The value of admission Troponin I to predict outcomes in suspected infections in elderly patients admitted in Internal Medicine: results from the SOFA-T collaboration, a multi-center study.

Elderly patients affected by suspected infection and declining clinical conditions can be admitted to stepdown units (SDU), but a risk stratification is necessary to optimize their management. Admission troponin I (aTnI) has a prognostic role, however, one of the most commonly used stratification tools, the Sequential Organ Failure Assessment score (SOFA), does not consider myocardial injury. With this paper, we aimed to evaluate the prognostic accuracy of a new score, named SOFA-T, considering both SOFA score and aTnI in a cohort of elderly patients admitted to the stepdown beds of two Internal Medicine departments. Patients aged > 65 years admitted in SDU of two different hospitals of the same region in a 12-months timeframe were retrospectively assessed obtaining age, sex, days of admission, in-hospital death, SOFA, aTnI and comorbidities. The best aTnI cutoff for in-hospital death was calculated with ROC curve analysis; dichotomous variables were compared with chi-squared test; continuous variables were compared with t test or Mann-Whitney test. We obtained a cohort of 390 patients. The best aTnI cutoff was 0.31 ng/ml: patients with increased aTnI had higher risk of in-hospital death (OR: 1.834; 95% CI 1.160-2.900; p = 0.009), and higher SOFA (6.81 ± 2.71 versus 5.97 ± 3.10; p = 0.010). Adding aTnI to SOFA increased significantly the area under the curve (AUCSOFA = 0.68; 95% CI 0.64-0.73; AUCSOFA-T = 0.71; 95% CI 0.65-0.76; p = 0.0001), with a slight improvement of the prognostic performance. In elderly patients admitted to SDU for suspected infection, sepsis or septic shock, aTnI slightly improves the accuracy of SOFA score of the in-hospital death prediction.

Tocilizumab in COVID-19 interstitial pneumonia.

BACKGROUND: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues. METHODS: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response. RESULTS: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response. CONCLUSIONS: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials.

Normal and five-fingered hand: comparative X-ray morphometry in the post-natal age.

BACKGROUND: Five-fingered hand (5-FH) with completely developed phalanges is a rare phenotype observed so far only in humans and characterised by three phalanges of the 1st ray. A long-lasting, debated question is if the missing element of the normal hand 1st ray is the metacarpal or the phalanx. In this study, comparative X-rays morphometry of long bones in normal and 5-FH is carried out with the aim to face this question through homology analysis of long bone segments in the transverse and longitudinal line of normal hand and 5-FH. MATERIALS AND METHODS: In the normal hand X-rays (n =20) and in a 5-FH X-rays series (n = 9) the relative length of each segment on the ray total length and the index of growth rate (IGR) were assessed. The calculation of the first parameter in normal hand bi-phalangeal thumb was carried out on the 3rd ray total length in the same hand. RESULTS: The parameters of relative length and the proximal/distal growth rate asymmetry in the post-natal period (assessed through the IGR) confirmed in 5-FH the homology of all the five segment on the transverse line. In the normal control hand, the relative length assessment methodology was biased by the missing segment of the thumb, therefore, the reference to the 3rd ray total length in the same hand (instead of the 1st), allowed the homology analysis of the thumb metacarpal and 1st phalanx with the lateral segments (2nd-5th ray) of the same hand. The 5-FH analysis was used to choose the more appropriate reference ray for the normal hand group. CONCLUSIONS: The comparative analysis of relative lengths and IGRs in the two groups suggested homology of the (anatomical) 1st metacarpal with the 2nd-5th proximal phalanges in the same hand and that of the (anatomical) 1st proximal phalanx with the 2nd-5th mid phalanges. These data suggest that the missing segment of the normal hand thumb is the metacarpal.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Joint attention behaviours and vocabulary development in children with Down syndrome.

BACKGROUND: Because of their difficulties in language development, various studies have focussed on the precursors of linguistic skills in children with Down syndrome. However, data on the predictive role of joint attention on language development in this population are inconsistent. The present study aimed to analyse attention behaviours in a group of children with Down syndrome. The existence of both concurrent and longitudinal relationships between joint attention and vocabulary development was investigated. METHOD: The participants were 18, 24-month-old, Italian children with Down syndrome. The children's attention skills were assessed during semi-structured free-play sessions in interaction with their mothers. A nominal exhaustive scheme was applied to code the children's behaviour. Moreover, the children's vocabulary development (both receptive and expressive) was assessed with the Italian version of the MacArthur-Bates Communicative Development Inventory at both 24 and 30 months. RESULTS: Data analyses showed that children with Down syndrome spent a large part of the interactive play session in joint attention situations. Moreover, the children's behaviour of proposing a joint attention focus to their communicative partners appeared to be a significant predictor of the children's vocabulary comprehension skills as assessed 6 months later. CONCLUSIONS: These results support the hypothesis of continuity between preverbal precursors and vocabulary development in a population with atypical development.

Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression.

MicroRNAs (miRNAs) have an important role in a wide range of physiological and pathological processes, and their dysregulation has been reported to affect the development and progression of cancers, including hepatocellular carcinoma (HCC). However, in the plethora of dysregulated miRNAs, it is largely unknown which of them have a causative role in the hepatocarcinogenic process. In the present study, we first aimed to determine changes in the expression profile of miRNAs in human HCCs and to compare them with liver tumors generated in a rat model of chemically induced HCC. We found that members of the miR-100 family (miR-100, miR-99a) were downregulated in human HCCs; a similar downregulation was also observed in rat HCCs. Their reduction was paralleled by an increased expression of polo like kinase 1 (PLK1), a target of these miRNAs. The introduction of miR-100 in HCC cells impaired their growth ability and their capability to form colonies in soft agar. Next, we aimed at investigating, in the same animal model, if dysregulation of miR-100 and PLK1 is an early or late event along the multistep process of hepatocarcinogenesis. The obtained results showed that miR-100 downregulation (i) is already evident in very early preneoplastic lesions generated 9 weeks after carcinogenic treatment; (ii) is also observed in adenomas and early HCCs; and (iii) is not simply a marker of proliferating hepatocytes. To our knowledge, this is the first work unveiling the role of a miRNA family along HCC progression.

[An unusual case of post-traumatic adult complex foot deformity]. / Un caso atípico de fractura de pie compleja postraumática en un adulto.

A peculiar clinical presentation of post-traumatic complex left foot fracture deformity is presented in this report as the result of a motorbike accident. Notwithstanding the significant deformity following forefoot fractures, the patient complained only of the recent onset of metatarsalgia. Of particular interest, is that this severe foot injury as well following deformity was overlooked, probably because patient had sustained head injury that was the main problem to treat due to life risk.

Evaluation of light emitting diode-based fluorescence microscopy for the detection of mycobacteria in a tuberculosis-endemic region.

OBJECTIVES: To evaluate fluorescence microscopy (FM) using light emitting diode (LED) technology for the detection of acid-fast bacilli at a tertiary referral centre in Mumbai, India, a tuberculosis-endemic country. DESIGN: LED FM was introduced into a laboratory experienced with Ziehl-Neelsen (ZN) microscopy but unfamiliar with FM. It was evaluated in parallel with routine ZN microscopy services and compared with mycobacterial culture as a reference standard. RESULTS: A total of 1357 pulmonary and 917 extra-pulmonary specimens were examined during the study. LED FM had 78.3% sensitivity and 92.0% specificity against mycobacterial culture when using pulmonary specimens, and 34.0% sensitivity and 88.8% specificity for extra-pulmonary specimens. The mean time per smear examination was 2.48 min for ZN vs. 1.41 min for LED FM. Several biases in study design and operation identified during analysis, which are likely to lead to underestimates of LED FM accuracy, are discussed in the context of future LED FM evaluations. CONCLUSIONS: Although LED FM has significant benefits over both ZN microscopy and conventional FM, its implementation and validation may be prone to difficulties which could hamper evaluation of its performance. Adequate training and detailed standard operating procedures are important to maximise accuracy.

[Relationship between central corneal thickness, intraocular pressure and severity of glaucomatous visual field loss]. / Correlación entre grosor corneal central, presión intraocular y afectación glaucomatosa del campo visual.

OBJECTIVE: to determine central corneal thickness in normal subjects, glaucomatous patients and ocular hypertension patients, to evaluate if the central corneal thickness is related to the presence of glaucoma or ocular hypertension. Furthermore, we aim to verify the relationship between central corneal thickness and severity of glaucomatous visual field loss. METHODS: comparative study including 150 eyes of 150 subjects, separated into three groups: normal (47 eyes), ocular hypertension (35) and glaucomatous (68). This last group was subdividided in three subgroups depending on the Hodapp-Parrish-Anderson criteria for scoring Humphrey visual field defects (initial, moderate and advanced). We evaluated the visual field, the central corneal thickness measured by pachymetry and the intraocular pressure measured by Goldmann tonometry. Results were analysed using the Student's t-test for normally distributed independent samples. RESULTS: the central corneal thickness was 526+/-25 microns (mean +/-standard deviation (SD)) in glaucomatous patients, 560+/-27 microns in ocular hypertension patients, and 556+/-27 microns in the normal group. Statistical significance could be found between the glaucomatous group of patients and the other groups (p< 0.01), but not between the ocular hypertension group and normal subjects (p= 0.4). The comparison between central corneal thickness of the subgroup with advanced damage of the visual field and the two other subgroups was also statistically significant (p< 0.01), but not between the subgroups of initial damage and moderate damage (p= 0.7). CONCLUSIONS: the central corneal thickness in glaucomatous patients is lower than in normal subjects and in ocular hypertension patients. Patients classified as having advanced damage in their visual field have significantly lower central corneal thickness measurements than patients classified as having initial or moderate damage.

64-Slice CT coronary angiography versus conventional coronary angiography: activity-based cost analysis.

PURPOSE: This study was done to analyse the costs of 64-slice computed tomography (CT) coronary angiography and conventional coronary angiography and determine the cost-effectiveness of the two modalities. MATERIALS AND METHODS: Detailed activity-based cost analyses of the two modalities were carried out at the departments of radiology and cardiology of a teaching hospital. The differential costs (equipment, variable, personnel), common costs and external costs were estimated. Finally, the full costs of the two procedures were obtained; the full cost of conventional coronary angiography also considered the cost of 1 day in hospital. The cost-effectiveness of the two procedures at different levels of pretest likelihood of coronary artery disease (CAD) was estimated. RESULTS: The costs of multidetector CT (MDCT) coronary angiography were as follows: differential cost 222.23 euro, common cost 5.50 euro, external cost 2.30 euro and full cost 230.03 euro. The costs of conventional coronary angiography were: differential cost 366.18 euro, common cost 0.50 euro, external cost 9.20 euro, hospitalisation cost 1,652 euro and full cost 2,027.88 euro. Cost-effectiveness analysis showed that the cost per correctly identified CAD patient decreased exponentially with increasing pretest likelihoods of CAD. MDCT coronary angiography was more cost effective than conventional coronary angiography up to a pretest likelihood of 86%. CONCLUSIONS: MDCT coronary angiography has far lower costs than conventional coronary angiography, and its cost-effectiveness is better in the large majority of patients.

The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F).

We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2(V617F) mutation obtained from polycythemia vera (PV) and essential thrombocythemia (ET) patients as well as the HEL cell line. The clonogenic activity of JAK2(V617F) mutated cells was inhibited by low concentrations of ITF2357 (IC(50) 0.001-0.01 microM), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2(V617F) as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2(V617F) mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2(V617F) mutation through a specific downmodulation of the JAK2(V617F) protein and inhibition of its downstream signaling.

The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells.

We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.

Transformation of amyloid-like fibers, formed from an elastin-based biopolymer, into a hydrogel: an X-ray photoelectron spectroscopy and atomic force microscopy study.

Previous studies have revealed the propensity of elastin-based biopolymers to form amyloid-like fibers when dissolved in water. These are of interest when considered as "ancestral units" of elastin in which they represent the simplest sequences in the hydrophobic regions of the general type XxxGlyGlyZzzGly (Xxx, Zzz = Val, Leu). We normally refer to these biopolymers based on elastin or related to elastin units as "elastin-like polypeptides". The requirement of water for the formation of amyloids seems quite interesting and deserves investigation, the water representing the natural transport medium in human cells. As a matter of fact, the "natural" supramolecular organization of elastin is in the form of beaded-string-like filaments and not in the form of amyloids whose "in vivo" deposition is associated with some important human diseases. Our work is directed, therefore, to understanding the mechanism by which such hydrophobic sequences form amyloids and any conditions by which they might regress to a non-amyloid filament. The elastin-like sequence here under investigation is the ValGlyGlyValGly pentapeptide that has been previously analyzed both in its monomer and polymer form. In particular, we have focused our investigation on the apparent stability of amyloids formed from poly(ValGlyGlyValGly), and we have observed these fibers evolving to a hydrogel after prolonged aging in water. We will show how atomic force microscopy can be combined with X-ray photoelectron spectroscopy to gain an insight into the spontaneous organization of an elastin-like polypeptide driven by interfacial interactions. The results are discussed also in light of fractal-like assembly and their implications from a biomedical point of view.

Spontaneous bilateral Achilles tendon rupture in a patient treated with oral levofloxacin.

A case of bilateral rupture of the Achilles tendon in a patient treated with levofloxacin for cystitis is reported. A 76-year-old woman suddenly developed painful ankles one day after levofloxacin treatment. Drug therapy was switched to amoxicillin/clavulanate on the fourth day. Sonography revealed a serious condition of tendinosis with complete bilateral full-thickness rupture on day 6. Tendons were both repaired in the same surgical session. Pathological anatomy of the specimens reported fatty tissue lobules with panniculitis and histiocytosis. Ankles were immobilized postoperatively with a plaster cast. Achilles tendon rupture may occur as an adverse side effect of short-term use of levofloxacin, a fluoroquinolone antibiotic. This adverse effect is a rare and poorly understood complication of this antibiotic therapy. A review of the literature is provided.

RNA interference against urokinase in hepatocellular carcinoma xenografts in nude mice.

The serine protease urokinase-type plasminogen activator (u-PA) is overexpressed in hepatocellular carcinoma (HCC) and its expression level is inversely correlated with the patients' survival. The purpose of this study was to examine the effects of vector-based RNA interference (RNAi) of u-PA on the growth of human HCC xenografts in nude mice in order to investigate the role of u-PA in human HCC. Our results showed that the subcutaneous injection of small interfering RNAs (siRNA) u-PA SKHep1C3 stable transfected cells (pS siRNA u-PA) led to a growth delay in xenograft development, compared to those generated from empty vector; the molecular characterization of nodules (carried out by PCR, RT-PCR and immunohistochemical analysis) revealed the presence of plasmid DNA, the u-PA gene expression knockdown, at both mRNA and protein levels, giving evidence of a long-term and target-specific inhibition by vector-based RNAi 11 weeks after cell inoculation. We further studied the effects of u-PA down modulation on extracellular matrix (ECM) proteins evaluating the expression and organization of fibronectin (FN; one of the main ECM proteins). Immunohistochemical and immunofluorescence analysis of FN revealed FN fibrils in pS siRNA u-PA xenografts and in pS siRNA u-PA cells, thus identifying the FN fibril organization as a downstream effect of u-PA knockdown in this system.

First implant acetabular components: historical aspects, a comparison of models and a review of the literature.

The article describes the features of the most commonly-used acetabular components in first implants in light of development in construction as regards intrinsic features, materials used, biological behavior, and design. The following versions are examined: screwable cone-shaped trunk, cemented polyethylene, cemented metal-back, HA-coated press-fit, expansion, dysplastic hip, and anti-dislocating components. The screwable cone-shaped trunk acetabular component takes hold in the acetabular bone through torsion and compression, and threading provides greater stability as compared to equivalent models that have wings or screws. Cemented polyethylene acetabular components are characterized by low costs and good results, on the condition that some specific parameters are respected (the presence of a dry bone bed, pressurization of the cement, use in elderly patients who do very little physical activity). Cemented metal-back acetabular components have features similar to polyethylene components, from which they differ because of the possibility of being able to substitute the internal polyethylene component without having to revision the entire acetabulum. HA-coated press-fit components have solved the problems encountered in cemented versions, such as loosening and the generation of polyethylene particulate, at the same time obtaining excellent osteo-integration. The expansion cup self-stabilizes thanks to a memory effect due to the contraction-relaxation mechanism with which it is lodged, adapting to the micro-movements of the acetabulum. Components used in the dysplastic hip are particular versions with a reduced diameter that have specific hooks that provide stabilization, capable of settling in the pathologic bone with minimum reaming of the same. Anti-dislocation cups are special models that have bipolar inserts or a ring (plastic or metal) that blocks the head in the prosthetic acetabulum, obstructing its dislocation.

The Bristow-Latarjet method in the treatment of shoulder instability that cannot be resolved by arthroscopy. A review of the literature and technical-surgical aspects.

Arthroscopy has surpassed traditional types of open surgery in the treatment of shoulder instability because of its mini-invasiveness and shorter rehabilitation time. Despite this, in some cases, such as those involving significant glenoid erosions and extensive capsular lesions, arthroscopic methods fail the objectives, and methods that were believed to have been surpassed are again used, such as the Bristow-Laterjet procedure. It is the purpose of this article to describe use of the method in light of the possibilities offered by arthroscopy.

Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome.

OBJECTIVE: To study the long term effectiveness of intravenous immunoglobulin and plasmapheresis associated with prednisone and cyclophosphamide in Churg-Strauss syndrome. SUBJECTS: and methods: We studied 18 subjects with new onset Churg-Strauss syndrome. All received the "standard" treatment based on prednisone (1 mg/kg/day for 1 month and then slowly tapered) and cyclophosphamide (2 mg/kg/day for 6 months in severe cases). In nine patients, synchronised cycles with plasmapheresis and intravenous immunoglobulin (2 g/kg) were repeated monthly for 6 months and every other month for a further three cycles. Clinical (disease activity monitored by Birmingham vasculitis activity score (BVAS) and damage index (modified Rankin score)) and functional (C reactive protein, blood eosinophil count, and electromyogram-electoneurogram) parameters were collected during treatment and the 3 year follow up period. RESULTS: After 12 months, all patients in the treatment group and four (44%) in the control group were in remission. At the end of the 3 year follow up period, we documented significant differences in BVAS (p<0.01), global damage (p<0.02), modified Rankin score (p<0.04), and the daily maintenance prednisone dose (p<0.002) between the two groups. We found a tendency towards lower frequency of relapse and incidence of osteoporosis in the treatment group. CONCLUSION: Complete clinical and functional recovery with a long term stable remission and a low incidence of side effects can be achieved by intravenous immunoglobulin associated with plasmapheresis in patients with Churg-Strauss syndrome.