How Useful are Mid-Arm and Calf Circumferences to Indicate Reduced Muscle Mass in Order to Recognize GLIM-Defined Malnutrition in Elderly Individuals?

AIMS: The aim of this study was to estimate cutoff values of mid-upper arm circumference (MUAC) and calf circumference (CC) for reduced muscle mass and analyze their accuracy in identifying malnutrition among individuals of 65 years of age or older in Bosnia and Herzegovina. MATERIALS AND METHODS: The study is a secondary analysis dataset assessing nutritional risk and malnutrition among 446 community-dwellers and nursing home residents in Bosnia and Herzegovina. Malnutrition assessment included phenotypic criterions (weight loss, low body mass index, and reduced muscle mass) and etiologic criterions (inadequate food intake, disease-related inflammation, or albumin levels) according to recommendations of the Global Leadership Initiative on Malnutrition (GLIM). Receiver operating curves were used to calculate MUAC and CC's cutoff values as compared to the Mini Nutritional Assessment (MNA). RESULTS: The optimal cutoff value for MUAC in men was 24 cm (AUC = 0.910, sensitivity 100%, specificity 77%), and in women 23 cm (AUC = 0.792, sensitivity 64%, specificity 83%). Optimal cutoff value of CC in men was 31 cm (AUC = 0.818, sensitivity 100%, specificity 67%) and in women 29 cm (AUC = 0.882, sensitivity 86%, specificity 74%). Two hundred fifty nine elderly individuals were categorized as malnourished/at risk for malnutrition per MNA. The prevalence of malnutrition based on GLIM criteria ranged from 19% to 30%. CONCLUSIONS: The study suggested that MUAC and CC may be used as the alternative indicators of muscle mass when other assessment methods are unavailable. Future validation and reliability studies for GLIM using anthropometric parameters as a proxy of reduced muscle mass are needed.

Evolution of European light-duty vehicle CO2 emissions based on recent certification datasets.

A new vehicle testing procedure (WLTP - Worldwide Light duty vehicle Test Procedure) was introduced in the European Union (EU) in 2017. In order to examine its actual impact on CO2 emissions for different vehicle technologies and categories, this study analysed data from vehicles certified and registered in the EU in 2019 and 2020. It was found that in average, for all vehicles sold in 2020, the increase in CO2 emissions due to the intoduction of the WLTP was 21% for passenger cars and 27% for vans. Also that diesel vehicles are impacted more than gasoline ones and that the impact on conventional hybrid vehicles is 27% and plug-in hybrid vehicles between 0% (in 2020) and 11% (in 2019). Models employed revealed that the increase in CO2 is mainly due to the higher test masses and more realistic road load coefficients of WLTP that result in higher cycle energy demands. Moreover, results confirmed that the impact of the WLTP's introduction is in line, both in terms of absolute increase and variability, with model-based predictions performed before fleet-wide data were made available.

[Cognitive and legal aspects in older people]. / Aspectos cognitivos y legales en personas mayores: "Sano Juicio".

In Chile, 7.1% of people aged over 60 years have some type of cognitive disorder. The frequency of the latter increases to 13% in people between 75-79 years and 36.2% in people over 85 years. The concept of mild cognitive impairment (MCI) and dementia have evolved over time. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the term minor and major neurocognitive disorder, replacing the DCL and dementia respectively. Major cognitive disorder impairs functional performance while minor disorders does not. There is an arbitrary discrimination against the elderly. A form of discrimination is the request made by some notaries of a medical certification of the cognitive function for older people willing to carry out a legal procedure. This request has the sole effect of pre-establishing evidence in favor of the notary and not protecting the testator or the vulnerable person. Assessing the ability of older people to care for themselves and their possessions has important implications for them and their families, since there is a serious risk of prejudice when someone is declared as disabled. Thus, considering the epidemiology of cognitive disorders in our country we propose a series of legal and medical discussion points aimed to protect autonomy and to protect individuals and their possessions when they have difficulties to control their decisions.

Early viral-specific T-cell testing predicts late cytomegalovirus reactivation following liver transplantation.

INTRODUCTION: Although antiviral prophylaxis is effective in preventing early cytomegalovirus (CMV) reactivation following liver transplantation (OLT), it predisposes patients to late CMV after prophylaxis has ceased. QuantiFERON-CMV (QFN-CMV, Qiagen, The Netherlands) measures an individual's viral-specific immune response. METHODS: Fifty-nine OLT recipients were prospectively monitored post-OLT in an observational cohort study. QFN-CMV was performed at regular time-points. An absolute QFN-CMV <0.1 IU/mL was considered non-reactive. RESULTS: 50/59 (84.7%) had a reactive QFN-CMV by M6. 38/59 (64.4%) had antiviral prophylaxis or treatment before M6, with 31/38 (81.6%) developing a reactive QFN-CMV by 6 months. Over 90% already had a reactive result as early as 3 months post transplant, 3 patients (5.08%) developed late CMV between 6-12 months (median 251 days)-all had a non-reactive M6 QFN-CMV. And 2/3 experienced CMV disease. Non-reactive M6 QFN-CMV was significantly associated with late CMV (OR = 54.4, PPV = 0.33, NPV = 1.00, P = .003). CONCLUSION: Although only 5% of recipients developed late CMV, 2/3 suffered CMV disease. M6 QFN-CMV has an excellent NPV for late CMV, suggesting patients who exhibit a robust ex vivo immune response at M6 can safely cease CMV monitoring. Furthermore, >90% already express viral-specific immunity as early as 3 months. Conceivably, antiviral prophylaxis could be discontinued early in these patients.

[Treatment of heparin-induced thrombocytopenia with rivaroxaban. Case report]. / Rivaroxaban para el tratamiento de la trombocitopenia inducida por heparina. Caso clínico.

Heparin-induced thrombocytopenia (HIT) is immune-mediated. It occurs more frequently with unfractionated heparin (UFH) than with low molecular weight heparins (LMWH). It is associated with thromboembolic rather than hemorrhagic events, as opposed to thrombocytopenia of other etiologies. The key in therapy is the cessation of heparin and the start of another anticoagulant. We report a 58 years old female with HIT secondary to the use of Enoxaparin who was successfully managed with Rivaroxaban. Our goal is to report a novel therapy and provide the evidence that supports its use.

Electronic estimations of renal function are inaccurate in solid-organ transplant recipients and can result in significant underdosing of prophylactic valganciclovir.

In a prospective study of solid-organ transplant recipients (n = 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft-Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (≤ 0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter).

[Infected myxoma as a cause of acute infective endocarditis]. / Infikovaný myxom jako prícina akutni infekcní endokarditidy.

Myxoma is the most frequent primary cardiac tumor. In the typical clinical picture mostly dominate signs of intracardial obstruction, embolisation or general signs of neoplastic process. The myxoma can mimic the course of acute endocarditis. Genuine proof of infection is rare. We report on a patient with familiar form of infected myxoma, who was treated succesfully with antiobiotic therapy and surgical extirpation of the tumor.

Mx proteins: GTPases with antiviral activity.

Mx proteins are synthesized in interferon-treated vertebrate cells. They have attracted much attention because some of them can block the multiplication of influenza A virus and certain other negative-stranded RNA viruses. Recently, Mx proteins have been shown to be GTPases with significant homology to dynamins and yeast VPS1, enzymes involved in intracellular protein trafficking. Several biochemical properties of dynamin and VPS1 are similar to those of Mx, promoting new speculation about how Mx proteins might interfere with virus multiplication.

Functional role of type I and type II interferons in antiviral defense.

Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal immune responses. Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.

Identification of a signal transduction response sequence element necessary for induction of a Dictyostelium discoideum gene by extracellular cyclic AMP.

The signal transduction pathways that lead to gene induction are being intensively investigated in Dictyostelium discoideum. We have identified by deletion and transformation analysis a sequence element necessary for induction of a gene coding for uridine diphosphoglucose pyrophosphorylase (UDPGP1) of D. discoideum in response to extracellular cyclic AMP (cAMP). This regulatory element is located 380 base pairs upstream of the transcription start site and contains a G+C-rich partially palindromic sequence. It is not required for transcription per se but is required for induction of the gene in response to the stimulus of extracellular cAMP. The cAMP response sequence is also required for induction of the gene during normal development. A second A+T-rich cis-acting region located immediately downstream of the cAMP response sequence appears to be essential for the basal level of expression of the UDPGP1 gene. The position of the cAMP response element coincides with a DNase I-hypersensitive site that is observed when the UDPGP1 gene is actively transcribed.

cDNA structures and regulation of two interferon-induced human Mx proteins.

Human cells treated with interferon synthesize two proteins that exhibit high homology to murine Mx1 protein, which has previously been identified as the mediator of interferon-induced cellular resistance of mouse cells against influenza viruses. Using murine Mx1 cDNA as a hybridization probe, we have isolated cDNA clones originating from two distinct human Mx genes, designated MxA and MxB. In human fibroblasts, expression of MxA and MxB is strongly induced by alpha interferon (IFN-alpha), IFN-beta, Newcastle disease virus, and, to a much lesser extent, IFN-gamma, MxA and MxB proteins have molecular masses of 76 and 73 kilodaltons, respectively, and their sequences are 63% identical. A comparison of human and mouse Mx proteins revealed that human MxA and mouse Mx2 are the most closely related proteins, showing 77% sequence identity. Near their amino termini, human and mouse Mx proteins contain a block of 53 identical amino acids and additional regions of very high sequence similarity. These conserved sequences are also present in a double-stranded RNA-inducible fish gene, which suggests that they may constitute a functionally important domain of Mx proteins. In contrast to mouse Mx1 protein, which accumulates in the nuclei of IFN-treated mouse cells, the two human Mx proteins both accumulate in the cytoplasm of IFN-treated cells.

Genetic variants of surfactant proteins A, B, C, and D in bronchopulmonary dysplasia.

BPD_28D (O2 dependency at 28 days of life) and BPD_36W (O2 dependency at 36 wks post-menstrual age) are diseases of prematurely born infants exposed to mechanical ventilation and/or oxygen supplementation. In order to determine whether genetic variants of surfactant proteins (SPs-A, B, C, and D) and SP-B-linked microsatellite markers are risk factors in BPD, we performed a family based association study using a Greek study group of 71 neonates (<30 wks gestational age) from 60 families with, 52 BPD_28D and 19 BPD_36W, affected infants. Genotyping was performed using newly designed pyrosequencing assays and previously published methods. Associations between genetic variants of SPs and BPD subgroups were determined using Transmission Disequilibrium Test (TDT) and Family Based Association Test (FBAT). Significant associations (p

Reduced melanoma tumor formation in mice immunized with DNA expressing the melanoma-specific antigen gp100/pmel17.

Plasmid DNA encoding gene products of viruses or other pathogens has recently been applied by intramuscular injection as a novel type of vaccine. It can induce cytotoxic T cell response in small animals and protect against challenge with influenza A viruses. Combinations with cytokines or DNA-encoding cytokines have been applied in order to increase the efficiency of protection. A DNA vaccine has been analyzed here against malignant melanoma encoding gp100/pmel17, a melanoma-associated antigen. A small animal model was used by injection of B16 melanoma cells to syngeneic C57Bl/6 mice. DNA vaccination before tumor cell challenge leads to about 50% reduction of tumor size. The cytokine gene coding for GM-CSF did not increase the efficiency but also led to tumor size reduction when applied alone.

Induction of the PML protein by interferons in normal and APL cells.

PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia (APL). The PML protein is specifically associated to nuclear bodies (NBs) whose alterations in APL were proposed to contribute to leukemogenesis. The role of this nuclear domain (which also harbors the Sp100 autoantigen and the NDP52 protein) is unknown. Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells. Interestingly, the NBs that contain the three IFN-induced proteins appear to be associated to speckles labelled by the IFN-mediator Mx1. These observations link NBs to IFN response pathways, which may contribute to the elucidation of the biological role of these structures. In APL cells, IFNs induced both PML and PML/RAR alpha expression, resulting in an increased sequestration of PML and RXRs in the microspeckles induced by the fusion protein. As PML has growth suppressing properties, it may mediate some of the antiproliferative effects of IFN. In APL, inactivation of PML may result in disruption of growth control.

Synergistic effect of a combined DNA and peptide vaccine against gp100 in a malignant melanoma mouse model.

Vaccination against tumors relies on tumor-associated antigens, and has been quite successful with synthetic peptides used as immunogens. Gp100 is a human melanoma-associated antigen (hgp100) with a highly homologous mouse counterpart, pmel17/gp100 (mgp100), that is expressed in melanocytes and highly tumorigenic B16 melanoma cells. Since mgp100 is poorly immunogenic in mice, we used a xenoimmunization approach and vaccinated with the hgp100 immunogene. To that end, plasmid DNA encoding hgp100 was applied as a vaccine in combination with three synthetic peptides corresponding to putative cytotoxic T cell epitopes of hgp100. Immunization with DNA and peptide-pulsed spleen cells had a synergistic effect and provided significant protection against a challenge with poorly immunogenic B16-F0 malignant melanoma cells in the syngeneic C57BL/6 mouse model. Vaccination with either plasmid DNA or peptides alone delayed the onset of tumor formation, and reduced tumor growth 2-fold and 30-fold, respectively. However, while all animals vaccinated with DNA encoding hgp100 or with peptides eventually developed tumors, 30% of the animals treated with both vaccines remained tumor free and survived for the entire observation period of 150 days. Depletion of T cell subsets revealed that the protective effect observed after vaccination with plasmid DNA was mediated by CD4+ and CD8+ T cells, while protection following vaccination with DNA encoding hgp100 in combination with peptides appears to depend on CD4+ T cells only. Furthermore, we could also demonstrate a therapeutic effect of the combined DNA/peptide regime. A single treatment cycle consisting of injections of plasmid DNA and peptide-pulsed spleen cells led to a fourfold reduction in the growth rate of preexisting tumors. The data presented demonstrate that immunization with xenoantigens induces cross-species priming leading to an immunological response against the tumor-specific antigens.

Aspectos cognitivos y legales en personas mayores: "Sano Juicio"

In Chile, 7.1% of people aged over 60 years have some type of cognitive disorder. The frequency of the latter increases to 13% in people between 75-79 years and 36.2% in people over 85 years. The concept of mild cognitive impairment (MCI) and dementia have evolved over time. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the term minor and major neurocognitive disorder, replacing the DCL and dementia respectively. Major cognitive disorder impairs functional performance while minor disorders does not. There is an arbitrary discrimination against the elderly. A form of discrimination is the request made by some notaries of a medical certification of the cognitive function for older people willing to carry out a legal procedure. This request has the sole effect of pre-establishing evidence in favor of the notary and not protecting the testator or the vulnerable person. Assessing the ability of older people to care for themselves and their possessions has important implications for them and their families, since there is a serious risk of prejudice when someone is declared as disabled. Thus, considering the epidemiology of cognitive disorders in our country we propose a series of legal and medical discussion points aimed to protect autonomy and to protect individuals and their possessions when they have difficulties to control their decisions.

DNA-based vaccine against La Crosse virus: protective immune response mediated by neutralizing antibodies and CD4+ T cells.

La Crosse virus (LACV)-mediated encephalitis is the most frequently reported arboviral disease in the United States, but to date no vaccine against this virus is available. We have established a new animal model, genetically targeted mice lacking a functional interferon type I receptor (IFNAR-1). These mice show an age-independent susceptibility to LACV and develop an acute encephalitis within 6 days of infection, thereby allowing the evaluation of vaccines against LACV. Taking advantage of this knockout mouse model, we have assessed the feasibility of DNA vaccination against this viral disease. Plasmid DNAs, encoding either the virus surface glycoproteins G1 and G2 or the internal nucleocapsid protein N, were used to immunize IFNAR-1-deficient mice. Mice vaccinated with DNA encoding the glycoproteins G1 and G2 produced neutralizing antibodies and exhibited a high degree of protection against challenge with high doses of LACV. Depletion of CD4+ T cells in mice vaccinated with DNA encoding G1/G2 reduced their capacity to control the infection. Virus titration and immunohistological analysis revealed that the protected mice showed no evidence of LACV particles in the brain. This indicates that the vaccine-induced immune response efficiently blocked viral spreading from the primary replication site to the brain. In contrast, immunization with DNA encoding protein N yielded only a partial protective effect that can be attributed to the cellular immune response. Taken together, this study shows that DNA vaccines can be designed to efficiently induce a protective immune response based on neutralizing antibodies and CD4+ T cells.

Long-lasting anti-metastatic efficiency of interleukin 12-encoding plasmid DNA.

Intramuscular injection of plasmid DNA encoding both subunits of the cytokine interleukin 12 (IL-12) exhibits strong antimetastatic activity against lung metastases induced by the malignant melanoma cell line B16-F10. The protective effect of IL-12 DNA is long-lasting, since administration of tumor cells 9 days after IL-12 DNA treatment prevented metastasis formation. No effects were observed with empty plasmid controls, DNA encoding the melanoma-associated antigen pmel17/gp100, the granulocyte-macrophage colony-stimulating factor GM-CSF, B7.1, or CpG-containing oligodeoxynucleotides. IL-12 DNA is required during early phases of metastasis formation and is ineffective when administered later. Its efficiency is dose dependent. The cytotoxic T cell response contributes to the antimetastatic effect as evidenced by genetically modified CD8- or perforin knockout mice. Depletion of natural killer (NK) cells by antibodies completely abrogated the effect. In contrast, the IL-12-induced antimetastatic effect was not mediated by interferon gamma (IFN-gamma) or tumor necrosis factor alpha (TNF-alpha) as shown with IFN-gamma receptor and TNF-alpha knockout mice, respectively. Toxic side effects by IL-12 were low. Our results suggest that plasmid DNA encoding IL-12 might have potential value as gene medicine against the initiation of metastasis formation.

Inhibition of human hematopoietic tumor formation by targeting a repressor Myb-KRAB to DNA.

In many hematopoietic malignancies, c-Myb, a nuclear transcription factor of hematopoietic cells, is an activated oncogene. To achieve a specific inhibition of hematopoietic tumor growth, an inducible fusion protein consisting of the Myb DNA binding domain (DBD) and the active repressor domain KRAB, the Krüppel-associated box of the developmental zinc-finger protein KOX-1, was generated. The MybDBD-KRAB fusion protein is a potent repressor of Myb-induced gene expression from Myb-responsive reporter genes containing several Myb binding sites. MybDBD-KRAB expressed in the human hematopoietic promyelocytic cell line HL60 significantly reduces cell proliferation by inducing apoptosis. Expression of MybDBD-KRAB in subcutaneously injected HL60 cells leads to inhibition of tumor formation in nude mice. The MybDBD-KRAB effect is specific to cell lines expressing c-Myb. It is conceivable to fuse the KRAB domain to other DBDs of oncogenic transcription factors and target them to their respective DNA response elements to selectively drive tumor cells into apoptosis.

Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA.

We have recently demonstrated that DNA coding for both subunits of the murine IL-12 heterodimer exhibits a strong antimetastatic effect against B16-melanoma in C57BL/6 mice and after intratumoral injection tumor regression. Here we show that the antimetastatic effect can be detected when the DNA is injected intramuscularly 30 days before tumor cell challenge. A long-term IL-12 expression was measured for up to 50 days in the serum with a peak at day 20 amounting to about 10 ng/mL in C57BL/6 mice. CpG oligodeoxynucleotides also induce IL-12 expression, however, only for a few hours. IL-12 DNA administration induces long-lasting systemic IFN -gamma production, whereas IL-4 and TNF-alpha levels remained undetectable. NK cell-depleted mice showed a strong but reduced expression of murine IL-12. Expression of DNA encoding human instead of murine IL-12 resulted in a significantly lower and transient expression, indicating that not plasmid-derived IL-12 production alone but the immune system of the host contributes to the long- lasting antimetastatic effect. It may be attributable to an autocrine feedback mechanism maintaining murine IL- 12 expression, whereby several cell populations including NK cells are involved.