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Purpose: Identifying efficacious measures to characterize dysphonia in complex neurodegenerative diseases is key to optimal assessment and intervention. This study evaluates the validity and sensitivity of acoustic features of phonatory disruption in amyotrophic lateral sclerosis (ALS). Method: Forty-nine individuals with ALS (40–79 years old) were audio-recorded while producing a sustained vowel and continuous speech. Perturbation/noise-based (jitter, shimmer, and harmonics-to-noise ratio) and cepstral/spectral (cepstral peak prominence, low–high spectral ratio, and related features) acoustic measures were extracted. The criterion validity of each measure was assessed using correlations with perceptual voice ratings provided by three speech-language pathologists. Diagnostic accuracy of the acoustic features was evaluated using area-under-the-curve analysis. Results: Perturbation/noise-based and cepstral/spectral features extracted from /a/ were significantly correlated with listener ratings of roughness, breathiness, strain, and overall dysphonia. Fewer and smaller correlations between cepstral/spectral measures and perceptual ratings were observed for the continuous speech task, although post hoc analyses revealed stronger correlations in speakers with less perceptually impaired speech. Area-under-the-curve analyses revealed that multiple acoustic features, particularly from the sustained vowel task, adequately differentiated between individuals with ALS with and without perceptually dysphonic voices. Conclusions: Our findings support using both perturbation/noise-based and cepstral/spectral measures of sustained /a/ to assess phonatory quality in ALS. Results from the continuous speech task suggest that multisubsystem involvement impacts cepstral/spectral analyses in complex motor speech disorders such as ALS. Further investigation of the validity and sensitivity of cepstral/spectral measures during continuous speech in ALS is warranted.

Chloroplast biogenesis requires synthesis of proteins in the nucleocytoplasm and the chloroplast itself. Nucleus-encoded chloroplast proteins are imported via multiprotein translocons in the organelle’s envelope membranes. Controversy exists around whether a 1-MDa complex comprising TIC20, TIC100, and other proteins constitutes the inner membrane TIC translocon. The Arabidopsis thaliana cue8 virescent mutant is broadly defective in plastid development. We identify CUE8 as TIC100. The tic100cue8 mutant accumulates reduced levels of 1-MDa complex components and exhibits reduced import of two nucleus-encoded chloroplast proteins of different import profiles. A search for suppressors of tic100cue8 identified a second mutation within the same gene, tic100soh1, which rescues the visible, 1 MDa complex-subunit abundance, and chloroplast protein import phenotypes. tic100soh1 retains but rapidly exits virescence and rescues the synthetic lethality of tic100cue8 when retrograde signaling is impaired by a mutation in the GENOMES UNCOUPLED 1 gene. Alongside the strong virescence, changes in RNA editing and the presence of unimported precursor proteins show that a strong signaling response is triggered when TIC100 function is altered. Our results are consistent with a role for TIC100, and by extension the 1-MDa complex, in the chloroplast import of photosynthetic and nonphotosynthetic proteins, a process which initiates retrograde signaling.

Chloroplast biogenesis requires synthesis of proteins in the nucleocytoplasm and the chloroplast itself. Nucleus-encoded chloroplast proteins are imported via multiprotein translocons in the organelle’s envelope membranes. Controversy exists around whether a 1 MDa complex comprising TIC20, TIC100 and other proteins constitutes the inner membrane TIC translocon. The Arabidopsis cue8 virescent mutant is broadly defective in plastid development. We identify CUE8 as TIC100. The tic100cue8 mutant accumulates reduced levels of 1 MDa complex components and exhibits reduced import of two nucleus-encoded chloroplast proteins of different import profiles. A search for suppressors of tic100cue8 identified a second mutation within the same gene, tic100soh1, which rescues the visible, 1 MDa complex-subunit abundance, and chloroplast protein import phenotypes. tic100soh1 retains but rapidly exits virescence, and rescues the synthetic lethality of tic100cue8 when retrograde signalling is impaired by the gun1 mutation. Alongside the strong virescence, changes in RNA editing and the presence of unimported precursor proteins show that a strong signalling response is triggered when TIC100 function is altered. Our results are consistent with a role for TIC100, and by extension the 1 MDa complex, in the chloroplast import of photosynthetic and non-photosynthetic proteins, a process which initiates retrograde signalling.One sentence summaryComplementary mutations in TIC100 of the chloroplast inner envelope membrane cause reductions or corrective improvements in chloroplast protein import, and highlight a signalling role.

Item does not contain fulltext BACKGROUND: Sepsis is a leading cause of morbidity and mortality after surgery. Most studies regarding sepsis do not differentiate between patients who have had recent surgery and those without. Few data exist regarding the risk factors for poor outcomes in pediatric postsurgical sepsis. Our hypothesis is pediatric postsurgical, and medical patients with severe sepsis have unique risk factors for mortality. METHODS: Data were extracted from a secondary analysis of an international point prevalence study of pediatric severe sepsis. Sites included 128 pediatric intensive care units from 26 countries. Pediatric patients with severe sepsis were categorized into those who had recent surgery (postsurgical sepsis) versus those that did not (medical sepsis) before sepsis onset. Multivariable logistic regression models were used to determine risk factors for mortality. RESULTS: A total of 556 patients were included: 138 with postsurgical and 418 with medical sepsis. In postsurgical sepsis, older age, admission from the hospital ward, multiple organ dysfunction syndrome at sepsis recognition, and cardiovascular and respiratory comorbidities were independent risk factors for death. In medical sepsis, resource-limited region, hospital-acquired infection, multiple organ dysfunction syndrome at sepsis recognition, higher Pediatric Index of Mortality-3 score, and malignancy were independent risk factors for death. CONCLUSIONS: Pediatric patients with postsurgical sepsis had different risk factors for mortality compared with medical sepsis. This included a higher mortality risk in postsurgical patients presenting to the intensive care unit from the hospital ward. These data suggest an opportunity to develop and test early warning systems specific to pediatric sepsis in the postsurgical population.

The ambient air of urban centres is polluted with potentially toxic chemicals mostly arising from the combustion or fuels used for transport, heating and industrial activities. Alongside the risk to the general public, atmospheric pollution could be considered an occupational health hazard to professional groups, such us traffic police or professional drivers working in urban areas. Molecular epidemiology can facilitate health risk assessment by investigating the relationship between exposure to environmental pollutants and quantification of biomarkers that lie on the pathway of carcinogenesis upstream of clinical disease. In particularly, biomarkers of early effects and susceptibility are playing an increase role in the investigation of the impact of air pollution on human carcinogenesis.

A frequent mutation in the cystathionine beta-synthase (CBS) gene (844ins68, a 68-bp insertion in the coding region of exon 8) was recently discovered. In the present study we investigated this mutation as a candidate risk factor for venous thrombosis.The prevalence of the 844ins68 CBS mutation was determined in 101 patients with objectively diagnosed deep venous thrombosis and in 101 healthy controls matched for age, sex and race. PCR amplification of a DNA fragment containing exon 8 of the CBS gene was employed to determine the genotypes. Additionally, Bsrl restriction enzyme digestion of the PCR products was performed in all samples from carriers of the insertion, to test for concurrent presence of a second mutation (T833C) in the CBS gene.The insertion was found in 21 out of 101 patients (20.8%; allele frequency 0.109) and in 20 out of 101 controls (19.8%; allele frequency 0.114), yielding a relative risk for venous thrombosis related to the 844ins68 CBS mutation close to 1.0. In addition, the T833C CBS mutation was detected in all alleles carrying the 844ins68 CBS insertion, confirming the co-inheritance of the two mutations.Our findings do not support the hypothesis that the 844ins68 mutation in the CBS gene is a genetic risk factor for venous thrombosis.

Possible synergistic effects of the combination of EDTA-tromethamine (EDTA-Tris) and three antimicrobial agents (cephaloridine, kanendomycin and enrofloxacin) against resistant Gram-positive and Gram-negative bacteria are reported. Bacteria were isolated from eight cases of chronic otitis externa, five cases of chronic dermatitis and four cases of recurrent cystitis in dogs which had previously been treated with one of the three antibiotics without success. Animals exposed to EDTA-tromethamine plus the antibiotic recovered completely within 10 days, and were controlled clinically and bacteriologically for 180 days. Local irrigation with EDTA-tromethamine solution was well tolerated and no side effects were recorded.

The pharmacokinetic behaviour of glycyrrhizin (1) was investigated in order to evaluate the difference in bioavailability after oral administration of licorice extract (LE) or glycyrrhizin (1) to rats and humans. For this study, two reliable HPLC methods were developed for the dosage of the levels of 1 and of its metabolite, the glycyrrhetic acid (2) in plasma samples. The determinations were carried out by HPLC on a reversed phase column with UV detector (251 nm), after a careful extraction step of 1 and 2 from the biological matrix. These methods afford good accuracy and satisfactory precision and they allow the determination of both compounds at levels as low as 200 ng/ml. The analytical results improved the knowledge of 1 pharmacokinetics, showing a significantly reduced bioavailability, when administered as LE compared to 1 when administered as such.

The primary basis of 5-nitro-3-thiophenecarboxanilides (NTCAs) direct-acting mutagenicity in Salmonella typhimurium appears to be the reduction of the nitro function to the corresponding hydroxylamine via diamagnetic and free radicals intermediates. In Ames test conditions, mutagenicity of NTCAs may be partly attributed to the action of reactive oxygen species and other radicals generated during the bioreductive process. The nitro anion radical seems to be particularly susceptible to react with oxygen and generate superoxide, as shown by the inhibitory effects exerted by superoxide dismutase on genotoxicity by most NTCAs in the study. On the other hand, hydroxyl radical-trapping agents such as mannitol, the enzyme catalase and other scavengers as 3-tert-butyl-4-hydroxyanisole (BHA), and vitamins C, A, and E showed weak inhibitory potency, and rather increased the mutagenic activity of some NTCAs. Our results contribute to the mechanistic understanding of genotoxic activity of NTCAs.

Objective. Assess outcome in children treated with inotrope, vasopressor, and/or vasodilator therapy for reversal of fluid-refractory and persistent septic shock.Design. Survey; case series.Setting. Three pediatric hospitals.Patients. Fifty consecutive patients with fluid-refractory septic shock with a pulmonary artery catheter within 6 hours of resuscitation.Interventions. Patients were categorized according to hemodynamic state and use of inotrope, vasopressor, and/or vasodilator therapy to maintain cardiac index (CI) >3.3 L/min/m2 and systemic vascular resistance >800 dyne-sec/cm5/m2 to reverse shock.Outcome Measures. Hemodynamic state, response to class of cardiovascular therapy, and mortality.Results. After fluid resuscitation, 58% of the children had a low CI and responded to inotropic therapy with or without a vasodilator (group I), 20% had a high CI and low systemic vascular resistance and responded to vasopressor therapy alone (group II), and 22% had both vascular and cardiac dysfunction and responded to combined vasopressor and inotropic therapy (group III). Shock persisted in 36% of the children. Of the children in group I, 50% needed the addition of a vasodilator, and in group II, 50% of children needed the addition of an inotrope for evolving myocardial dysfunction. Four children showed a complete change in hemodynamic state and responded to a switch from inotrope to vasopressor therapy or vice versa. The overall 28-day survival rate was 80% (group I, 72%; group II, 90%; group III, 91%).Conclusions. Unlike adults, children with fluid-refractory shock are frequently hypodynamic and respond to inotrope and vasodilator therapy. Because hemodynamic states are heterogeneous and change with time, an incorrect cardiovascular therapeutic regimen should be suspected in any child with persistent shock. Outcome can be improved compared with historical literature.

I en tidigare uppsats i Lakartidningen (Amati et al:1980b) har vi gett en oversiktlig redovisning av nagra statistiska uppgifter rorande det forsta tillampningsaret av den psykiatriska vardreformen i Italien och beskrivit vilken effekt reformlagen haft i stort for hela Italien. I denna artikel amnar vi lite mer i detalj redogora for olika aspekter pa varden vid nagra fa centra som rnedverkar i ett storre pagaende evalueringsprojekt rorande avinstitutionaliseringen i Italien.

Summary The aim of this work was to study the sex ratio in Asellus aquaticus and to find out whether thereare arrenogenic or theligenic families. Families with tendency to theligeny, arrenogeny and normal ratio have been found. The possibility of these tendencies being hereditary has been checked. Cross breeding has proved that it is so. It has also been tried to establish whether the male or the female have more importance in determining the sex. Although further research on the subject, is required, it can be said that probably the male is more important. Attempts at selection for arrenogeny and theligeny have been made with contrasting results. The polygenic hypothesis seems the more probable in explaining sex determination in Asellus.

Calcium (15 mM/10 9 platelets) determines, in isolated rabbit platelets, an aggregation which is a function of the concentration and incubation time. ADP (10 −4 M) alone does not produce a significant aggregation but only a release of 5-HT, which is a little less than that induced by calcium ions. A synergism between ADP and calcium is observed which underlines the importance of this last as a trigger factor. This is confirmed by the inhibition (10%) caused by cyclic-3′, 5′-AMP (10 −4 M) on platelet aggregation induced by calcium.

A group of 20 female neurotic inpatients has been treated with 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one-(chlordesmethyldiazepan)- 7-chloro-5(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) according to a double-blind cross-over design. For each drug clinical evaluations were performed by means of Hamilton's rating scale for anxiety states and of Overall and Gorham's brief psychiatric rating scale, at the beginning, after the first week and at the end of the two-week period of treatment, in opposite sequence. A statistically greater efficacy of chlordesmethyldiazepam in comparison to lorazepam was observed. Results are discussed with regard to benzodiazepine structure-activity relationships.

S-adenosyl-L-methionine (SAMe), a physiologic substance present in all living organisms, is very unstable at room temperature; however, BioResearch Laboratories of Milan have recently succeeded in stabilizing this molecule without changing its biological activity in any way. The solution of this problem made it possible to proceed from merely biochemical investigations of SAMe to pharmacologic work in animals and clinical trials in man.

Experimental work on the acute, chronic, and fetal toxicity of SAMe was carried out by Stramentinoli and his colleagues (19). The intravenous LD50 in rats is more than 2000 mg/kg, or the equivalent of 140–150 g in a man of 70 kg. In man, on the other hand, clinical trials have revealed a definite action of the substance in the CNS with doses as little as 80/zg/kg; the largest dose so far administered intravenously to humans is 0.5 g daily and has produced no visible side effects.

S-adenosyl-L-methionine (SAMe) serves as the methyl group donor for several transmethylase enzyme systems, the best known being catechol-O-methyltransferase (COMT), whose intracellular distribution is similar to that of SAMe (3); many other transmethylation reactions, however, are SAMe-dependent (6).

In order to further our understanding of transmethylation processes (2) in the CNS, which are now thought to play a role in the biochemistry of behavior through an action on the mediators of such behavior, namely the biogenic amines, we have done some work seeking correlations between the subcellular distribution of S-adenosyl-L-methionine (SAMe) and that of catechol-O-methyltransferase (COMTs), the latter being the best-known transmethylases. The premises of this investigation were as follows: (a) SAMe is one of the methyl donors occurring in the CNS, where it shows a characteristic topographic distribution. According to Baldessarini and Kopin (3) the highest concentrations of SAMe occur in the basal nuclei of the brain (14.2 µ/g of tissue) and the lowest occur in the cerebellum (10.8 µ/g of tissue), with a mean value of 12.5 µ/g for the encephalon as a whole. Such values are of the order of about one-fourth those detected in the adrenal glands (48.0 ± 10.0 µ/g), these being the organs that contain more SAMe than any other in the body. The distribution of SAMe can be deduced indirectly from that of the “methionine-activating enzyme,” which governs the synthesis of SAMe. According to Volpe and Laster (11) the assay of brain tissues for methionine-activating enzyme (MAE) give the following concentrations in decreasing order: hypophysis 142.0 ± 11,2; cerebellum 131.0 ± 4.8; hypothalamus 80.2 ± 3.2; cerebral parietal cortex 79.7 ± 2.6; hippocampus 67.5 ± 3.0; thalamus 59.8 ± 2.7; white parietal matter 53.0 ± 2.8. These data, unlike Baldessarini and Kopin’s (3), indicate higher concentrations of MAE in the cerebellum.

Lipid composition of muscles of 14 patients with neurogenic muscular atrophies was determined, and compared statistically to that of 8 normal controls. The neurogenic muscular atrophies show no alteration in the lipid content, but single phospholipid fractions were modified. The lecithin content was significantly diminished in patients with neurogenic muscular atrophy, particularly in the chronic and infantile-juvenile forms, whereas sphingomyelin and phosphatidylserine were increased, but not significantly.

Among catecholamines, norepinephrine (NE) and dopamine (DA) serve as synaptic mediators in the central nervous system (CNS). The dopaminergic pathways constitute the ascending nigrostriatal system and connect the dorsal neurons of the interpeduncular nucleus with the accumbens nucleus and the olfactory tubercle (20). The noradrenergic pathways, all of them ascending, originate from neurons in the pons and medulla oblongata and spread partly to the hypothalamus, preoptic area, septum, amygdala, hippocampus, and cingulate gyrus, and partly to the neocortex.

Five patients with multiple sclerosis and four normal subjects have been followed for over two years. Plasma phospholipid levels and phospholipid fatty acid composition have been assayed periodically. The increased amount of plasma lysolecithin already described by us has been confirmed in this longitudinal study. A significant increase in saturated fatty acids of lysolecithin has also been demonstrated. In contrast, the lecithin concentration and fatty acid composition do not show any significant variations. The lysolecithin saturated/unsaturated fatty acid ratio was different in the same patients at different times, but no correlation was established between these variations and the clinical symptoms measured using the Kurtzke scale. The possible significance of saturated fatty acid increase in lysolecithin in the pathogenetic mechanisms of multiple sclerosis is discussed.