Allelic loss at TP53 is not related to p53 protein overexpression in primary human endometrial carcinomas

We examined loss of heterozygosity (LOH) at the TP53 gene in primary human endometrial carcinomas (EC), and investigated the relationship between allelic loss, p53 protein overexpression, pRb-1 pathway alterations and MIB-1 proliferative activity. Applying the non-isotopic PCR-RFLP/VNTR-silver staining techniques, we investigated TP53 LOH in 46 tumors at four polymorphic loci. Out of 42 informative carcinomas, LOH was found in 19% of the cases studied. In general, there was no significant relationship between LOH and the clinical and pathological variables of cancer, including patient age, clinical stage, histological grade or depth of myometrial invasion. Interestingly, none of 7 tumors associated with hyperplasia revealed allelic imbalance, whereas 8 of 27 (30%) tumors without hyperplasia exhibited LOH (p=0.312; Fisher's exact test). Overexpression of nuclear p53 was not correlated with allelic loss at TP53 (p=0.336, Fisher's exact test). It is worth pointing out that p53 immunoreactivity was significantly related to proliferative activity of cancer (R=0.42, p=0.0037; Spearman's rank correlation test). A tendency towards a poorer outcome was reported in EC patients displaying TP53 LOH during short-time follow-up (p=0.093; log-rank test). None of the tumors simultaneously showed LOH at TP53 and RB1 genes (R=-0.211, p=0.16; Spearman's rank correlation test). p16INK4A alterations (LOH and gene deletion) occurred concomitantly, with 3 tumors showing the TP53 allelic loss, whereas the cyclin D1/cdk4 complex was overexpressed in a case with TP53 LOH. Altogether, losses at TP53 were not associated with p53 nuclear overexpression, but may affect a subset of EC patients characterized by an unfavorable prognosis at short-time follow-up. Allelic loss at TP53 seems to arise independently of LOH at the RB1 gene in carcinomas of the uterine corpus in humans. Disruptions at p16INK4A and/or cdk4/cyclin D1 concomitantly occurring with TP53 LOH may participate in the development of a subset of endometrioid-type ECs.     

Flicker perimetry (CFF) in patients with lens opacities--first report

PURPOSE: Comparison of standard W/W and CFF perimetry in patients with cataract and lens opacities. MATERIAL AND METHODS: Visual field was measured on Octopus 301 perimeter with option flicker perimetry. W/W and CFF perimetry (Program G1 in TOP strategy) was performed in 44 eyes with cataract and lens opacities. RESULTS: Defects in visual field with CFF perimetry were found in 24% of cases but with W/W perimetry in 100% of cases. CONCLUSIONS: Perimetry CFF is a new tool for early detection and follow up of visual field defects in patients with cataract and lens opacities.     

Surgical management of deep chemical burns of the eyelids

Chemical burns of the eyelids are common, and this may lead to ocular damage. A direct insult of the eyes that result in permanent damage, is rare in facial burns. The majority of the chemical burns of eyelids are partial-thickness that heal spontaneously in 1 week. Whereas, 10 percent are full-thickness burns that require release of contractures and grafts. Wound contracture can cause ectropion of the eyelid, resulting in exposure keratitis, conjunctivitis, corneal ulcers, perforation, and even blindness. At our departments, thirteen patients with 28 chemical burns of eyelids of third-degree, were reviewed. The eyelids had burns wounds with granulation and necrotic tissue. All patients had severe cicatrical ectropion. The eyelids were released with incisions running along the eyelid margin, down to the orbicularis muscle, including the distal part of the levator palpebrae superioris muscle, when necessary. To cover the resulting defects, we use generous full-thickness skin grafts, if available, for both the upper and lower eyelids. Rarely has a tarsorrhaphy been required, and properly constructed dressing provides satisfactory eyelid margin immobilization and conjunctival hygiene. Eighteen full-thickness grafts in 10 patients are reported 8 to 12 weeks after grafting. In seven eyelids, 3 patients developed ectropion and required reconstruction of the eyelids. Our series demonstrates that the early grafting of eyelid burns with full-thickness grafts, can prevent the development of recurrent cicatrical ectropion. Split-thickness grafting should be limited to cases where we can not find the hairless donor site for full-thickness skin grafts.     

The visual acuity impairment as the only sign of cerebral aneurysms--case report

Cerebral aneurysms are the most common reason of subarachnoid haemorrhage at the age of 50-60. Though the results of such haemorrhage are severe (high morbidity and mortality), it is quite often, the first noticeable sign of the problem. Previous symptoms i. e. headache, ophthalmic disturbances, temporary neurological symptoms are often passed over. The authors present the case of a young woman with cerebral aneurysms, in which the visual acuity impairment was the only symptom of the disease.     

Antinociception after intrathecal biphalin application in rats: a reevaluation and novel, rapid method to confirm correct catheter tip position

The opioid peptide dimmer biphalin [(Tyr-D-Ala-Gly-Phe-NH-)(2)] has high potency both in vivo and in vitro. Its antinociceptive activity depends on the route of administration: the lowest potency is after subcutaneous, and the highest after intrathecal or inracerebroventricular administration. We tested the analgesic activity of biphalin in a wide range of doses after intrathecal administration to rats. Doses as low as 0.005 nmol produced significant analgesia. Increasing the dose up to 2 nmol elevated and prolonged antinociception without any evident side effects, indicating that biphalin is an extremely potent opioid after intrathecal application with a wide therapeutic window. The highest dose tested (20 nmol) produced full analgesia and body rigidity lasting 2-3 h. After muscle tone returned to normal, antinociception lasted for several more hours. During these studies we observed a correlation between responses to biphalin and catheter placement. Postmortem verification of catheter placement revealed that in those rats in which high-dose biphalin did not produce analgesia or muscle rigidity, the catheter was positioned incorrectly or the flow of drug solution was obstructed. Therefore, a secondary conclusion is that assessment of transient rigidity after administration of a high dose of biphalin may be used as an easy method to confirm intrathecal placement of the catheter.     

L-arginine and cardiovascular system

L-arginine is a basic endogenous amino acid. Its significant metabolic role as the product of ammonia detoxification, the urea cycle metabolite, the precursor of proteins, ornithine, urea and creatinine, and the amino acid involved in the formation of active enzyme centers was very well established. The current interest in this amino acid refers mainly to its close relation with an important signal molecule nitric oxide (NO). Literature review demonstrates that L-arginine, the only substrate of the NO production, affects cardiovascular system (blood vessels and heart). The majority of experimental and clinical studies clearly show a beneficial effect of L-arginine on endothelium in conditions associated with its hypofunction and thus with reduced NO synthesis. Some clinical studies involving healthy volunteers or patients suffering from hypertension and diabetes indicate that it may also regulate vascular hemostasis. Moreover, experiments performed on animals and in vitro data also suggest that L-arginine may have a complex antiaggregatory, anticoagulatory and profibrinolytic effect. Therefore, a novel therapeutic potential of L-arginine should be taken into consideration.     

Zinc and depression. An update

Unsatisfactory clinical efficacy and a variety of adverse effects of current antidepressant drugs have incited search for better therapy. Zinc, an antagonist of the glutamate/N-methyl-D-aspartate (NMDA) receptor, exhibits antidepressant-like activity in rodent tests/models of depression. Similarly to antidepressants, zinc induces brain derived neurotrophic factor (BDNF) gene expression and increases level of synaptic pool of zinc in the hippocampus. Clinical observations demonstrated serum hypozincemia in depression, which was normalized by effective antidepressant treatment. Moreover, our preliminary clinical study demonstrated the benefit of zinc supplementation in antidepressant therapy. All the data indicate the important role of zinc homeostasis in psychopathology and therapy of depression and potential clinical antidepressant activity of this ion.     

H nuclear magnetic resonance spectroscopic investigation of urine for diagnostic and clinical assessment of methanol intoxication

Occasional or suicidal methanol intoxications are a permanent problem for most Poisoning Centers around the World. Therefore it is important to look for new diagnostic and clinical prognostic methods. In the present paper 5 cases of methanol intoxication were analyzed. At first the methanol concentrations in blood and urine were estimated with headspace gas chromatography technique. Next the urine samples were examined with 1H NMR spectroscopy, then the levels of ethanol, methanol and its metabolite, formate, lactate and trimethylamine-N-oxide with dimethylamine were evaluated. The concentrations of the above compounds were correlated with the patient's clinical status, the level of ethanol and methanol and biochemical parameters. The results indicate the correlation between clinical course of intoxication, prognostication and lactate level. There were no significant parallels for formate level as acidosis causing metabolite and initial methanol levels. In the urine samples of intoxicated patients the increased trimethyl-N-oxide and dimethylamine levels were observed, which may indicate renal cortex damage. Contrary to the opinion of some clinicians, methanol intoxication may be connected with renal functional disturbances. 1H NMR examination of urine appears to be an excellent tool to evaluate the clinical course of methanol intoxication.     

Identification of biliary metabolites of ifosfamide using 31P magnetic resonance spectroscopy and mass spectrometry

Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo ¹H-decoupled ³¹P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution ³¹P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19±1.47 mM; mean ± sd), carboxyifosfamide (2.04±1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05±2.38 mM). The unknown resonance was identified using liquid chromatography - mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW = 531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of ±drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients.