Spectral algorithms for supervised learning.

We discuss how a large class of regularization methods, collectively known as spectral regularization and originally designed for solving ill-posed inverse problems, gives rise to regularized learning algorithms. All of these algorithms are consistent kernel methods that can be easily implemented. The intuition behind their derivation is that the same principle allowing for the numerical stabilization of a matrix inversion problem is crucial to avoid overfitting. The various methods have a common derivation but different computational and theoretical properties. We describe examples of such algorithms, analyze their classification performance on several data sets and discuss their applicability to real-world problems.

Psychotic disorder and focal epilepsy in a left-handed patient with chromosome XYY abnormality.

OBJECTIVE: To discuss the relationship between XYY chromosome abnormality, psychiatric disorders and epilepsy. METHOD: Single case report. RESULTS: A 34-year-old man with 47, XYY karyotype and normal intelligence was followed-up at a neuropsychiatric clinic for over 30 years. He was first seen at age 3 years with a history of delayed motor and language development and an immunodeficiency syndrome. At age 8 years he developed refractory focal epilepsy, and in late adolescence he started to exhibit increasingly prominent obsessive thoughts, paranoid ideation, and aggressive sexual fantasies and behaviour. CONCLUSIONS: When interpreted within the context of previous literature reports, this case suggests a pathophysiological link between XYY chromosome abnormality, characteristic psychiatric symptoms and epilepsy disorder.

Effect of divalent and monovalent cations on calf thymus PCNA-independent DNA polymerase delta and its 3'----5' exonuclease.

Recent data suggest that DNA polymerases alpha and delta might have a coordinate functional role at the replication fork. In this communication we show that Mg2+ is likely the natural metal activator for both enzymes. Mn2+, a known mutagenic agent, is a competitive inhibitor of Mg2+ for DNA polymerase delta and acompetitive for DNA polymerase alpha. The 3'----5' exonuclease activity associated with DNA polymerase delta is not affected upon addition of Mn2+. Be2+, another mutagenic agent, on the other hand, has an inhibitory effect on the 3'----5' exonuclease, but not on the DNA polymerase delta. The data presented might explain the mutagenic and carcinogenic potential of these two divalent cations.

Inhibitor analysis of calf thymus DNA polymerases alpha, delta and epsilon.

Quantitative effects of inhibitors of the replicative DNA polymerases (pol) alpha, delta and epsilon from calf thymus are reported under similar assay conditions. Carbonyldiphosphonate was a competitive inhibitor of pols delta and epsilon, with 4- to 6-fold selectivity compared to pol alpha. Aphidicolin inhibited pols alpha and delta with 6- to 10-fold selectivity compared to pol epsilon. The 'butylphenyl' nucleotides, BuPdGTP and BuAdATP, inhibited pol alpha with at least 1000-fold selectivity compared to pols delta and epsilon. The use of these inhibitors under similar assay conditions permits the discrimination of the three enzymes.

Lack of stereospecificity of some cellular and viral enzymes involved in the synthesis of deoxyribonucleotides and DNA: molecular basis for the antiviral activity of unnatural L-beta-nucleosides.

Among enzymes involved in the synthesis of nucleotides and DNA, some exceptions have recently been found to the universal rule that enzymes act only on one enantiomer of a chiral substrate and that only one of the enantiomeric forms of chiral molecules may bind effectively at the catalytic site, displaying biological activity. The exceptions include: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucloside mono- and diphosphate kinases, cellular and viral DNA polymerases, such as DNA polymerase alpha, terminal transferase and HIV-1 reverse transcriptase. The ability of these enzymes to utilize unnatural L-beta-nucleosides or -nucleotides as substrate may be exploited from chemotherapeutic point of view.

Molecular modeling and synthesis of inhibitors of herpes simplex virus type 1 uracil-DNA glycosylase.

We recently reported the properties of the first selective inhibitors of herpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the virus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromolar range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the structure was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimized model, the activity of several octAU analogues was predicted, and the values compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be active as UDG inhibitors. These compounds will be useful to determine if UDG, like the viral thymidine kinase, is required for reactivation of HSV1 from latency in nerve cells.

Retained gastric antrum syndrome diagnosed by [99mTc] pertechnetate scintiphotography in man: hormonal and radioisotopic study of two cases.

Retained-antrum syndrome is a rare condition, occurring in Billroth II gastrectomised patients, in which an ulcer recurs associated with high levels of circulating gastrin. Some gastrin tests are useful to differentiate a retained antrum from a gastrinoma, but a firm diagnosis is sometimes very difficult. We have studied two cases of retained-antrum syndrome both by gastrin tests and by [99mTc] pertechnetate scintiphotography. By this method a prominent area of activity was observed on the anatomic site of the duodenal stump bottom. It appeared after 20 or 30 min and lasted for the 2 hr of observation. After surgical resection, no area of activity was observed at the scintiphotographic followup. No false positive was observed out of the more than 30 subjects studied. Scintiphotography by pertechnetate seems able to demonstrate the presence and the size of retained gastric antrum in B II gastrectomised patients with recurrent ulcer.

Long-term exposure to zidovudine affects in vitro and in vivo the efficiency of phosphorylation of thymidine kinase.

The purpose of this study was to investigate the mechanism of acquired cellular resistance to AZT, a mechanism that has been described as a potential source of drug resistance in addition to viral mutations. To study this phenomenon the kinetics parameters of thymidine kinase (TK) activity have been defined in CEMazt, a cell line previously selected for resistance to AZT, in comparison with the parental AZT-sensitive CEM cells. The results revealed that the value of the maximum velocity (Vmax) of TK activity for deoxythymidine (dThd) phosphorylation is decreased in CEMazt as compared to the wild-type cell line (Vmax: CEM = 105.3 +/- 17.6 nmol/hr/mg of protein; CEMazt = 0.3 +/- 0.02 nmol/hr/mg of protein; p < 0.001). Furthermore, the enzyme affinity versus dThd is lower in CEMazt as compared to CEM (Km: CEM = 0.9 +/- 0.2 microM; CEMazt = 1.6 +/- 0.2 microM; p < 0.01). Consequently phosphorylation efficiency, expressed as the ratio between Vmax and Km, is also reduced in CEMazt (p < 0.001). To evaluate whether such a phenomenon may also occur in patients, ex vivo experiments were carried out by using PBMCs from HIV-infected patients, treated or not treated with AZT. The results (mean values from 10 patients for each group) indicate that a prolonged treatment (> 6 months) with AZT may modify the enzymatic kinetics of TK, leading to a significant reduction in the phosphorylation efficiency of the enzyme (4.07 +/- 1.7 in treated patients versus 13.5 +/- 1.7 in untreated patients; p < 0.001). These results indicate that AZT treatment can also induce a defect in TK activity in patients.

Psychiatric comorbidity and psychosocial stress in patients with tension-type headache from headache centers in Italy. The Italian Collaborative Group for the Study of Psychopathological Factors in Primary Headaches.

A multicenter study was carried out in 10 Italian Headache Centers to investigate the prevalence of psychosocial stress and psychiatric disorders listed by the IHS classification as the "most likely causative factors" of tension-type headache (TTH). Two hundred and seventeen TTH adult outpatients consecutively recruited underwent a structured psychiatric interview (CIDI-c). The assessment of psychosocial stress events was carried out using an ad hoc questionnaire. The psychiatric disorders that we included in the three psychiatric items of the fourth digit of the IHS classification were depressive disorders for the item depression, anxiety disorders for the item anxiety, and somatoform disorders for the item headache as a delusion or an idea. Diagnoses were made according to DSM-III-R criteria. At least one psychosocial stress event or a psychiatric disorder was detected in 84.8% of the patients. Prevalence of psychiatric comorbidity was 52.5% for anxiety, 36.4% for depression, and 21.7% for headache as a delusion or an idea. Psychosocial stress was found in 29.5% of the patients and did not differ between patients with and without psychiatric comorbidity. Generalized anxiety disorder (83.3%) and dysthymia (45.6%) were the most frequent disorders within their respective psychiatric group. The high prevalence of psychiatric disorders observed in this wide sample of patients emphasizes the need for a systematic investigation of psychiatric comorbidity aimed at a more comprehensive and appropriate clinical management of TTH patients.

Contingent negative variation indicates phasic arousal for externally cued unilateral eye blink in human subjects.

The contingent negative variation (CNV) as a slow cortical potential was used to investigate cortical processing of externally cued, voluntary unilateral eye blink. Probands blinked as a response within a modified two-stimulus reaction time paradigm. Reaction time and amplitudes of CNV were determined. The activity of the orbicularis oculi muscles (OO) was registered by surface electromyography (EMG). Probands who performed unilateral eye blinks with accurately inhibiting contralateral OO activity showed a significantly higher negativity of the early CNV component compared with the bilateral eye blink condition. This effect was confined to the beginning of unilateral blinking performance. It is suggested that the unilateral eye blink is a challenging motor task, initially requiring an increased cortically driven arousal and attention as revealed by increased early CNV components.

DNA synthesis enzymes and proliferating cell nuclear antigen in normal and neoplastic nerve cells.

The activity of nuclear DNA polymerases alpha, beta and delta/epsilon, uracil-DNA glycosylase, thymidine kinase and the presence of Proliferating Cell Nuclear Antigen (PCNA) have been examined in developing rat glial cells, in rat and human glioma, in human neuroblastoma and in differentiated neuroblastoma cell lines in vitro. During glial development the activity of all enzymes tested, except DNA polymerase beta, markedly decreased, suggesting their coordinate regulation in respect to the proliferative state of the cells. Glioma and neuroblastoma cell lines restore the enzymatic activities that were no longer expressed in normal adult cells. Neuroblastoma cell lines induced to differentiate in vitro by retinoic acid showed a decline of the activities of DNA polymerase alpha, DNA polymerase delta/epsilon, uracil-DNA glycosylase and thymidine kinase similar to that observed during in vivo differentiation. We also demonstrate that PCNA is not detectable in glial and neuronal cells at all developmental stages, but can be found in tumor nerve cells. A possible use of enzymatic assays or anti-PCNA antibodies to detect brain tumors is discussed.

Alteration of thymidine kinase activity in cells treated with an antiviral agent.

A lymphoblastoid cell line, CEM, was rendered resistant to zidovudine (AZT) in vitro by exposure to low but gradually increasing concentrations of the drug. This type of cellular resistance seems to be due to a defect of thymidine kinase (TK) activity that is acquired by cells grown in the presence of AZT. In fact, enzymatic studies with extracts from AZT-resistant cells (CEMazt), have shown that the value of the maximum velocity (Vmax) of TK activity measured with AZT and for deoxythymidine (dThd) is decreased as compared to sensitive CEM cells. Furthermore, the enzyme affinity for AZT and dThd is reduced in CEMazt. Further experiments have shown that such cells do not show resistance to other nucleoside analogs, such as ddI, ddC, AraT and D4T, suggesting that the phosphorylation pathways different from those involving TK are unaltered. Ex vivo experiments performed by using peripheral blood mononuclear cells (PBMC) from HIV infected individuals revealed that a prolonged treatment with AZT may modify the affinity of TK for dThd, thus suggesting that the aforementioned phenomenon may occur also in vivo.

Activity profiles of enzymes that control the uracil incorporation into DNA during neuronal development.

We have shown that DNA polymerase beta, the only nuclear DNA polymerase present in adult neurons, cannot discriminate between dTTP and dUTP, having the same Km for both substrates. This fact suggests that during reparative DNA synthesis, in adult neurons, dUMP residues can be incorporated into DNA. Since uracil DNA-glycosylase functions to prevent the mutagenic effects of uracil in DNA coming as a product of deamination of cytosine residues or as a result of dUMP incorporation by DNA polymerase, we have studied the perinatal activity of uracil DNA-glycosylase and of 2 enzymes (nucleoside diphosphokinase and dUTPase) involved in dUTP metabolism. Our data indicate that during neuronal development there is a rapid decrease in uracil DNA-glycosylase which could impair the removal of uracil present in DNA in adult neurons. However, misincorporation of dUMP into DNA might be kept to a low frequency by the action of dUTPase present at all developmental stages.

Clinical and stabilometric monitoring in a case of cerebellar atrophy with vitamin E deficiency.

The authors describe a case of early onset ataxia with cerebellar atrophy and vitamin E deficiency, treated with alpha-tocopherol supplementation and physically rehabilitated by postural biofeedback. Clinical assessments, serum vitamin E levels and postural evaluation by means of a stabilometric platform continued for about 2 years and significant clinical improvement was recorded. Our study confirms that combined physical therapy and vitamin E supplementation may result in improvement of cerebellar function. Motor improvement is directly related to vitamin E serum levels, providing further confirmation that normal vitamin E levels are crucial for proper brain functions.

Aphidicolin inhibits in vitro the activity of pseudorabies virus (PRV) DNA polymerase and in vivo the viral proliferation.

We have purified and characterized Pseudorabies virus (PRV) DNA polymerase from infected TK- mouse cells. PRV DNA polymerase has a 3'- > 5' exonuclease activity; it is stimulated by ionic strength, requires magnesium for optimal activity and it is more sensitive to aphidicolin than eukaryotic and HSV-1 replicative DNA polymerases. Aphidicolin inhibits in vitro PRV DNA polymerase competitively with respect to dCTP with a Ki of 0.06 microM and completely blocks viral growth in vivo at 4.4 microM. The high sensitivity to aphidicolin of animal herpesvirus DNA polymerases might allow a topical use of this drug in the treatment of animal herpesvirus keratitis and stomatitis.

Combined surgical and endovascular treatment of a traumatic pseudo-aneurysm of the brachiocephalic trunk with anatomical anomaly.

The authors report a case of combined surgical and endovascular treatment of a traumatic pseudo-aneurysm of the innominate artery in which the left common carotid artery originated from the brachiocephalic trunk. After a conventional surgical intervention with the implantation of the left common artery on the left subclavian artery, to correct the anatomic anomaly, a safe and effective endovascular stent-graft placement excluded the aneurysm. This new technique proposes a good chance for polytraumatized patients to receive a better prognosis and a much faster rehabilitation.

Exclusion of an internal carotid aneurysm by a covered stent.

The authors report a case of a patient with thromboembolic strokes caused by a high internal carotid artery aneurysm. Considering the position and the anatomic structure of this aneurysm the sac was excluded transluminally by placing an endovascular covered stent.

[Use of slowly resorbing mesh in the repair of kidney rupture due to rejection]. / Uso di rete a riassorbimento lento nel recupero di reni rotti per rigetto.

Personal experience about the use of Vicryl mesh in a case of kidney rupture following rejection is presented. The stopping of bleeding and recovery of diuresis were obtained almost immediately after intervention.

Synthesis and in vitro activity of D- and L-enantiomers of 5-(trifluoromethyl)uracil nucleoside derivatives.

Recently, beta-L-nucleoside analogues have emerged as a new class of sugar modified nucleosides with potential antiviral and/or antitumoral activity. As a part of our ongoing research on this topic, we decided to synthesize 5-CF3-beta-L-dUrd (7), the hitherto unknown L-enantiomer of Trifluridine, an antiherpetic drug approved by FDA but only used in topical applications due to concomitant cytotoxicity. 5-CF3-beta-L-dUrd (7) as well as some other related L-nucleoside derivatives were stereospecifically prepared and tested in vitro against viral (HSV-1 and HSV-2) and human thymidine kinases (TK).

[Alcohol withdrawal syndrome. Effects of short-term treatment with dapiprazole]. / Sindrome da astineza alcoolica. Effetti del trattamento "short-term" con dapiprazolo.

A study on dapiprazole, a new psychotropic agent, in the treatment of patients during the alcohol withdrawal syndrome, is reported. On the basis of evaluations made on the severity of the physical and psychic symptoms of withdrawal, the conclusion is drawn that the new psychotropic agent, administered at gradually increasing doses of 40 to 90 mg/kg for 7 days, completely controls the clinical symptomatology at least in 70% of the cases treated.