Progesterone-receptor index in meningiomas: correlation with clinico-pathological parameters and review of the literature

For recurrent and untreatable meningiomas alternative therapies, such as anti-progesterone treatment, have been sought. However, the few clinical studies have not determined progesterone receptor (PgR) expression in most cases, and studies correlating quantitative PgR expression (PgR index) with clinico-pathological variables are scarce. The aim of our study was to assess the PgR indices in a consecutive series of meningiomas and correlate these values with clinico-pathological parameters. We analyzed immunohistochemically 82 consecutive meningioma specimens (73 primary and nine recurrent tumors) for PgR and Ki-67 antigen (MIB-1). The male/female ratio was 1:1.7, and median age at the time of surgery was 57 years (range 29–77 years). The series comprised 55 grade I (subtyped as 36 meningothelial, seven fibrous, nine transitional, two psammomatous, and one angiomatous), 23 grade II, and one grade III meningiomas. Nuclear immunostaining for PgR was positive in 56 meningioma specimens (71%). PgR index was 21.4±2.8% (mean ± SE; range 0–79%). Significantly higher expression was found in male patients in the age group <50 years than in those 60 years and in grade I meningothelial meningiomas than in fibrous and transitional subtypes. There was a trend to lower PgR indices in non-benign meningiomas. Cell proliferation rate (MIB-1 index) was 4.4±0.4% (mean ± SE; range 0.3–15.4%). Significantly higher MIB-1 indices were found in male than female patients,in recurrent than primary and in grade II than grade I meningiomas. We observed a trend to higher PgR indices in meningiomas with MIB-1 index <5%. In sum, the highest PgR index in our series was observed in patients under the age of 50 years with WHO grade I meningiomas of the meningothelial subtype and low cell proliferation indices. If hormonal therapy has a direct action on the PgR, these patients should respond best to anti-progesterone treatment. We conclude that PgR index is variable in meningioma, depending on clinical parameters and histopathological features. Stratification of anti-progesterone therapy trials on the basis of PgR index should be considered.     

MIB-1 staining index of pediatric meningiomas

OBJECTIVE: For adult meningiomas, the staining index (SI) for the anti-Ki-67 monoclonal antibody MIB-1 is well correlated with histological atypia and tumor recurrence. MIB-1 SIs for meningiomas in the pediatric population have not been previously reported. Meningiomas tend to be more histologically aggressive and to recur more frequently in children, compared with adults. The objectives of this study were to determine whether MIB-1 SIs are correlated with pathological atypia and recurrence among pediatric meningiomas and to compare the MIB-1 SIs of pediatric meningiomas with those of adult meningiomas. METHODS: MIB-1 SIs were assessed on paraffin-embedded sections of 14 pediatric meningiomas (patient age, 2-17 yr), 5 of which contained atypical or malignant features. For comparison with benign pediatric meningiomas, MIB-1 SIs were also assessed on paraffin-embedded sections of 14 adult meningiomas (patient age, 38-90 yr), none of which displayed atypical or malignant features or recurred within a 5-month median follow-up period. RESULTS: MIB-1 SIs of pediatric meningiomas ranged from 1.2 to 31.6% (median, 9.1%). Significant differences were observed between the MIB-1 SIs for tumors with atypical or malignant features (median, 12.3%; range, 7.0-31.6%) and those for tumors without atypia (median, 7.0%; range, 1.2-12.6%; P = 0.045). There were six recurrences after gross total resection, during a 36.5-month median follow-up period. All five of the tumors with pathological atypia recurred; one tumor without atypia recurred. Significant differences were observed between MIB-1 SIs for nonrecurrent tumors (median, 6.6%; range, 1.2-12.2%) and those for recurrent tumors (median, 12.5%; range, 7.0-31.6%; P = 0.012). The median MIB-1 SI for adult control specimens was 8.8% (range, 1.2-19.3%), which did not differ significantly from that for pediatric meningiomas without atypia (P = 0.68). CONCLUSION: For this cohort of pediatric meningiomas, pathological atypia and the tendency to recur were correlated with elevated MIB-1 SIs. The median MIB-1 SI for pediatric meningiomas without histological atypia did not differ significantly from that for adult meningiomas without atypia, suggesting that the more aggressive clinical features of meningiomas in children may be attributable to factors other than the rate of cellular proliferation.     

Clinical and radiological features related to the growth potential of meningioma

Clinical and radiological features that help predict the growth potential of meningioma would be beneficial. The purpose of this study is to clarify the characteristics related to proliferating potential using the MIB-1 staining index. We analyzed the relationship of MIB-1 staining indices to characteristics of 342 consecutive patients with meningioma surgically removed between 1995 and 2004 by logistic regression analysis. One hundred and forty-nine of the patients with meningioma were ≥60 in age; 89 male; 48 recurrent; 203 symptomatic; 157 at the skull base; 124 over 20 cm³; 24 multiple; 136 with edema; 117 with calcification. The MIB-1 staining index in 56 of 296 grade I meningiomas in WHO classification was ≥ 3.0; in 27 of 28 grade II; and in 17 of 18 grade III, respectively. Logistic regression analysis demonstrated that male (odds ratio [OR], 2.374, p=0.003), recurrence (OR, 7.574, p=0.0001), skull base (OR, 0.540, p=0.035), calcification (OR, 0.498, p=0.019) were independent risk factors for a high MIB-1 staining index (≥3.0); age, symptomatic, volume, multiple, edema were not. Male, recurrence, non-skull base, absence of calcification are independent risk factors for a high proliferative potential. These should be taken into consideration when managing meningiomas.     

The Role of Stereotactic Radiosurgery in the Management of Benign, Atypical, and Malignant Meningiomas

Stereotactic radiosurgery and fractionated Stereotactic radiotherapy (SR) offer precise localization of radiation dose (Gy) for the treatment of meningioma (M). For the multimodal treatment with preservation of function, SR is complementary to both microsurgery (S) and conventional external beam radiotherapy (XRT). The role of SR in the management of atypical and malignant meningiomas, however, remains unexplored. Fifty consecutive patients with meningioma: 18 males (60.1 +/– 2.3 years) and 32 females (56.9 +/– 2.2 years) (p = NS) received SR. Thirty-one patients had surgery 69.6 +/– 13.9 months (95% CI: 53.3–98.0) prior to SR. For patients having S, the incidence of atypical or malignant versus benign meningiomas (14 versus 17 patients) increased with age (p = 0.03). Twenty patients had XRT approximately 18 months prior to SR. For antecedent XRT, the range of doses was 3600–6400 cGy (median: 5040 cGy). Following failure of S and/or XRT, patients had SR. Compared to other series, the mean tumor volumes for SR were comparatively large: 9.8 +/– 1.3 cm³ (range 0.3–37.1 cm³). The median SR dose was 3500 cGy (range 540–5400 cGy) administered in seven fractions (range 1–30). Linear regression analysis showed a consistent method for fractionation: the number of administered fractions increased (p = 0.053) and the total dose increased (p = 0.054) with tumor size. During the interval for follow–up (17.9 +/– 2.9 months), one patient with malignant meningioma required surgery for progression 8 months after SR. In the remaining patients, post-SR MRIs showed control (unchanged or smaller tumor volume) regardless of histology. These results show that SR may provide control of M regardless of grade.     

Noninvasive evaluation of the malignant potential of intracranial meningiomas performed using proton magnetic resonance spectroscopy

OBJECT: Controversy exists about correlations between histological tumor grade and magnetic resonance (MR) spectroscopy data. The authors studied single-voxel proton MR spectroscopy as a noninvasive way to evaluate grade of malignancy in intracranial meningiomas. METHODS: The authors compared the results of MR spectroscopy with those derived by the MIB-1 staining index (SI) in 29 meningiomas. Proton MR spectroscopy was performed using stimulated echo acquisition and volume-localized solvent-attenuated proton nuclear MR sequences before surgery or other therapy. Twenty-four tumors were histologically benign (13 meningothelial, three fibrous, four transitional, three angiomatous, and one chordoid); four were atypical (Grade II), and one was papillary (Grade III). The mean MIB-1 SI in the benign group was significantly lower than those in the other groups (p = 0.0041). The mean choline-containing compound (Cho)/ creatine and phosphocreatine (Cr) ratios in the benign and nonbenign groups were 2.56+/-1.26 and 7.85+/-3.23, respectively (p = 0.0002). A significant linear correlation was observed between the Cho/Cr ratio and the MIB-1 SI (r0.05 = 0.74, p<0.001). Necrosis was present histologically in four of the five meningiomas classified either as atypical or papillary. Magnetic resonance spectroscopy revealed a methylene signal in these meningiomas that was not detected in benign meningiomas. Of the five meningiomas in which only a lactate signal was observed, two were benign and the MIB-1 SI in these two benign meningiomas was higher than the mean value for the benign group. Alanine, detected in 12 of 30 meningiomas, did not correlate with either tumor grade or Cho/Cr ratio. CONCLUSIONS: Proton MR spectroscopy is a useful diagnostic method for determining the proliferative or malignant potential of meningiomas according to the Cho/Cr ratio. A lactate and/or methylene signal suggests a high-grade tumor.     

78. Experimentelle Bestimmung der Knochendurchblutung mit Fluor 18

Zusammenfassung Die entwickelte, indirekte Messung der Knochendurchblutung gründet sich auf die Bestimmung einer initialen Kurzzeitclearance für das knochenaffine Radionuklid Fluor-18 entsprechend Behandlungsgrundlagen von Fredrikson u. Mitarb. (1955).In Vorversuchen kann die hohe Knochenaffinität einer Aluminium-Fluor-18-Komplexverbindung dahingehend bestätigt werden, daß 56,5% der in die A. nutricia der Hundetibia injizierten Aktivität nach einmaliger Passage des Knochens und 4minutiger Kreislaufzeit in der Tibia nachweisbar sind.An Hunden werden 120–150 Ci Fluor-18 in die V. jugularis injiziert, gleichzeitig mit einer Spitzenpumpe kontinuierlich Blut aus der A. carotis entnommen. Die gewählte 4 min-Clearance-Periode endet mit Tötung des Versuchstieres (sofortiger Kreislaufstillstand) und Abstellen der Entnahmepumpe. Sofortige Messung der von Weichteilen gesäuberten Skeletelemente wie auch der Blutproben im Ganzkörperzähler. Ergebnisse. Die Knochendurchblutung erwachsener Tiere liegt deutlich unter der Jugendlicher. Während die Clearancewerte jugendlicher Hunde von der Tibia über das Femur zum Wirbel hin abnehmen (25,4, 21,7, 18,4 ml × min^–1 × 100 g^–1), steigen sie bei Erwachsenen von der Tibia über das Femur zum Wirbelkörper an (4,0, 6,4, 11,3 ml × min^–1 × 100 g^–1).Die Gesamtdurchblutung der Hundetibia aller Altersgruppen wird mit 10,3 ml × min^–1 × 100 g Feuchtgewicht des Knochens ermittelt. Höchste Clearancewerte erreichen Metaphysen-Epiphysenabschnitte (14,3 bzw. 12,1 ml × min^–1 × 100 g^–1) gegenüber der Diaphyse (Compactastruktur) 5,1 ml × min^–1 x 100 g^–1.Bei einem 16jährigen Patienten mit einem osteogenen Sarkom des Tibiakopfes kann unter veränderten Versuchsbedingungen die Clearancebestimmung an der menschlichen Tibia durchgeführt werden. Ermittelte Werte- Diatale Epiphysen-Metaphysenregion 0,8, Diaphysen 0,5 ml × min^–1 × 100 g^–1. Die wesentlich höheren Clearancewerte im Tumor und umgebenden Knochen (1,4 bzw. 6,0 ml × min^–1 × 100 g^–1) werden als Ausdruck der stark vermehrten Knochendurchblutung im Tumorbereich gewertet.

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Experimental determination of the bone circulation with fluor 18

Summary The method of indirect measurement of the bone circulation evolved by us is based on the determination of an initial short-term clearance of Fluorine 18 radio-nucleide which has an affinity for bone tissue, according to the basic method of Fredrikson and collaborators (1955).In preliminary trials, the great affinity to bone of an aluminium-fluorine-18 compound was confirmed in that 56.5% of the material injected into the arteria nutricia can still be detected after one bone passage and 4-min circulation in the tibia.120–150 Ci of Fluorine 18 are injected into the jugular vein of dogs and at the same time blood is continuously removed from the carotid artery with the aid of a pump. The 4-min clearance period ends with the killing of the animal (immediate circulatory arrest) and switching off of the pump. Immediate measurements of the skeletal elements, cleaned of soft tissue, and total blood-cell counts are carried out. Results. The bone circulation of fully-grown animals is definitely less than that of young animals. While clearance values in young dogs decrease progressively from the tibia to the femur to the vertebrae (25.4, 21.7, 18.4 ml × min^–1 × 100 g^–1), they increase progressively from the tibia to the femur and vertebrae (4.0, 6.4, 11.3 ml × min^–1 × 100 g^–1) in adult animals.The total circulation in the tibia of dogs of all agegroups was measured and amounted to 10.3 ml × min-' × 100 g moist weight of the bones. Highest clearance values were reached in the metaphyseal and epiphyseal sections (14.3 and 12.1 ml × min^–1 × 100 g^–1, respectively, as compared with the diaphysis (compact structure), 5.1 ml × min^–1 × 100 g^–1.In a 16-year old patient with an osteogenic sarcoma of the head of the tibia, clearance measurements on the tibia could be carried out by altering the method of the investigation. The readings obtained were: distal epiphyseal-metaphyseal area, 0.8, and diaphysis, 0.5 ml × min^–1 × 100 g^–1. The substantially higher clearance value in the tumour and the surrounding bone (1.4 and 6.0 ml × min^–1 × 100 g^–1) respectively, was considered to be an expression of the considerably increased circulation in the bone affected by the tumour.

     

Significance of MIB-1 staining indices in meningiomas: comparison of two counting methods

The authors evaluated the predictability of MIB-1 immunohistochemistry for growth and recurrences of meningiomas using two different counting methods: 1) in the area of the highest MIB-1 labeling (HL method) and (2) in randomly selected fields (RS method). The MIB-1 staining indices (SIs) determined by the HL method were approximately twice as high as those by the RS method, and the correlation coefficient between them was high (R = 0.86) in 139 meningiomas when transformed logarithmically. The differences in SIs in histologic grades were significant with either method. Tumor doubling time (Td) was calculated in 22 meningiomas from serial radiologic examinations. The RS method yielded a slightly higher correlation coefficient between log Td and log SI than the HL method. When the authors examined the predictability of recurrence in 112 totally removed meningiomas, the RS method distinguished the recurrent group more definitively. Several benign meningiomas with low SIs by the RS method exhibited focal accumulation of MIB-1-positive cells. Although they were assigned high MIB-1 values by the HL method, these meningiomas did not recur, and therefore obscured the prognostic importance of the MIB-1 value with the HL method. Focal accumulation of MIB-1-positive cells in meningiomas is not likely to correlate with their biologic aggressiveness.     

P53 Overexpression and Proliferative Potential in Malignant Meningiomas

Summary  Meningiomas are generally benign, but some meningiomas show malignancy with invasion and high recurrence rates. We investigated whether alterations in p53 protein may contribute to malignant progression in meningiomas. Immunostaining for p53 protein was performed on paraffin and frozen sections from 61 patients with different grades of meningiomas using monoclonal antibodies (mAbs) DO-1 and pAb240. Immunoblot analysis was performed to quantitate the amount of p53 protein. Mutations in p53 genes were assessed by single-strand conformational polymorphism (SSCP) analysis. MIB-1 immunostaining was used to detect proliferative potentials of meningiomas. We found an overexpression of p53 protein in all of five cases of anaplastic meningiomas by immunohistochemistry using DO-1 mAb. No p53 positive cells were recognized in atypical meningiomas, and several cells were weakly stained in only two of 52 benign meningiomas.  p53 staining index and immunoblot analysis indicated increasing amounts of p53 protein associated with subsequent recurrences of anaplastic meningiomas. The MIB-1 staining index was positively correlated with tumour grade and p53 protein overexpression. Immunostaining of frozen sections using the mutant-specific mAb pAb240, as well as mutation gene analysis by SSCP, indicate that the overexpressed p53 protein is not a mutant- but wild-type p53 protein. Four atypical meningiomas did not recur after surgical removal and radiation, while 4 anaplastic meningiomas with overexpressed p53 protein recurred repeatedly at short intervals even after radiation. Our results suggest that accumulation of p53 protein associated with highly proliferative potentials is a common and characteristic feature that may indicate malignant biological behaviour in meningiomas.     

Phenytoin plasma levels after intraoperative administration,for the prevention of post-craniotomy seizures

Summary Since in a previous study (preliminary report) (18) the iv. administration of 15 mg × kg^–1 of phenytoin (PNT) over 30 min in men produced toxic levels (25g/ml), a smallerr iv. dose of 7 mg×kg^–1 was given during anaesthesia to 80 patients under going craniotomy, for the prevention of post-operative seizures.Plasma PNT concentrations were studied in 22 patients before its iv. infusion 20min, 40min, and 1, 2, 3, 5, 8 and 12 hours later.Mean serum phenytoin levels were 9.3,31.9,27.8,25.5,19.4,17.2, 15.4 and 19.2^* g/ml respectively.In this study it appeared that although the initial dose was 50% smaller than before, toxic levels were still encountered one hour after PNT administration (therapeutic range 10–25 g/ml). Bearing in mind that in both our studies PNT appeared to have approximately the same efficacy in seizure prevention (from 95–97%), we suggest, that 7–10mg × kg^–1 would be adequate if administered as an intraoperative iv. infusion over an hour and that whenever possible serial serum levels should be monitored.     

Quantitative Ultrasound of the Calcaneus in Greek Women: Normative Data are Different From the Manufacturer's Normal Range

Quantitative ultrasound (QUS) is considered a useful method in evaluating bone status. The aim of the present study was to establish the reference data for the QUS measurements of the calcaneus in a Greek population. We measured a QUS parameter, stiffness index (SI), at the right calcaneus in 1500 women using the Achilles express Ultrasonometer (GE Lunar, Madison, WI). Participants were divided into 7 groups according to their age with a 10-yr span in each group. A progressive decline was found in the SI values after the age of 39 yr in the current study. When the SI values were compared between the age groups, high statistically significant differences were obvious, especially between 20–29 and 50- to 59-yr age groups and 60–69 and 70- to 79-yr age groups (p < 0.0005). Additionally, in the Greek normal range (GNR), the SI values of those aged 60–69 and 70–79 yr were significantly higher (81.84 ± 16.14 and 77.45 ± 17.65, respectively) than those in the manufacturer's normal range (MNR; 75.84 ± 16.14 and 69.10 ± 17.65, p < 0.005, respectively). Using the manufacturer's values, significantly fewer women were classified as normal (48% vs 67.3%), although those with T-score ≤ −2.5 were more (15.7%) compared with our Greek value (1.5%), and classification of subjects into risk-of-fracture categories was significantly different (kappa: 0.459, 66.2%, p < 0.0005). Multiple regression analysis showed that weight was the most significant predictor for SI in the age groups 30–39 (β = 0.280, p < 0.05), 40–49, 60–69, and 70–79 yr (β = 0.185, p < 0.005; β = 0.329, p < 0.0005; β = 0.494, p < 0.0005, respectively). Using conventional categories of risk, we report a different classification of our subjects from those proposed by the manufacturer, supporting the concept that data specific to the Greek population are necessary.     

Soluble circulating cell adhesion molecules in haemolytic uraemic syndrome

Plasma concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) were measured by enzyme-linked immunosorbent assay in four groups of children. Group 1 consisted of 20 patients with acute diarrhoea-associated haemolytic uraemic syndrome (D+HUS), the aetiology of HUS being verocytotoxin-producingEscherichia coli infection in each case. Controls consisted of 11 patients who had previously had D+HUS (group 2), 12 with chronic renal failure (group 3) and 8 healthy controls (group 4). When compared with healthy controls, the acute D+HUS group had higher sVCAM-1 (median 1,875 ng/ml, range 1,200–6,450 ng/ml vs. 1,200 ng/ml, range 975–2,125 ng/ml), von Willebrand factor antigen, (1.9 U/ml, range 0.85–5.1 U/ml vs. 0.55 U/ml, range 0.3–1.57 U/ml), white cell count (WBC, 14.5×10⁹/l, range 7.8–43.1 10⁹/l vs. 8.9 10⁹/l, range 5.7–10.8 10⁹/l) and neutrophil count (PMN, 10.1×10⁹/l, range 4.3–26.5 10⁹/l vs. 4.3 10⁹/l, range 3.7–6.6 10⁹/l), allP<0.005, and sICAM-1 was reduced (230 ng/ml, range 130–340 ng/ml vs. 400 ng/ml, range 260–690 ng/ml),P<0.05. Within the acute D+HUS group there was a significant correlation between sICAM-1 and PMN (r=0.56,P<0.01). There was no correlation between any adhesion molecule and plasma creatinine or von Willebrand factor. Comparing the acute HUS group with children with chronic renal failure, WBC (P<0.001), PMN (P<0.01) and sVCAM-1 (P<0.01) were significantly elevated, but there was no difference between the von Willebrand factor (P=0.08) or the sICAM-1 (P>0.1). sVCAM-1 is elevated and sICAM-1 decreased in acute D+HUS. This pattern of altered adhesion molecule concentration is unlike that in adults with vasculitis and suggests that different endothelial regulatory factors are at play.     

Effects of fluoride on in vitro calcification of tendon matrix

Summary Ca²⁺ and P_i uptake induced in vitro by a collagenous matrix derived from bovine tendon is inhibited by 1×10^–6 to 2×10^–5 M NaF and stimulated by 2×10^–5 to 2×10^–3 M NaF. Fluoride uptake occurs only over the latter concentrtion range. The uptake of Ca²⁺, P_i, and F^–1 progresses toward a limiting extent at which the molar Ca/P and Ca/F values are 1.6 to 1.7 and 4.5 to 5.7, respectively. Although the matrix-bound mineral, previously formed in the absence of NaF, readily undergoes dissolution when exposed to a Ca²⁺- and P-free medium of pH<7.4, the bound mineral phase formed in the presence of NaF does not. We conclude that fluoroapatite is the primary matrix-bound mineral. The uptake of fluoride, Ca²⁺. and P_i by both uncalcified and previously calcified matrices is inhibited by methylenediphosphonate and by phosphonoacetate as is calcification in the absence of NaF. Kinetic studies indicate that formation of a CaP complex precedes the uptake of F^–1 and suggest that F^–1 and OH^–1 compete for interation with the CaP complex during the calcification process. We concluded that fluoroapatite formation induced by the collagenous matrix occurs by a multistep pathway comparable to that proposed previously for hydroxyapatite formation.This investigation was supported by NIH Grant AM 11528.     

Laser pulse duration must match the estimated thermal relaxation time for successful photothermolysis of blood vessels

The relationship between photothermal damage to blood vessels of diameter,d, and laser pulse duration,t _p, was verified in a series of studies using the chick chorioallantoic membrane (CAM). A total of 879 individual CAM blood vessels (d=50–130m) was irradiated, using a laser pulse duration of 0.45 or 10 ms. Laser-induced vascular damage was observed in real time, recorded on videotape, and evaluated in a double-blind fashion. Permanent damage was confirmed by inspection 24 h after laser exposure. Under the conditions of this experiment, only when laser pulse durations are approximately equal to the estimated thermal relaxation times () of the CAM microvessels can the critical core intravascular temperature, necessary to destroy vessels irreversibly, be achieved and sustained for sufficient time. Shorter pulse durations are more effective for damaging smaller blood vessels; conversely, longer pulse durations are more effective for damaging larger diameter vessels.     

Intravenous calcitriol for treatment of hyperparathyroidism in children on hemodialysis

This double-blind, placebo-controlled study evaluated the safety and efficacy of intravenous (IV) calcitriol (Calcijex) for treatment of secondary hyperparathyroidism (2°HPT) in pediatric end-stage renal disease (ESRD) patients on hemodialysis (HD). After a 2 to 6-week washout period of all vitamin D compounds, patients with two consecutive PTH values >400 pg mL^–1, calcium levels 10.5 mg dL^–1 and calcium×phosphorus product values 70 mg² dL^–2 were eligible for the treatment phase. Patients received a bolus injection of calcitriol or placebo three times a week, immediately after dialysis for up to 12 weeks. Initial doses (0.5–1.5 g) were based on the severity of 2ºHPT. The dose was increased every two weeks by 0.25 g until there was at least a 30% decrease in PTH from baseline, or Ca>11.0 mg dL^–1, or Ca×P>75 mg² dL^–2. Overall, 11/21 (52%) patients in the calcitriol group had two consecutive 30% decreases from baseline in serum PTH compared with 5/26 (19%) patients in the placebo group (P=0.03). The mean total alkaline phosphatase decreased from 274 to 232 IU L^–1 in the calcitriol group and increased from 547 to 669 IU L^–1 in the placebo group (P=0.002). The mean bone-specific alkaline phosphatase decreased from 72.5 to 68 g L^–1 in the calcitriol group and increased from 105.3 to 148.5 g L^–1 in the placebo group (P=0.03). The incidence of two consecutive occurrences of elevated calcium×phosphorus (Ca×P>75 mg² dL^–2) product was higher in the calcitriol group than in the placebo group (P=0.01). Two consecutive occurrences of phosphorus >6.5 mg dL^–1 occurred in 71% of the calcitriol group and 46% of the placebo group (P=0.14). Calcium levels >10.5 mg dL^–1 were more common in the calcitriol group than in the placebo group (P=0.01). There was a direct relationship between serum phosphorus concentration and the percentage change in PTH from baseline in both the calcitriol group (r=0.46; P<0.0001) and the placebo group (r=0.21; P=0.0005). This study demonstrates that IV calcitriol, at initial doses of 0.5–1.5 g, effectively reduces PTH levels in pediatric HD patients and that patients should be closely monitored for hyperphosphatemia and elevated Ca×P product.     

Clinico-pathological study of meningiomas with haemorrhagic onset

Summary ¶Background. Haemorrhage from meningiomas is rare and the underlying pathophysiological mechanisms remain to be determined. We sought to identify these mechanisms by studying clinical and histological records of 6 meningioma patients treated at our institution. Patients and methods. We retrospectively studied 6 patients with meningiomas whose acute onset was due to haemorrhage. We evaluated clinical features and imaging studies. The vascularity and proliferative nature of these tumours were examined immunohistochemically and tissue factor (TF) immunoreactivity was assessed. For comparison we evaluated 25 non-haemorrhagic meningiomas. Findings. At onset, the haemorrhages mimicked stroke in all 6 patients. On imaging studies, 3 of the haemorrhages were intra- and extratumoural, the other 3 were extratumoural only. Hyperintensity on T2-weighted MRI was a characteristic of these meningiomas. Histologically, they were of 3 subtypes, meningothelial (n=3), transitional (n=2), and anaplastic (n=1). The MIB-1 labelling index of the 5 WHO Grade I meningiomas was 5.8±2.2. The mean number of CD31-positive blood vessels did not differ in haemorrhagic and non-haemorrhagic meningiomas. The TF-positivity rate of haemorrhagic meningiomas was higher than of non-haemorrhagic meningiomas. Interpretation. The proliferative nature of the meningiomas and TF expression in tumour cells may have contributed to the eventual haemorrhage of the meningiomas in our series.Published online August 7, 2003     

Effects of retroviral-mediated tissue plasminogen activator gene transfer and expression on adherence and proliferation of canine endothelial cells seeded onto expanded polytetrafluoroethylene

Purpose: Seeding prosthetic arterial grafts with genetically modified endothelial cells (ECs) has the potential to substantially improve graft function. However, preliminary applications suggest that grafts seeded with retrovirally transduced ECs yield a significantly lower percent surface coverage than those seeded with nontransduced ECs. The objective of this study was to test the hypothesis that canine ECs transduced with the human tissue plasminogen activator (tPA) gene would have a lower rate of adherence to pretreated expanded polytetrafluoroethylene (ePTFE) both in vitro and in vivo and that they would proliferate at a slower rate on pretreated ePTFE in vitro.Methods: Early passage ECs derived from canine external jugular vein were transduced with the retroviral MFG vector containing the gene for human tPA. ECs exposed to media alone served as controls. Iodine 125 – labeled ECs were seeded in vitro onto ePTFE graft segments pretreated with canine whole blood, fibronectin (50 μg/ml), or media alone, and the percent of ECs adherent at 1 hour were determined (n = 3). Additional tPA-transduced and –nontransduced ECs were grown for 10 days on either fibronectin (50 μg/ml) – pretreated ePTFE wafers or tissue culture plastic pretreated with gelatin (1%) or fibronectin (50 μg/ml), and the EC proliferation rates were determined (n = 3). Furthermore, ¹²⁵I-labeled ECs were seeded onto fibronectin (50 μg/ml) – pretreated ePTFE graft segments implanted as carotid and femoral artery interposition grafts (n = 3). The grafts were harvested after 1 hour, and the percent of ECs adherent was determined.Results: Human tPA was detected by immunohistochemical staining in 61% ± 5% of the transduced ECs and was expressed at 35.4 ± 12.9 ng/hr/10⁶ cells. Fibronectin and whole blood pretreatment of the ePTFE grafts led to greater EC adherence in vitro than did media alone (90.9% ± 5.3% vs 77.8% ± 5.8% vs 4.7% ± 1.1%, p ≤ 0.05). No significant difference in the rates of adherence or proliferation was seen in vitro between the transduced and nontransduced ECs. No significant difference in proliferation was found for the transduced ECs on the three matrices tested in vitro. In contrast, adherence of the transduced ECs in vivo was significantly lower than that of nontransduced ECs (64.7% ± 2.1% vs 73.7% ± 4.1%, p ≤0.05) 1 hour after implantation.Conclusions: Lower rates of surface endothelialization by genetically modified ECs in vivo do not appear to be due to an impaired capacity to initially adhere or proliferate on the synthetic graft but may result from decreased adherence after exposure to in vivo hemodynamic forces. (J VASC SURG 1995;22:795-803.)     

Inhibition of Calcium Oxalate Monohydrate (COM) crystal growth by pyrophosphate,citrate and rat urine

Summary An assay system for the measurement of the rate of Calcium Oxalate Monohydrate (COM) seed crystal growth in a metastable solution of calcium chloride and sodium oxalate containing traces of ¹⁴C-oxalic acid was used to assess the inhibitory activity of pyrophosphate (10^–5 M-10^–4 M), citrate (10^–4 M-10^–3 M) and urines of normal and pyridoxine deficient rats. Both pyrophosphate and citrate were strong inhibitors of COM crystal growth and caused a 50% decrease in crystal growth rate at 1.50×10^–5 M and 2.85×10^–4 M respectively. Normal rat urine strongly inhibited the COM crystal growth, while pyridoxine deficient animals showed a significant (p< 0.01) decrease in mean inhibitory activity as compared to pair-fed controls. A lowered urinary inhibitory potential accompanied with hyperoxaluria and hypercalciuria, which is known to be associated with pyridoxine deficiency, may be a contributory risk of calcium oxalate crystallization and stone formation.     

KB-R9032, newly developed Na<Superscript>+</Superscript>/H<Superscript>+</Superscript> exchange inhibitor,attenuates reperfusion-induced arrhythmias in isolated perfused rat heart

Purpose This study was conducted to elucidate the effects of KB-R9032, a newly developed Na⁺-H⁺ exchange inhibitor, on reperfusion-induced ventricular arrhythmia in the isolated perfused rat heart.Methods Male Wistar rat hearts (n = 48; 12 for each group) were perfused with modified Krebs-Ringers solution equilibrated with 5% carbon dioxide in oxygen by means of the Langendorff technique. An occluder was placed around the left anterior descending coronary artery (LAD). Heart rate, coronary flow, and ECG were monitored. Drug-free perfusate was used for 10min before switching to a perfusate containing various concentrations of KB-R9032. The added concentrations of KB-R9032 varied in the range of 0 (control) to 1 × 10^–5mol·l^–1. Each heart was subjected to regional ischemia (occlusion of LAD for 11min) and to 3min of reperfusion (release of the ligation).Results In the control group, reperfusion-induced ventricular fibrillation (VF) occurred in 91.7%, and the duration was 158.2 ± 14.4s (mean ± SEM); however, 1 × 10^–7, 1 × 10^–6, and 1 × 10^–5mol·l^–1 KB-R9032 reduced the incidence of VF to 75.0%, 42.9%, and 6.7%, respectively (P < 0.05 at 1 × 10^–5mol·l^–1 of KB-R9032) and reduced the duration of VF to 64.8 ± 22.1, 16.8 ± 10.1, and 1.2 ± 1.2s, respectively (P < 0.05 at 1 × 10^–6 and 1 × 10^–5mol·l^–1 of KB-R9032).Conclusion It was shown in this study that the Na⁺/H⁺ exchange inhibitor KB-R9032 suppresses reperfusion arrhythmias in the ischemia-reperfusion model of isolated rat heart.     

Urinary biochemical profile of patients with ureteric calculi in Jodhpur region (north western India)

Summary Urine chemistry of 42 normal subjects (NS) and 59 ureteric stone formers (SF) from Jodhpur region of Rajasthan, India is presented. Twenty four hour urinary levels of calcium, oxalic acid and uromucoids were significantly higher and levels of magnesium, citric acid and inorganic phosphorus were significantly lower in SF as compared to NS. No significant difference was observed in the uric acid, sodium and potassium levels in the two groups. Significant correlation was observed between calcium and magnesium; calcium and oxalic acid; calcium and citric acid; magnesium and oxalic acid; and oxalic acid and citric acid in NS on the basis of mmol/l but not on the basis of mmol/24 h. Calcium and oxalic acid correlation was uninfluenced by magnesium and citric acid levels. The log of risk factor index (RI) was higher (p< 0.001) in SF (–1.652) as compared to NS (–2.103). The log of ion activity product (IAP) was also higher (p< 0.001) in SF (–3.192x10^–3) than in NS (–2.914x10^–1). Based on RI and IAP, a scale has been devised for the prediction of the risk of stone formation and recurrence.     

Surgical treatment of cerebellopontine angle meningiomas in elderly patients

Summary Background. The aim of this study is to assess the morbidity and mortality of meningioma surgery in patients over 70 years of age harbouring a tumour at the cerebellopontine angle as one representative location of the posterior fossa in comparison with a matched group of young patients.Method. A retrospective analysis based on clinical charts, surgical records, histological records, imaging studies and follow up records was conducted to select patients over 70 years who underwent surgery for cerebellopontine angle meningiomas. Tumours with comparable size and location were matched with the younger group.Findings. There were 421 meningiomas located in the cerebellopontine angle, 21 patients were older than 70 years (range 70–84). Median Karnofsky-Index at presentation was 80 (50–90), 16 patients had a physical status grading ASA 2 and 5 patients ASA 3. The average length of hospital stay was 22 days (7–99 days). The postoperative median Karnofsky score at time of discharge was 80 (50–90). The most common medical complication was postoperative pneumonia in 4 patients, among them 3 patients had lower cranial nerve disturbances postoperatively. There were 56 younger patients (mean age 52.4 years; range 24.5–69.75 years) with corresponding tumour size and location. Pre-op Karnofsky score was 80 (70–90), 53 patients were graded as ASA 2 and 3 patients as ASA 3. Length of hospital stay was 13.6 days (8–32 days). Post-op Karnofsky score was 80 (50–90). Among 5 patients with postoperative lower cranial nerve disturbances no patient had pneumonia postoperatively. There was no peri-operative mortality in either group.Conclusions. With modern neurosurgical techniques and neuro-anesthesia elderly patients with CPA meningiomas can be operated on with acceptable low morbidity and good neurological outcome but recovery from surgery lasts longer compared to younger patients. However, postoperative lower cranial nerve deficits in elderly patients may not be well tolerated compared with younger patients.