the prediction of recurrence of histologically benign, macroscopically removed meningiomas.

Ovarian size in postmenopausal women.

Ovarian volumes have been determined by pelvic ultrasonography in 2246 apparently healthy postmenopausal women of whom 2221 were included in the statistical analysis. Factors associated with gonadal size have been identified, and reference ranges for derived indices have been determined for use (in association with criteria for abnormal morphology) in a screening programme for ovarian carcinoma. The right ovary was present in 98.9% of subjects and the left in 99.1%. The mean (SD; range) of right and left ovarian volumes were 3.58 (1.40; 1.00-14.01) and 3.57 (1.37; 0.88-10.9) ml respectively. Significant predictors of ovarian volume were years since the menopause, weight, parity, age at menopause, a history of hormone replacement therapy, and previously diagnosed breast cancer. Abnormal ovarian volumes were assessed from a score equal to the (observed mean log volume (MLV) minus the predicted MLV)/0.327. A simplified nomogram has been prepared for routine clinical use. The relative abnormality of one ovary was assessed from a ratio score equal to loge (larger ovarian volume/smaller ovarian volume)/0.211 compared with the 99th centile for the Gaussian distribution.

Cytogenetic studies in 50 meningiomas.

In a series of 50 meningiomas, cytogenetic studies showed that almost half had a normal diploid karyotype. The remainder had monosomy 22, some with a normal diploid line also present. The initial monosomy was often followed by further chromosome loss, and occasionally by structural abnormalities, some with distinctive characteristics. Chromosomes most often involved in structural rearrangements were 1, 14, 10, and 19, and those most often lost were 17 and Y. The type of chromosome abnormalities seen were similar to those described for senescent human cell cultures, which suggests that common chromosomal mechanisms may be operative in benign tumors and senescent cells. Although meningiomas occur more commonly in females, the chromosomally abnormal tumors are distributed evenly between males and females. Within the group of tumors with structural chromosomal abnormality, there seems to be a bias toward meningotheliomatous histology, but otherwise the karyotype changes seen independent of the histologic type of tumor.

DNA in meningioma tissues and explant cell cultures. A flow cytometric study with clinicopathological correlates.

Flow cytometry was performed on stored frozen tissues and explant cell cultures from 39 meningiomas using ethidium bromide and mithramycin in a selective staining technique for deoxyribonucleic acid (DNA). The ploidy index and percentage of cells in the G0/G1, S, and G2/M phases were calculated for each specimen. The results were compared with the age and sex of the patients; the site, the histological subtype, and mitotic rate of the neoplasms; and the estrogen- and progesterone-receptor levels assayed in cytosol-enriched supernatants from cryostat-cut sections. Sixteen neoplasms (41%) were aneuploid. These included two recurrent neoplasms, seven of the eight neoplasms from patients with multiple meningiomas, and three clinically aggressive neoplasms (one hemangiopericytic and two anaplastic meningiomas). Significant correlations were found between values for the ploidy index (r = 0.75, p less than 0.01), the percentage of S-phase cells (r = 0.82, p less than 0.01), and the percentage of G2/M-phase cells (r = 0.69, p less than 0.05) in vivo and in vitro. The results support the suggestion that flow cytometry for DNA in meningiomas may be of value in predicting the behavior of these neoplasms, and indicate that under controlled conditions explant cell cultures may provide a useful model for the proliferative characteristics of meningiomas in vivo.

Relationships between psychological symptoms, somatic complaints and menopausal status.

The importance of distinguishing climacteric symptoms from other psychological and somatic complaints has been repeatedly stressed, but as yet no detailed guidelines are available to assist the clinician in the day-to-day management of patients. Previous epidemiological surveys of climacteric symptoms have been criticised because of inadequate methodology. We have attempted to overcome most of these problems and to provide a more detailed analysis of the relationships between menopausal status and psychological and somatic symptoms. Eight hundred and fifty pre-, peri- and post-menopausal women, aged 45-65 yr, took part in a cross-sectional survey of general health, psychosocial factors and current symptomatology. They were a non-menopause clinic sample and were blind to the purpose of the study. Using a principal components analysis, the relationships between symptoms were examined. Certain psychological and somatic symptoms occurred together in specific clusters. Some of these symptom clusters, e.g., vasomotor symptoms and sexual difficulties, were best predicted solely by menopausal status, while others, such as psychological and somatic symptoms, were more clearly associated with psychosocial factors. On the basis of these results, guidelines for the assessment of climacteric and post-menopausal women can be suggested.