Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.

Justification Of Empiric Methodology to Determine Dexmedetomidine Dose for the TREX Study.

INTRODUCTION: Dexmedetomidine is the sedative agent administered in combination with remifentanil and low dose of sevoflurane in the interventional arm of the ongoing TREX trial (Trial Remifentanil DExmedetomidine). The TREX pilot study (published in Paediatr Anaesth 2019;29:59-67) established infusion rates higher than those initially proposed. This could be attributed to an inappropriate target concentration for sedation or incorrect initial pharmacokinetic parameter estimates. METHODS: The TREX study is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicentre, superiority trial comparing neurological outcome after standard sevoflurane anaesthesia with dexmedetomidine/remifentanil and low dose sevoflurane anaesthesia in children aged less than 2 years undergoing anaesthesia of 2 hours or longer. In this report, dexmedetomidine pharmacokinetics were analysed in the interventional arm of the Italian population. RESULTS: There were 162 blood samples from 32 infants (22 male and 10 female). The median (IQR) age was 12 (5.2-15.5) months, weight 9.9 (7.3-10.8) kg. Duration of anaesthesia ranged from 2-6 hours. None of the children were born premature (median postnatal age 39 weeks, IQR 38-40 weeks). A 3-compartment PK model that incorporated allometric scaling and a maturation function demonstrated plasma concentration observations from the current Italian arm of the TREX study were consistent with those predicted by a "universal" model using pooled data obtained from neonates to adults. CONCLUSIONS: This current PK analysis from the Italian arm of the TREX study confirms that plasma concentration of dexmedetomidine is predictable using known covariates such as age and size. The initial target concentration (0.6 µg.L-1 ) used to sedate children cared for in the intensive care after cardiac surgery was inadequate for infants in the current TREX study. A target concentration 1 mcg.L-1 , corresponding to a loading dose of 1 mcg.kg-1 followed by an infusion of 1 mcg.kg-1 .hour-1 , provided adequate sedation.

MAPO index for risk assessment of patient manual handling in hospital wards: a validation study.

Manual handling of disabled patients - as regards movement - is one of the major factors affecting acute low back pain of exposed nursing staff. In the absence of quantitative methods assessing this kind of risk, the Research Unit Ergonomics of Posture and Movement of Milan developed in 1997 a risk assessment method called Movement and Assistance of Hospital Patients (MAPO), which is applicable in hospital wards.A first study conducted in 1999 allowed the identification of three levels of MAPO index corresponding with increasing probabilities of being affected by acute low back pain. In accordance with the well-known traffic light model, for MAPO index values between 0 and 1.5 the risk is considered to be absent or negligible. For values between 1.51 and 5.00 the risk is considered to be moderate. For values exceeding 5.00 the risk is considered to be high. In view of the limitations of the previous study, the results needed confirmation and so, in 2000-2001, another cross-sectional study was carried out, which included 191 hospital wards for acute and chronic patients and 2603 exposed subjects. This paper presents the analytical results of the association between the MAPO index and acute low back pain in this new data sample. The agreement between results of the two studies indicates that the MAPO index can be used as a risk index, although with some caution, as detailed in the paper. It can assess the risk exposure level of patient manual handling in wards and can be a useful tool for planning effective preventive actions to reduce the risk of work-related musculoskeletal disorders in health-care workers looking after disabled patients.

[Proposal and preliminary validation of a check-list for the assessment of occupational exposure to repetitive movements of the upper lims]. / Proposta e validazione preliminare di una check-list per la stima dell'esposizione lavorativa a movimenti e sforzi ripetuti degli arti superiori.

Over the last few years the Authors developed and implemented, a specific check-list for a "rapid" assessment of occupational exposure to repetitive movements and exertion of the upper limbs, after verifying the lack of such a tool which also had to be coherent with the latest data in the specialized literature. The check-list model and the relevant application procedures are presented and discussed. The check-list was applied by trained factory technicians in 46 different working tasks where the OCRA method previously proposed by the Authors was also applied by independent observers. Since 46 pairs of observation data were available (OCRA index and check-list score) it was possible to verify, via parametric and nonparametric statistical tests, the level of association between the two variables and to find the best simple regression function (exponential in this case) of the OCRA index from the check-list score. By means of this function, which was highly significant (R2 = 0.98, p < 0.0000), the values of the check-list score which better corresponded to the critical values (for exposure assessment) of the OCRA index looked for. The following correspondance values between OCRA Index and check-list were then established with a view to classifying exposure levels. The check-list "critical" scores were established considering the need for obtaining, in borderline cases, a potential effect of overestimation of the exposure level. On the basis of practical application experience and the preliminary validation results, recommendations are made and the caution needed in the use of the check-list is suggested.

[The application of Title V of Legislative Decree 626/94 to the hospital care environment: a new model of approach to the prevention and safety in work environments service]. / Applicazione del titolo V del D.lgs. 626/94 in ambito ospedaliero assistenziale: un nuovo modello di approccio del servizio di prevenzione e sicurezza negli ambienti di lavoro.

The paper reports the results of a study carried out by a Prevention and Safety of Working Environments Service in checking the application of Law 626/94, especially Chapter V, in hospital environments. Via the study it was possible to identify the risks due to manual handling of patients and therefore to manage compliance with the requirements and obligations of the said Law, as regards health surveillance of exposed subjects (programme to ascertain specific job fitness) and development of plans aimed at reducing the specific risks. The project proposed by the EPM Research Unit was submitted to the health administrations via the control service (Prevention and Safety in Working Environments Service) with the aim of experimenting a new method of assessment of risk due to patient handling. In this context, the control service combined enforcement with a more influential role of safety consultant, thereby playing a more modern role of encouraging employers to undertake preventive measures, alongside the traditional role of safeguarding workers' health.

[The pharmacological action of rubidium chloride in depression]. / Azione del cloruro di rubidio nella depressione.

In the last few years antidepressant activity or Rubidium chloride has risen new interest. The drugs develops his action on dopaminergic stimulation reducing the depressive pattern. Fifteen depressed inpatients were studied for three weeks treated with Rubidium chloride (540 mg/day) and periodically monitored after hospitalization. Speed therapeutic efficacy has been shown, with lack of side effects. The results are discussed.

Reversible and irreversible modifications of beta-lactoglobulin upon exposure to heat.

Modifications in the exposure to the solvent of hydrophobic residues, changes in their organization into surface hydrophobic patches, and alterations in the dimerization equilibrium of beta-lactoglobulin upon thermal treatment at neutral pH were studied. Exposure of tryptophan residues was temperature dependent and was essentially completed on the time scale of seconds. Reorganization of generic hydrophobic protein patches on the protein surface was monitored through binding of 1,8-anilinonaphthalenesulfonate, and was much slower than changes in tryptophan exposure. Different phases in surface hydrophobicity changes were related to the swelling and the subsequent collapse of the protein, which formed a metastable swollen intermediate. Heat treatment of beta-lactoglobulin also resulted in the formation of soluble oligomeric aggregates. The aggregation process was studied as a function of temperature, demonstrating that (i) dimer dissociation was a necessary step in a sequential polymerization mechanism and (ii) cohesion of hydrophobic patches was the major driving force for aggregation.

Occupational triphenyltin acetate poisoning: a case report.

A case of triphenyltin acetate (TPTA) poisoning is described. The patient, who had been exposed mainly to cutaneous absorption, showed acute stages of an urticarial eruption, signs of hepatic injury, slight glucose intolerance, and electroencephalographic abnormalities. Concomitant with the highest concentrations of tin in plasma and the peak of tin excretion in urine, neutrophils did not show the normal increase in actin polymerisation after stimulation with a chemotactic peptide (100 nM fMLP). The peak of urinary excretion of tin occurred between the fifth and the sixth day after poisoning; subsequently, the rate of excretion became slow, suggesting biphasic kinetics with the possibility of a cumulative trend.

Thyrotropin and prolactin responses to different doses of thyrotropin-releasing hormone in depression.

The effects of low doses of thyrotropin-releasing hormone (TRH, 50 and 200 micrograms) on thyrotropin (TSH) and prolactin levels have been studied in depressed women and compared with the depressive condition and with the results of the dexamethasone suppression test (DST). TRH administration elicited blunted hormonal responses that were not correlated either with the age of the patients or with DST results. Different effects were observed in subgroups of depressive patients classified according to DSM III and ICD. No correlation was found between hormone responses and the scores of Hamilton Rating Scale and Montgomery Depression Scale. The effects of 50 micrograms on TSH were significant and inversely correlated with Anxiety Rating Scale scores. No dose-response effect was apparent of prolactin and TSH in depressed patients, suggesting an impaired function of pituitary TRH receptors.

Electroencephalography in the early diagnosis of HIV-related subacute encephalitis: analysis of 185 patients.

Of subjects with asymptomatic HIV infection or Lymphoadenopathy Syndrome, 185 were studied by means of electroencephalography coupled with computerized spectral analysis and mapping (EEG-CSA). Abnormal EEGs were found in 30 of 118 (25.4%) patients with asymptomatic infection (CDC Group II) and in 20 of 67 (29.9%) patients with Lymphoadenopathy Syndrome (CDC Group III). The most common EEG abnormalities were represented by theta slowing on the frontal and fronto-temporal lobes and, in some cases, by delta slowing and paroxysmal sharp activity on the forebrain. Among 50 patients with abnormal EEGs, 16 showed some abnormalities on neuropsychological testing, whereas mild signs of cerebral atrophy were evident on CT scan in only 12 patients. These findings suggest that EEG-CSA could be a useful and sensitive method in the early detection and monitoring of HIV-related subacute encephalitis.

Viloxazine in depressed women: clinical response and cardiovascular effects.

The antidepressant effect of viloxazine (300 and 500 mg/day) was investigated for 4 weeks in 26 depressed women. The decrease in the Hamilton Depression Rating Scale score indicated a prompt overall clinical improvement, the depressed mood and suicide items showing the highest percent diminution. The highest plasma level of viloxazine was reached at day 7 and decreased during treatment only with the 500 mg dosage. Blood pressure and pulse rate responses to orthostatic stress were slightly affected and showed few untoward cardiovascular reactions to drug treatment. The decrease of noradrenaline plasma levels in both postural positions might indicate a lower sympathetic nervous system tone.

[Female alcoholism and household conditions]. / Alcolismo femminile e condizione casalinga.

Alcoholism in women, above all in housekeepers, tends to destroy both families and society. This kind of alcoholism is frequently based on neurosis and depression. Alcoholism in women is supposed to be caused by: genetic factors, psychological factors and social factors. Therefore these components are linked both to neuroendocrinology of female and the way of life of housekeepers.

Skeletal muscle changes following myelotomy in paraplegic patients.

Pourpre's dorsal T-shaped myelotomy was performed on three paraplegic patients in which medical and electro-physiological procedures proved to be ineffective concerning muscle spasms. The myelotomy led to the elimination of spasms and of muscle hypertonicity in the lower limbs. Biopsies of the rectus femoris muscles were performed bilaterally one year before and two months following myelotomy. The first biopsy revealed fascicular atrophy, with type I fibre preferential atrophy, which is usually found in paraplegic patients. After myelotomy some histological differences were seen: reduction of type II fibre diameter and the presence of target-targetoid fibres and of atrophic dark fibres. There was a difference of fibre pattern type in hypertonic spastic muscles compared to that seen in spasm relieved by myelotomy. The morphological changes seen after myelotomy are interpreted as denervation changes because of the surgical lesion by the myelotomy on the anterior horn cells.

A clinical and pharmacological study of the antidepressant activity of viloxazine in adult and elderly patients.

This work deals with the results of a clinical experience with viloxazine (VLZ) carried out on 43 depressed subjects of the female sex categorized with D.S.M. III criteria. Clinical ratings were made by means of the Hamilton Scale for depression and the Taylor self rating scale for anxiety. The results prove the efficacy of the drug in all the examined patients, along with the rapidity of effects in comparison with the tricyclic antidepressants. The elderly patients improved better than the adult subjects, especially when the depression was of the inhibited type.