Dissecting the prognostic signature of patients with astrocytoma isocitrate dehydrogenase-mutant grade 4: a large multicenter, retrospective study.

BACKGROUND: The World Health Organization (WHO) 2021 classification of central nervous system (CNS) tumors classified astrocytoma isocitrate dehydrogenase-mutant (A IDHm) with either microvascular proliferation and/or necrosis or homozygous deletion of CDKN2A/B as CNS grade 4 (CNS WHO G4), introducing a distinct entity and posing new challenges to physicians for appropriate management and prognostication. PATIENTS AND METHODS: We retrospectively collected information about patients diagnosed with A IDHm CNS WHO G4 at three reference neuro-oncological Italian centers and correlated them with survival. RESULTS: A total of 133 patients were included. Patients were young (median age 41 years) and most received post-operative treatment including chemo-radiation (n = 101) and/or temozolomide maintenance (n = 112). With a median follow-up of 51 months, the median overall survival (mOS) was 31.2 months, with a 5-year survival probability of 26%. In the univariate analysis, complete resection (mOS: 40.2 versus 26.3 months, P = 0.03), methyl-guaninemethyltransferase (MGMT) promoter methylation (mOS: 40.7 versus 18 months, P = 0.0136), and absence of telomerase reverse transcriptase (TERT) promoter mutation (mOS: 40.7 versus 18 months, P = 0.0003) correlated with better prognosis. In the multivariate models, lack of TERT promoter mutation [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07-0.82, P = 0.024] and MGMT methylation (HR 0.40, 95% CI 0.20-0.81, P = 0.01) remained associated with improved survival. CONCLUSIONS: This is the largest experience in Western countries exploring the prognostic signature of patients with A IDHm CNS G4. Our results show that MGMT promoter methylation and TERT promoter mutation may impact clinical outcomes. This may support physicians in prognostication, clinical management, and design of future studies of this distinct diagnostic entity.

Laparoscopic lateral ovarian transposition: a fertility sparing procedure.

This article reports the case of a 30-year-old woman who, in 2003, had diffuse large B-cell lymphoma of the left vaginal fornix, associated with sclerosis. After six chemoimmunotherapy cycles the patient underwent a laparoscopic procedure for lateral ovarian transposition to spare ovarian function before radiotherapy. Six months after the transposition the evaluation of ovarian function was performed. The hypothalamic-pituitary-ovary axis was normal. Three years after radiation therapy (2006) the patient spontaneously conceived. Her pregnancy proceeded regularly. She had an uneventful vaginal delivery. Lateral ovarian transposition with tubal anatomy preservation, which is an underused technique, can be successfully used to spare ovarian function in women who undergo pelvic radiotherapy and to let them achieve spontaneous pregnancy.

Efficacy and tolerability of once-daily cephalexin in canine superficial pyoderma: an open controlled study.

OBJECTIVES: The aims of this study were to evaluate the efficacy and tolerability of oral cephalexin given at 30 mg/kg once daily in dogs with superficial pyoderma and to compare them with those of oral cephalexin given at 15 mg/kg twice daily. METHODS: Twenty dogs with superficial pyoderma were treated with cephalexin at 30 to 60 mg/kg orally once daily (group A) and compared with 20 dogs treated at a dose of 15 to 30 mg/kg orally twice daily (group B). Dogs were treated until 14 days after clinical remission. Type and distribution of lesions, pruritus and general health status were assessed every 14 days using a numerical scale until 14 days after treatment discontinuation. Total scores for each evaluation day were compared between the two groups as well as time to obtain resolution and percentage of relapses. RESULTS: Resolution of superficial pyoderma was obtained in all dogs in 14 to 42 days (median 28 days for both groups), with no difference between groups. Six dogs experienced vomiting or diarrhoea but did not require discontinuation of the treatment. Only one dog (in group A) relapsed nine days after treatment discontinuation. CLINICAL SIGNIFICANCE: Once-daily cephalexin is as effective as twice-daily cephalexin in the treatment of canine superficial pyoderma.

Serum progesterone at human chorionic gonadotropin injection significantly correlate with female age.

AIM: In in vitro fertilization-embryo transfer (IVF-ET) higher age and low responses are associated with accelerated luteinization of mature follicles rather than diminished responsiveness. The aim of this study was to determine whether an elevated serum progesterone (P) on the day of human chorionic gonadotropin (hCG) administration during gonadotropin stimulation for IVF-ET is associated with age. METHODS: E2 (17beta estradiol) and P concentrations on the day of hCG administration, number and quality of oocytes and embryos, and clinical pregnancies were retrospectively analyzed in 460 women undergoing IVF-ET. We evaluated patients according to age; the 25-30 age group (n=140), the 31-35 age group (n=100), the 36-40 (n=90), and the 41-45 age group (n=130). RESULTS: In the 25-30 age group (n=140) P was 0.67+/-0.3 ng/mL, in the 31-35 age group (n=100) P was 0.87+/-0.2 ng/mL, in the 36-40 age group (n=90) P was 0.95+/-0.2 ng/mL, in the 41-45 age group (n=130) P was 1+/-0.2 ng/mL. The difference between the 25-30 age group and the 41-45 age group was statistically significant (P<0.05). CONCLUSIONS: Periovulatory levels of serum P vary according to ovarian response to controlled ovarian hyperstimulation. Periovulatory P may reflect inadequate steroidogenesis. In women stimulated with recombinant follicle stimulating hormone for IVF, the serum P on the day of hCG administration increases with age.

Mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leucocytes.

Hydrocortisone (10 microgram/ml) greatly inhibits the prostaglandin release by rat peritoneal leucocytes phagocytosing killed bacteria. The inhibition, which occurs after an initial latency of 30 min, is completely reversed by either actinomycin D (0.5 microgram/ml) or cycloheximide (1 microgram/ml). Since these antibiotics are known inhibitors of DNA-dependent RNA synthesis and protein synthesis respectively, it appears that the mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leucocytes involves stimulation of transcription and induction of protein synthesis.

Hydrocortisone-induced inhibitor of prostaglandin biosynthesis in rat leucocytes.

Rat peritoneal luecocytes incubated with hydrocortisone (10 micrograms/ml) release a factor which inhibits prostaglandin generation. The steroid-induced inhibitor, which mediates the anti-phospholipase effect of antiinflammatory steroids, may be a protein or a polypeptide since its formation is blocked by cycloheximide, a known inhibitor of protein synthesis.

A comparison of the acute inflammatory response in adrenalectomised and sham-operated rats.

Carrageenin pleurisy was induced in adrenalectomised (ADX) and sham-operated (SHO) rats. The magnitude and duration of inflammation, as estimated by fluid exudation and cell migration, was greatly increased (approximately doubled) in ADX rats compared with that in their SHO controls. The content of eicosanoids (6-keto-prostaglandin F1 alpha (6-keto-PGF 1 alpha), thromboxane B2 (TXB2), and leukotriene B4 (LTB4] in inflammatory exudates from ADX rats was significantly (2-4 fold) greater than that of their SHO controls. Resident macrophages obtained from ADX rats produced more eicosanoids per cell per unit time when stimulated in vitro with zymosan, than did cells from the SHO controls. Administration of glucocorticoids blocked the inflammatory response and reduced the release of eicosanoids both in vitro and in vivo in both groups of rats. These data are consistent with the notion that physiological amounts of glucocorticoids exert a tonic inhibitory action on phospholipase activity in normal animals and that the increased secretion of these hormones during the inflammatory response serves to check and control the development of inflammation.

Glucocorticoids induce the formation and release of anti-inflammatory and anti-phospholipase proteins into the peritoneal cavity of the rat.

1 Dexamethasone and hydrocortisone induced the release of anti-phospholipase proteins into the peritoneal cavities of rats. 2 Adrenocorticotrophic hormone (ACTH) also releases these proteins in normal but not in adrenalectomized rats. 3 Peritoneal lavage proteins were separated by ion-exchange and size exclusion chromatography. The anti-phospholipase activity occurred in four separate fractions with the major component having an apparent mol. wt. of 40 k. 4 Column fractions containing these anti-phospholipase proteins had anti-inflammatory effects in the rat carrageenin pleurisy model whereas other fractions were inactive. 5 The proteins appear to be identical to macrocortin and lipomodulin, the 'second messengers' of glucocorticoid hormone action on the arachidonate system.

Distinct inhibition of membrane-bound and lysosomal phospholipase A2 by glucocorticoid-induced proteins.

Anti-inflammatory steroids induce the release in vivo of antiphospholipase proteins (APP) into the peritoneal cavities of rats. APP were partially purified by ion- exchange chromatography. The main anti-phospholipase activity was recovered in two zones of the elution gradient named APP I and APP II; their molecular weight (mol. wt) was determined with molecular sieve chromatography. Two phospholipase A2 (PLA2) activities were identified from rat peritoneal leucocytes, one with a pH optimum at 4.5 (a lysosomal enzyme) and one with pH optimum at 8.5 (a membrane-bound enzyme); the selective secretion of the former was observed when leucocytes were stimulated by phagocytosis. The effect of APP on both enzyme activities was studied on enzyme preparations from resting leucocytes. APP were also added to leucocytes incubated with or without phagocytozable material. After incubation, PLA2 activities were determined both inside the cells and in the culture medium. APP I revealed a mol. wt of 200 k with a small fragment of 15 k and inhibited membrane-bound PLA2; APP II revealed a mol. wt of 40 k and inhibited lysosomal PLA2.

In vivo and in vitro inhibition of platelet aggregation by SV-IV, a major protein secreted from the rat seminal vesicle epithelium.

In summary, the present study documents that platelet aggregation triggered by thrombin, ADP, collagen and PAF both in vivo and in vitro, was prevented by SV-IV in a dose-dependent manner. Only platelet aggregation by AA was not affected by the protein, thus suggesting a possible involvement of PLA2 inhibition in the molecular mechanism at the basis of SV-IV anti-thrombotic effect.

Immunosuppressive and anti-inflammatory properties of a major protein secreted from the epithelium of the rat seminal vesicles.

The nonspecies specific immunosuppressive and anti-inflammatory properties of a major protein (SV-IV) secreted from the epithelium of rat seminal vesicles (SV) are described. To detect the immunosuppressive effect, peripheral blood lymphocytes (PBL) were pretreated for 2 hr at 37 degrees with SV-IV, and the protein was maintained in the incubation medium during the whole culture time. We obtained evidence that, during preincubation of PBL and SV-IV the protein was transformed by a transglutaminase (TGase) released from PBL into modified low and high molecular weight forms able to bind to PBL surfaces. It is suggested that T lymphocytes are the possible targets of the immunosuppressive effect. SV-IV seems to inhibit only the early phase of the proliferative response of T lymphocytes to mitogens without having any direct effect on the enzymatic system involved in DNA synthesis. Moreover, the protein SV-IV was also shown to possess an anti-inflammatory property due to a block of the arachidonic acid cascade at the level of the enzyme phospholipase A2 (PLA2). The physiological significance of the immunosuppressive and anti-inflammatory properties of SV-IV are discussed in relation to different aspects of the mammalian reproduction.

Substance P inactivation by transglutaminase in vitro.

Gamma(glutamyl5)spermine derivative of substance P (Spm-SP) was synthesized in vitro in the presence of purified guinea pig liver transglutaminase and Ca2+. The spermine adduct of the neuropeptide was purified by HPLC on a reversed-phase column and characterized by fast atom bombardment mass spectrometry. The biological activities of Spm-SP were tested by assaying, in comparison with substance P, its ability to induce both the contractions of smooth muscle in vitro and the edema formation in vivo. Spm-SP was shown not to elicit contractile responses in the isolated rat stomach strip and duodenum and not to antagonize the spasmogenic effect evoked by the native neuropeptide. Furthermore, Spm-SP was unable, when administered into rats by plantar injection, either to provoke an acute inflammatory response in the hind limb or to antagonize the edema formation induced by a concurrent administration of substance P. These results indicate that the introduction of a large size hydrophilic moiety at the glutamine5 level negatively affects the ability of the neuropeptide to bind to its receptor(s), thus supporting the view that the hydrophobic middle portion of substance P plays a key role in receptor recognition.

Endogenous nitric oxide modulates morphine-induced changes in locomotion and food intake in mice.

Opioids increase the dopaminergic turnover in nucleus striatum and nucleus accumbens of mice, causing behavioural changes such as increased locomotion and food intake. We have now shown that L-arginine administration increases morphine-induced locomotion and changes in food intake in mice. D-Arginine had no effect, suggesting a stereospecific mechanism. Furthermore NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduced the morphine-induced effects. These results suggest that endogenous nitric oxide could play a role in the modulation of dopaminergic effects elicited by morphine.

Involvement of NK receptors and beta-adrenoceptors in nitric oxide-dependent relaxation of rabbit aorta rings following electrical-field stimulation.

Electrical-field stimulation caused an endothelium-dependent relaxation in rabbit aorta rings precontracted by phenylephrine. The relaxation was reduced in a dose-dependent manner by morphine, benzalkonium, [D-Pro2,D-Trp7,9]substance P and an beta-adrenoceptor antagonist, propranolol. The vasodilatation was enhanced by superoxide dismutase and abolished by haemoglobin and NG-monomethyl-L-arginine. The inhibitory effect of NG-monomethyl-L-arginine was reversed by L-arginine, the precursor of nitric oxide biosynthesis, but not by its enantiomer, D-arginine. These data show that the electrically induced relaxation is independent on nitric oxide released by NK receptors and beta-receptors. Moreover, morphine, by reducing substance P release, decreased the magnitude of electrically induced relaxation, suggesting an indirect role of opioids in the regulation of the peripheral circulation through the control of nitric oxide release. Furthermore our observations confirm the hypothesis that subtypes of beta-adrenoceptors releasing nitric oxide participate in the regulation of vascular tone.

Protective effect of SV-IV on platelet-activating factor-induced hypotension, bronchoconstriction and gastric mucosal injury.

The inhibitory effect of one of the major proteins secreted by the rat seminal vesicles (SV-IV) on platelet-activating factor (PAF)-induced biological activities was investigated in vivo. SV-IV was found to prevent dose dependently both hypotension and acute bronchospasm caused by PAF administration in guinea-pigs. In addition, SV-IV inhibited both PAF- and ethanol-induced gastric mucosal injury in a dose-dependent manner.

Relationship between the anti-phospholipase and anti-inflammatory effects of glucocorticoid-induced proteins.

Glucocorticoid-induced anti-phospholipase proteins were partially purified by using ion-exchange and molecular sieve chromatography. These proteins, as well as dexamethasone itself, inhibited the hind-paw rat oedema induced by carrageenin. This inhibition was reversed by arachidonic acid, Anti-phospholipase proteins as well as hydrocortisone, also reduced the formation of prostaglandin E2 and leukotriene B4 by phagocytosing leucocytes. A specific monoclonal antibody was able to reverse the inhibition of eicosanoid formation. The mechanism of the anti-inflammatory effect of glucocorticoids and anti-phospholipase proteins is discussed in the light of these results.

L-arginine modulates morphine-induced changes in locomotion in mice.

In mice opioids increase dopaminergic turnover in nucleus striatum and nucleus accumbens, causing behavioural changes such as increased locomotion. In this study we have shown that L-arginine administration increases morphine-induced locomotion in mice. D-Arginine had not effect, suggesting a stereospecific mechanism. Furthermore NG-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, reduced morphine-induced effect. These results suggest that endogenous nitric oxide could play a role in the modulation of dopaminergic effects elicited by morphine.

Polyamide microcapsules containing jojoba oil prepared by inter-facial polymerization.

Jojoba oil containing polyamide microcapsules having diameter of approximately 5 microm were prepared by inter-facial polycondensation by direct method (oil-in-water). Qualitative effects of both the formulation and the process parameters on microcapsules characteristics were investigated by SEM observations. Morphological analysis showed the dependence of the external membrane compactness on the chemical nature of the water-soluble polyamine and the oil-soluble acid polychloride: 1,6-hexamethylenediamine (HMDA) and terephthaloyl dichloride (TDC) were found to favour the production of smooth and dense surfaces. The use of ultrasonic irradiations during the dispersion step to get a further reduction of microcapsules size was also evaluated.