Socio-economic inequalities in the use of drugs for the treatment of chronic diseases in Italy.

BACKGROUND: Since the use of medicines is strongly correlated to population health needs, higher drug consumption is expected in socio-economical deprived areas. However, no systematic study investigated the relationship between medications use in the treatment of chronic diseases and the socioeconomic position of patients. The purpose of the study is to provide a description, both at national level and with geographical detail, of the use of medicines, in terms of consumption, adherence and persistence, for the treatment of major chronic diseases in groups of population with different level of socioeconomic position.  METHODS: A cross-sectional study design was used to define the "prevalent" users during 2018. A longitudinal cohort study design was performed for each chronic disease in new drug users, in 2018 and the following year. A retrospective population-based study, considering all adult Italian residents (i.e. around 50.7 million people aged ≥ 18 years). Different medications were used as a proxy for underlying chronic diseases: hypertension, dyslipidemia, osteoporosis, diabetes and chronic obstructive pulmonary disease. Only "chronic" patients who had at least 2 prescriptions within the same subgroup of drugs or specific medications during the year were selected for the analysis. A multidimensional measures of socio-economic position, declined in a national deprivation index at the municipality level, was used to identify and estimate the relationship with drug use indicators. The medicine consumption rate for each pharmacological category was estimated for prevalent users while adherence and persistence to pharmacologic therapy at 12 months were evaluated for new users. RESULTS: The results highlighted how the socioeconomic deprivation is strongly correlated with the use of medicines: after adjustment by deprivation index, the drug consumption rates decreased, mainly in the most disadvantaged areas, where consumption levels are on average higher than in other areas. On the other hand, the adherence and persistence indicators did not show the same trend. CONCLUSIONS: This study showed that drug consumption is influenced by the level of deprivation consistently with the distribution of diseases. For this reason, the main levers on which it is necessary to act to reduce disparities in health status are mainly related to prevention. Moreover, it is worth pointing out that the use of a municipal deprivation indicator necessarily generates an ecological bias, however, the experience of the present study, which for the first-time deals with the complex and delicate issue of equity in Italian pharmaceutical assistance, sets the stage for new insights that could overcome the limits.

Sexuality Assessment of the Brazilian Population: An Integrative Review of the Available Instruments.

This paper provides an integrative review of psychometric instruments targeting sexual function and clinical measures of sexuality available to the Brazilian population. Our aim was to summarize the existing measures, indicating current development needs related to the quality of psychometric evidence, research design and untapped theoretical ground that could be relevant for clinical practice and research in sexuality. Electronic databases were searched. Additional records were found through a manual search. The general search terms and operators were (scale OR inventory OR questionnaire) AND (validation) AND (sexual beliefs OR sexuality OR sexual behavior OR sexual function OR sexual satisfaction) AND (Brazil or Brazilian). The results indicate a total of 18 developed or transculturally adapted and/or validated scales and questionnaires available in Brazilian Portuguese, covering sexual dysfunctions and clinical measures. Despite development, adaptation and validation efforts, there is a critical need for better psychometric and sampling strategies as well as norms for the clinical interpretation of test results. Ecological validity is also a challenge. At present, sexual assessments in Brazil offer some useful information, but reaching the applied clinical field remains a challenge.Supplemental data for this article is available online at https://doi.org/10.1080/0092623X.2022.2035869 .

Nanoscale refractory doped titanium nitride field emitters.

Refractory materials exhibit high damage tolerance, which is attractive for the creation of nanoscale field-emission electronics and optoelectronics applications that require operation at high peak current densities and optical intensities. Recent results have demonstrated that the optical properties of titanium nitride, a refractory and CMOS-compatible plasmonic material, can be tuned by adding silicon and oxygen dopants. However, to fully leverage the potential of titanium (silicon oxy)nitride, a reliable and scalable fabrication process with few-nm precision is needed. In this work, we developed a fabrication process for producing engineered nanostructures with gaps between 10 and 15 nm, aspect ratios larger than 5 with almost 90° steep sidewalls. Using this process, we fabricated large-scale arrays of electrically-connected bow-tie nanoantennas with few-nm free-space gaps. We measured a typical variation of 4 nm in the average gap size. Using applied DC voltages and optical illumination, we tested the electronic and optoelectronic response of the devices, demonstrating sub-10 V tunneling operation across the free-space gaps, and quantum efficiency of up to 1 × 10-3at 1.2µm, which is comparable to a bulk silicon photodiode at the same wavelength and three orders of magnitude higher than with nearly identical gold devices. Tests demonstrated that the titanium silicon oxynitride nanostructures did not significantly degrade, exhibiting less than 5 nm of shrinking of the average gap dimensions over few-µm2areas after 10 h of operation. Our results will be useful for developing the next generation of robust and CMOS-compatible nanoscale devices for high-speed and low-power field-emission electronics and optoelectronics applications.

Vaccine hesitancy in the era of COVID-19.

OBJECTIVES: In 2019, a new coronavirus has been identified and many efforts have been directed toward the development of effective vaccines. However, the willingness for vaccination is deeply influenced by several factors. So the aim of our review was to analyze the theme of vaccine hesitancy during COVID-19 pandemic, with a particular focus on vaccine hesitancy toward COVID-19 vaccine. STUDY DESIGN: Narrative review. METHODS: In November 2020, we performed a search for original peer-reviewed articles in the electronic database PubMed (MEDLINE). The key search terms were "Vaccine hesitancy AND COVID-19". We searched for studies published during COVID-19 pandemic and reporting information about the phenomenon of vaccine hesitancy. RESULTS: Fifteen studies were included in the review. The percentage of COVID-19 vaccine acceptance was not so high (up to 86.1% students or 77.6% general population); for influenza vaccine, the maximum percentage was 69%. Several factors influenced the acceptance or refusal (ethnicity, working status, religiosity, politics, gender, age, education, income, etc.). The most given reasons to refuse vaccine were as follows: being against vaccines in general, concerns about safety/thinking that a vaccine produced in a rush is too dangerous, considering the vaccine useless because of the harmless nature of COVID-19, general lack of trust, doubts about the efficiency of the vaccine, belief to be already immunized, doubt about the provenience of vaccine. CONCLUSIONS: The high vaccine hesitancy, also during COVID-19 pandemic, represents an important problem, and further efforts should be done to support people and give them correct information about vaccines.

Influence of implant scanbody material and operator on scanning fluency and polygonal mesh numbers of digital impression: an in vitro study.

The purpose of this study is to evaluate the influence of implant scanbody (ISB) material and operator on scanning fluency and polygonal mesh numbers of a confocal microscopy intraoral scanning (IOS). An edentulous maxillary master model with 6 implant analogues was assembled. Thereafter 3 ISBs featured with same geometry but different materials (polyetheretherketone (PK), titanium (T) and PK with a titanium base (PKT)) were produce and scanned according to a randomized sequence by three different operators. The confocal microscopy IOS resulted in 45 STL test files that were processed to a dedicate software to obtain the request data. The overall analysis of fluency (imm/sec) showed the following results: mean 11.997 imm/sec, SD 2.355. The multivariate analysis showed statistical significance of material (p<.0001) and operator (p<.0001) influence. The univariate analysis referred to polygonal mesh numbers expressed the following results: mean 30327.8, SD 2432.5. The multivariate analysis stressed how there is a related effect to materials (p<.0001) and operator (p=0.0205). PKT represented the material with the best results for both. Analyzing the overall distribution histogram for scanning fluency, the IOS device seems to work with higher frequency at level of 13 imm/sec. The distribution of the measurements in the reference histograms showed an effect related to both variables referring to scanning fluency as well as to polygonal mesh numbers. Operator can be considered as a random effect; regarding the materials, the difference between PKT and PK can be related to the different base material. The dissimilar optical properties of T justify the different behavior.

Multimodal surveillance of healthcare associated infections in an intensive care unit of a large teaching hospital

BACKGROUND: Healthcare-associated infections (HAIs), or nosocomial infections, represent a significant burden in terms of mortality, morbidity, length of stay and costs for patients hospitalized in intensive care units (ICUs). Surveillance systems are recommended by national and international institutions to gather data on HAIs in order to develop and evaluate interventions that reduce the risk of HAIs. STUDY DESIGN: Here we describe the methodology and the results of the surveillance system implemented in the ICU of the Policlinico Umberto I, a large teaching hospital in Rome, from April 2016 to October 2018. METHODS: The multimodal infection surveillance system integrates four different approaches: i) active surveillance of inpatients; ii) environmental microbiological surveillance; iii) surveillance of isolated microorganisms; and iv) behavioral surveillance of healthcare personnel. Data were collected on catheter-related bloodstream infections, ventilation-associated pneumonia, catheter-associated urinary tract infections and primary bloodstream infections that developed in patients after 48 h in the ICU. For environmental surveillance 14 points were selected for sampling (i.e. bed edges, medication carts, PC keyboards, sink faucets). The system of active surveillance of HAIs also included surveillance of microorganisms, consisting of the molecular genotyping of bacterial isolates by pulsed-field gel electrophoresis (PFGE). From 1 November 2016, monitoring of compliance with guidelines for hand hygiene (HH) and proper glove or gown use by healthcare personnel was included in the surveillance system. After the first six months (baseline phase), a multimodal intervention to improve adherence to guidelines by healthcare personnel was conducted with the ICU staff. RESULTS: Overall, 773 patients were included in the active surveillance. The overall incidence rate of device-related HAIs was 14.1 (95% CI: 12.2-16.3) per 1000 patient-days. The monthly device-related HAI incident rate showed a decreasing trend over time, with peaks of incidence becoming progressively lower. The most common bacterial isolates were Klebsiella pneumoniae (20.7%), Acinetobacter baumannii (17.2%), Pseudomonas aeruginosa (13.4%) and Staphylococcus aureus (5.4%). Acinetobacter baumannii and Klebsiella pneumoniae showed the highest proportion of isolates with a multidrug-resistant profile. A total of 819 environmental samples were collected, from which 305 bacterial isolates were retrieved. The most frequent bacterial isolates were Acinetobacter baumannii (27.2%), Staphylococcus aureus (12.1%), Enterococcus faecalis (11.1%), Klebsiella pneumoniae (5.2%) and Pseudomonas aeruginosa (4.7%). All Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae environmental isolates were at least multidrug-resistant. Genotyping showed a limited number of major PFGE patterns for both clinical and environmental isolates of Klebsiella pneumoniae and Acinetobacter baumannii. Behavioral compliance rates significantly improved from baseline to post-intervention phase. CONCLUSIONS: By integrating information gathered from active surveillance, environmental microbiological surveillance, surveillance of bacterial isolates and behavioral surveillance of healthcare personnel, the multimodal infection surveillance system returned a precise and detailed view of the infectious risk and microbial ecology of the ICU.

The effects of dehydroepiandrosterone on sexual function: a systematic review.

OBJECTIVE: Faced with the growing interest about the action of dehydroepiandrosterone (DHEA) and its benefits, as well as the negative impacts that sexual dysfunctions have on people's quality of life, this systematic review was undertaken with the objective of evaluating the effect of DHEA use on aspects of sexual function. METHOD: An electronic search was conducted in the databases of PubMed, ISI Web of Science and Virtual Health Library (VHL) combining the terms 'DHEA treatment' and 'DHEA use' with terms such as 'sexual dysfunction', 'sexual frequency' and 'libido'. No limits on time and language were imposed. Clinical studies were considered eligible where individuals for any reason made use of DHEA and if they had any aspect of sexual function assessed. Preclinical studies and systematic reviews were considered ineligible. RESULTS: The search identified 183 references and 38 were considered eligible. DHEA improved aspects such as sexual interest, lubrication, pain, arousal, orgasm and sexual frequency. Its effect was better in populations with sexual dysfunction, especially in perimenopausal and postmenopausal women. CONCLUSION: Considering the studies currently published, DHEA is effective in improving several aspects of sexual function, but this effect did not reach all the populations studied.

A new predictive equation for evaluating women body fat percentage and obesity-related cardiovascular disease risk.

BACKGROUND: Obesity represents a global public health problem due to its association with cardiovascular diseases and reduced lifespan. The most widely used classification of obesity is expressed as Body Mass Index (BMI); however, this formula is an imprecise adiposity measurement that ignores several important factors involved. Body Adiposity Index (BAI) was more recently proposed as an indirect evaluation of percentage body fat (PBF). PBF is a direct measure of person's relative body fat and a better predictor of obesity-related risk diseases than BMI and BAI. Since obesity and consequent diseases are considered epidemic, new accurate formulas for epidemiological studies are of interest to the scientific community. Because direct measurement of body composition could be quite expensive, the aims of our work were to analyse the distributions of PBF by Dual X-ray absorptiometry, and the creation of new predictive equation using only anthropometric measures that could be helpful to clinicians to assess easily body fat of female patients. METHODS/RESULTS: A sample of 1,031 Caucasian Italian women was recruited and BMI, BAI and PBF were evaluated. With the aim of developing a predictive model of PBF a multivariate regression model was fitted to observed data. CONCLUSIONS: The definition of universally recognized PBF by gender and age could have public health implications. In this study, we developed a new predictive PBF equation that does not require the use of medical instruments or skilled measurement techniques and that may be easily applicable to Italian women.

The bone anabolic therapy.

Teriparatide (TPTD), the amino-terminal parathyroid hormone recombinant peptide [PTH (1­34)], is a drug with a proven anabolic action on the bone, effective in preventing vertebral and non-vertebral fragility fractures. Recent publications have investigated in great detail the TPTD action on the cortical bone, highlighting the increased strength in the critical zone of the hip with high risk of fracture in osteoporotic patients Poole (PLoS ONE 6:e16190, 2011). In November 2002, TPTD was approved by the FDA for use in post-menopausal women and men with osteoporosis at high risk of fracture and in patients with glucocorticoid-induced osteoporosis and, since then, has been used to treat more than 1 million patients worldwide (J Bone Miner Res 27(12):2429-2437, 2012). The unchanged safety profile and the well-known mechanism of action of this drug have led doctors to explore the use of TPTD in other conditions such as delayed fracture healing, non-union, osteonecrosis of the jaw, etc. The positive reports that have resulted from these studies are helping to hypothesize a new perspective on the wider use of this drug, but warrant further clinical investigation to consolidate these results.

Stage IV sarcoidosis: comparison of survival with the general population and causes of death.

The objectives of this study were to compare the survival of sarcoid patients with pulmonary fibrosis with that of the general population and to determine the causes of death and the incidence of evolutive complications. This retrospective cohort included 142 sarcoid patients in radiographic stage IV (74 males; mean ± SD age 48.1 ± 12 yrs). Their survival was compared with that of the general French population, matched for the year and age at diagnosis of stage IV disease, sex and length of follow-up. Expected survival probabilities were calculated year-by-year on the basis of probabilities provided by official demographic data for France. Survival curves were based on the Kaplan-Meier method and compared using the log-rank test. During the follow-up period (7.1 ± 4.8 yrs), pulmonary hypertension (PH) was observed in 29.7% of cases and aspergilloma in 11.3%. Long-term oxygen therapy was required in 12%. Survival was 84.1% at 10 yrs, which was worse than for the general population (p = 0.013). 16 (11.3%) patients died from the following causes: refractory PH (n = 5), chronic respiratory insufficiency (n = 4), acute respiratory insufficiency (n = 2), haemoptysis due to aspergilloma (n = 1), heart sarcoidosis (n = 1), nocardiosis (n = 1) and unknown causes (n = 2). Survival is significantly decreased in stage IV patients. 75% of fatalities are directly attributable to respiratory causes.

Baseline characteristics of the population enrolled in the Italian Observational Study on Severe Osteoporosis (ISSO).

OBJECTIVES: Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. METHODS: Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, bone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. RESULTS: Most patients were elderly women (90.5%), mean age±SD was 72.9±8.8 years. Nearly all (91.3%) had experienced ≥ 1 vertebral fracture (mean±SD, 3.6±2.2 per patient), 37.5% had ≥ 1 non-vertebral fracture (mean±SD, 1.4±0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58±0.25 and VAS score 49.2±23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p<0.001, EQ-5D VAS score p=0.025 and p<0.016, respectively). Many patients were physically inactive (81.1%). One third (34.7%) of population had co-morbidities and 60.5% were on chronic concomitant treatments. Few subjects reported a maternal history of osteoporosis (15.5%), regular consumption of alcohol (13.3%) or were current smokers (11.5%). Nearly two-thirds (71.5%) had already been treated for osteoporosis, mainly with bisphosphonates. Calcium and vitamin D supplements were taken by 13% and 15.5% of the total population, respectively. CONCLUSIONS: At enrollment, the population of ISSO study mostly consisted in aging women, who had osteoporosis with high fracture risk, poor HRQoL and suffered from significant back pain. Most of them had already been treated by bisphosphonates but without calcium and vitamin D supplements. Back pain, as well as non-vertebral and multiple vertebral fractures, were associated with lower HRQoL.

Effect of copper oxide nanoparticles on two varieties of sweetpotato plants.

Little information is available on the interaction of CuO nanoparticles (nCuO) with tuberous roots. In this study, Beauregard-14 (B-14, low lignin) and Covington (COV, high lignin) sweetpotato varieties were cultivated until maturity in soil amended with nCuO, bulk copper oxide (bCuO) and CuCl2 at 25-125 mg/kg. The Cu treatments had no significant influence on chlorophyll content. Gas exchange parameters were not affected in B-14. In COV, however, at 125 mg/kg treatments, bCuO reduced the intercellular CO2 (11%), while CuCl2 increased it by 7%, compared with control (p ≤ 0.035). At 25 mg/kg nCuO increased the length of COV roots (20.7 ± 2.0 cm vs. 14.6 ± 0.8 cm, p ≤ 0.05). In periderm of B-14, nCuO, at 125 mg/kg, increased Mg by 232%, while the equivalent concentration of CuCl2 reduced P by 410%, compared with control (p ≤ 0.05). The data suggest the potential application of nCuO as nanofertilizer for sweetpotato storage root production.

Rummaging through the bin: Modelling marine litter distribution using Artificial Neural Networks.

Marine litter has significant ecological, social and economic impacts, ultimately raising welfare and conservation concerns. Assessing marine litter hotspots or inferring potential areas of accumulation are challenging topics of marine research. Nevertheless, models able to predict the distribution of marine litter on the seabed are still limited. In this work, a set of Artificial Neural Networks were trained to both model the effect of environmental descriptors on litter distribution and estimate the amount of marine litter in the Central Mediterranean Sea. The first goal involved the use of self-organizing maps in order to highlight the importance of environmental descriptors in affecting marine litter density. The second goal was achieved by developing a multilayer perceptron model, which proved to be an efficient method to estimate the regional quantity of seabed marine litter. Results demonstrated that machine learning could be a suitable approach in the assessment of the marine litter issues.

Erythrocyte phosphoglucomutase activity of bipolar I patients currently using lithium or carbamazepine.

Lithium has been used for the last five decades to treat bipolar disorder, but the molecular basis of its therapeutic effect is unknown. Phosphoglucomutase is a key enzyme in the metabolism of glycogen. In yeast, rabbit and human HEK293 cells, it is inhibited by lithium in the therapeutic concentration range. We measured the phosphoglucomutase activity in erythrocytes and the inhibitor constant for lithium in a population of healthy subjects and compared them to those of bipolar patients treated with lithium or carbamazepine. The specific activity of phosphoglucomutase measured in vitro in erythrocytes from control subjects presented a normal distribution, with the difference between the lowest and the highest activity being approximately 2-fold (0.53-1.10 nmol mg Hb-1 min-1). Comparison of phosphoglucomutase activity in untreated bipolar patients and control subjects showed no significant difference, whereas comparison between bipolar patients treated with carbamazepine or lithium revealed significantly lower mean values in patients treated with carbamazepine (747.3 +/- 27.6 vs 879.5 +/- 35.9 pmol mg Hb-1 min-1, respectively). When we studied the concentration of lithium needed to inhibit phosphoglucomutase activity by 50%, a bimodal distribution among the population tested was obtained. The concentration of LiCl needed to inhibit phosphoglucomutase activity by 50% was 0.35 to 1.8 mM in one group of subjects and in the other it was 3 to 4 mM. These results suggest that phosphoglucomutase activity may be significant in patients with bipolar disorder treated with lithium and carbamazepine.

A Fatal Sepsis Caused by Hyaluronate Knee Injection: How Much the Medical History and the Informed Consent Might Be Important?

The incidence of Osteoarthritis (OA) is gradually increasing worldwide due to two main reasons: longer life expectation and increased functional demand. Several treatment options have been proposed for this disease. Conservative treatment has the goal to improve the quality of life, reduce pain, and prevent the progression of the disease. Hyaluronate viscosupplementation is one of the most used infiltrative treatments for OA, but, despite its common use, clinical efficacy is still under question. Though adverse reactions for this medical option are actually rare, septic arthritis is a very scaring complication. We present a case report of a 59-year-old man who has been submitted to only one knee hyaluronate injection and consequently reported a severe septic arthritis and systemic sepsis, which lead to the death of the patient. We recommend producing correct guidelines for a clean aseptic procedure of injection to obtain proper consensus from the patient and to pay attention to his clinical history and comorbidities before acting any kind of invasive treatment, including joint injection.

Tissue-specific transcriptional initiation and activity of steroid sulfatase complementing dehydroepiandrosterone sulfate uptake and intracrine steroid activations in human adipose tissue.

Expression analysis by reverse transcriptase (RT)-PCR indicates that human adipose tissue is not likely to perform de novo synthesis of steroid hormones from cholesterol because the mRNAs of cytochromes P450scc and P450c17, and of the steroidogenic-related proteins, steroidogenic acute regulatory protein and steroidogenic factor 1, were not detected. Instead, our data support an intracrine role of adipose tissue, in which adrenal dehydroepiandrosterone sulfate (DHEA-S), the most abundant circulating androgen in man, is selectively uptaken, desulfated, and converted into bioactive androgens and estrogens. Three organic anion-transporting polypeptides-B, -D, and -E, presumably involved in DHEA-S transmembrane transport, were demonstrated at the mRNA level. While sulfotransferase expression was not found, the occurrence of steroid sulfatase (STS), converting DHEA-S to DHEA, was established at the mRNA, protein and catalytic activity levels. The 5'-rapid amplification of cDNA ends analysis showed that STS transcription in adipose tissue is regulated by the use of two promoters which differ from the prevalent placental one. The adipose transcripts contain a distinct untranslated first exon, 0a or 0b, followed by a common partially translated exon 1b, and nine other exons that are also shared by the main placental transcript. The presence of an upstream open reading frame in the new transcript variants could lead to an N-terminal divergence restricted to the cleavable signal peptide and thus not interfering with the catalytic activity of the mature STS protein. The adipose transcripts are also present in the placenta as minor isoforms. Western blotting revealed the characteristic approximately 64 kDa band of STS in both the placenta and adipose tissue. The specific enzymatic activity of STS in adipocytes was 118 pmol/10(6) cells per hour, about 50-100 times lower than in the placenta. A similar rate of [3H] DHEA-S uptake plus desulfation was measured in preadipocytes and adipocytes, equivalent to 40-45 pmol/10(6) cells per hour. Thus, an excessive accumulation of fat may out-compete other peripheral organs that are also dependent on intracrine DHEA-S utilization, especially when the adrenal production is low or declining with aging.

Dysfunction in the coagulation system and schizophrenia.

Although different hypotheses have been formulated to explain schizophrenia pathogenesis, the links between them are weak. The observation that five psychotic patients on chronic warfarin therapy for deep-vein thrombosis showed long-term remission of psychotic symptoms made us suspect that abnormalities in the coagulation pathway, specifically low tissue plasminogen activator (tPA) activity, could be one of the missing links. Our hypothesis is supported by a high prevalence of conditions affecting tPA activity in drug-naive schizophrenia, such as antiphospholipid antibodies, elevated cytokine levels, hyperinsulinemia and hyperhomocysteinemia. We recently screened a group of schizophrenia patients and controls for conditions affecting tPA activity. Free-protein S deficiency was highly prevalent among patients, but not found in controls. Free-protein S and functional protein C are natural anticoagulants that form complexes that inhibit tPA inhibitors. All participants had normal protein C levels, suggesting that protein S could have a role in schizophrenia, independent of protein C. Chronic patients and those studied during acute episodes had between three and six conditions affecting tPA and/or protein S activity, while patients in remission had up to two, which led us to postulate that multiple conditions affecting tPA and/or protein S activity could contribute to the full expression of schizophrenia phenotype. This paper describes the physiological roles of tPA and protein S, reviewing how their activity influences pathogenesis and comorbidity of schizophrenia. Next, it analyzes how activity of tPA and protein S is influenced by biochemical abnormalities found in schizophrenia. Last, it suggests future directions for research, such as studies on animal models and on therapeutic approaches for schizophrenia aiming at increasing tPA and protein S activity.

Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice.

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium-stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stimulated AC activity in the hippocampus, hypothalamus, thalamus, and brainstem. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-region long-term depression after low-frequency stimulation, and AC8 KO mice also fail to activate CRE-binding protein in the CA1 region after restraint stress. To define the behavioral consequences of AC8 deficiency, we evaluated AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety when subjected to repeated stress such as repetitive testing in the plus-maze or restraint preceding plus-maze testing. These results demonstrate a novel role for AC8 in the modulation of anxiety.

The C-terminal half of the colicin A pore-forming domain is active in vivo and in vitro.

The pore-forming domain of colicin A (pfColA) fused to a prokaryotic signal peptide (sp-pfColA) is transported across and inserts into the inner membrane of Escherichia coli from the periplasmic side and forms a functional channel. The soluble structure of pfColA consists of a ten-helix bundle containing a hydrophobic helical hairpin. Here, we generated a series of mutants in which an increasing number of sp-pfColA alpha-helices was deleted. These peptides were tested for their ability to form ion channels in vivo and in vitro. We found that the shortest sp-pfColA mutant protein that killed Escherichia coli was composed of the five last alpha-helices of sp-pfColA, whereas the shortest peptide that formed a channel in planar lipid bilayer membranes similar to that of intact pfColA was the protein composed of the last six alpha-helices. The peptide composed of the last five alpha-helices of pfColA generated a voltage-independent conductance in planar lipid bilayer with properties very different from that of intact pfColA. Thus, helices 1 to 4 are unnecessary for channel formation, while helix 5, or some part of it, is important but not absolutely necessary. Voltage-dependence of colicin is evidently controlled by the first four alpha-helices of pfColA.