Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer's Disease.

BACKGROUND: Increasing evidence indicates that ß-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. OBJECTIVES: To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. DESIGN: prospective analysis of serum samples, clinical, biological, and demographic variables. SETTING: Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. PARTICIPANTS: 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). MEASUREMENTS: serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. RESULTS: Age was the strongest independent predictor of sBACE1 variance (ß=0.425, p<0.0001), followed by sex (ß=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (ß=-0.168, p<0.0001) and hypertension (ß=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. CONCLUSIONS: We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age.

Elevated Blood Homocysteine and Risk of Alzheimer's Dementia: An Updated Systematic Review and Meta-Analysis Based on Prospective Studies.

OBJECTIVE: To investigate whether high serum homocysteine (Hcy) levels is associated with the risk of developing Alzheimer's disease (AD) by performing a meta-analysis based on updated published data. METHODS: We conducted a comprehensive research using Medline (Pubmed), Scopus, Web of Science and EMBASE databases to identify all prospective studies published any time to July 7, 2020 evaluating the association between elevated Hcy levels and AD risk. RESULTS: From an initial screening of 269 published papers, 9 prospective investigations conducted on a total of 7474 subjects with mean follow-up of 9.5 years (range: 3.7-10) were included in the meta-analysis. Eight seventy-five of these subjects converted to AD. Hcy was significantly higher in these individuals (HRadjusted:1.48, 95% CI:1.23-1.76, I2=65.6%, p<0.0001) compared with who did not convert to AD. There was a significant publication bias (Egger's test, t=6.39, p=0.0003) and this was overcome by the trim and fill method, which allowed to calculate a bias-corrected imputed risk estimate of HRadjusted:1.20, 95% CI:1.01-1.44, Q value=41.92. CONCLUSIONS: The present meta-analysis found that having higher Hcy increases the risk of AD in the elderly and this finding is consistent with the widely suggested role of this non-proteinogenic α-amino acid in AD neurodegeneration.

Dyslipidaemia and mortality in COVID-19 patients: a meta-analysis.

BACKGROUND: The prevalence and prognostic implications of pre-existing dyslipidaemia in patients infected by the SARS-CoV-2 remain unclear. AIM: To assess the prevalence and mortality risk in COVID-19 patients with pre-existing dyslipidaemia. DESIGN: Systematic review and meta-analysis. METHODS: Preferred reporting items for systematic reviews and meta-analyses guidelines were followed in abstracting data and assessing validity. We searched MEDLINE and Scopus to locate all the articles published up to 31 January 2021, reporting data on dyslipidaemia among COVID-19 survivors and non-survivors. The pooled prevalence of dyslipidaemia was calculated using a random-effects model and presenting the related 95% confidence interval (CI), while the mortality risk was estimated using the Mantel-Haenszel random-effect models with odds ratio (OR) and related 95% CI. Statistical heterogeneity was measured using the Higgins I2 statistic. RESULTS: Of about 18 studies, enrolling 74 132 COVID-19 patients (mean age 70.6 years), met the inclusion criteria and were included in the final analysis. The pooled prevalence of dyslipidaemia was 17.5% of cases (95% CI: 12.3-24.3%, P < 0.0001), with high heterogeneity (I2 = 98.7%). Pre-existing dyslipidaemia was significantly associated with higher risk of short-term death (OR: 1.69, 95% CI: 1.19-2.41, P = 0.003), with high heterogeneity (I2 = 88.7%). Due to publication bias, according to the Trim-and-Fill method, the corrected random-effect ORs resulted 1.61, 95% CI 1.13-2.28, P < 0.0001 (one studies trimmed). CONCLUSION: Dyslipidaemia represents a major comorbidity in about 18% of COVID-19 patients but it is associated with a 60% increase of short-term mortality risk.

Energy cost for the proper ionization of active site residues in 6-phosphogluconate dehydrogenase from T. brucei.

The catalytic mechanism of 6-phosphogluconate dehydrogenase requires the inversion of a Lys/Glu couple from its natural ionization state. The pKa of these residues in free and substrate bound enzymes has been determined measuring by ITC the proton release/uptake induced by substrate binding at different pH values. Wt 6-phosphogluconate dehydrogenase from Trypanosoma brucei and two active site enzyme mutants, K185H and E192Q were investigated. Substrate binding was accompanied by proton release and was dependent on the ionization of a group with pKa 7.07 which was absent in the E192Q mutant. Kinetic data highlighted two pKa, 7.17 and 9.64, in the enzyme-substrate complex, the latter being absent in the E192Q mutant, suggesting that the substrate binding shifts Glu192 pKa from 7.07 to 9.64. A comparison of wt and E192Q mutant appears to show that the substrate binding shifts Lys185 pKa from 9.9 to 7.17. By comparing differences in proton release and the binding enthalpy of wt and mutant enzymes, the enthalpic cost of the change in the protonation state of Lys185 and Glu192 was estimated at ≈6.1kcal/mol. The change in protonation state of Lys185 and Glu192 has little effect on Gibbs free energy, 240-325cal/mol. However proton balance evidences the dissociation of other group(s) that can be collectively described by a single pKa shift from 9.1 to 7.54. This further change in ionization state of the enzyme causes an increase of free energy with a total cost of 1.2-2.3kcal/mol to set the enzyme into a catalytically competent form.

Hypoxia induces cell damage via oxidative stress in retinal epithelial cells.

Retinal diseases (RD), including diabetic retinopathy, are among the most important eye diseases in industrialized countries. RD is characterized by abnormal angiogenesis associated with an increase in cell proliferation and apoptosis. Hypoxia could be one of the triggers of the pathogenic mechanism of this disease. A key regulatory component of the cell's hypoxia response system is hypoxia-inducible factor 1 alpha (HIF-1α). It has been demonstrated that the induction of HIF-1α expression can be also achieved in vitro by exposure with cobalt chloride (CoCl2), leading to an intracellular hypoxia-like state. In this study we have investigated the effects of CoCl2 on human retinal epithelium cells (hRPE), which are an integral part of the blood-retinal barrier, with the aim to determine the possible role of oxidative stress in chemical hypoxia-induced damage in retinal epithelial cells. Our data showed that CoCl2 treatment is able to induce HIF-1α expression, that parallels with the formation of reactive oxygen species (ROS) and the increase of lipid 8-isoprostanes and 4-hydroxynonenal (4-HNE) protein adducts levels. In addition we observed the activation of the redox-sensitive transcription factor nuclear factor-kappaB (NFkB) by CoCl2 which can explain the increased levels of vascular endothelial growth factor (VEGF). The increased number of dead cells seems to be related to an apoptotic process. Taken together these evidences suggest that oxidative stress induced by hypoxia might be involved in RD development through the stimulation of two key-events of RD such as neo-angiogenesis and apoptosis.

A new fork-shaped condylar and osteotomy plate.

The authors present their experience with a new crossed condylar and osteotomy plate, which is innovative because of the features of its design, and the instrumentation used for its application, as compared to the traditional AO blade plate. The plate is called "fork-shaped" because there are 2 prongs in place of the blade with a "U" profile, and it involves the use of more accurate and less traumatic instrumentation to implant it. The results of a study conducted on a group of 20 patients, who were homogeneous for pathology and surgery, treated by a fork-shaped osteotomy plate, compared with an equal number of patients treated by a blade plate, are reported. The results were better in the group treated with a fork plate because there was a more accurate correspondence with the preoperative planning, and because there were fewer intraoperative complications, and time required for surgery was shorter.

Femoral osteotomy in the treatment of adult dysplastic hip.

The authors define the current role of femoral osteotomy in the treatment of the sequelae of congenital hip dysplasia (CHD) in the adult in light of the increasing orientation towards prosthetization. They report a personal philosophy on the subject after analyzing the criteria on which are based indications for osteotomy, the various types of osteotomy, the influence of osteotomy on other skeletal regions, the problems of prosthetization on osteotomy, and expectations concerning of the quality of the life of the patients submitted to osteotomy.

The anchor nail in osteosynthesis of fractures of the humerus.

Osteosynthesis with a humeral anchor nail may be listed along with other methods of intramedullary fixation for the treatment of diaphyseal fractures. The authors report their experience with 33 cases of humeral fractures treated between July 1987 and July 1991. Results were excellent in 61% of the cases, good in 24%, and fair in 15%; no particular complications were reported. The authors believe that the anchor nail constitutes a system of osteosynthesis involving only a small amount of trauma, and allowing for positive elastic stability for the consolidation of the fracture, as well as being a sufficiently safe system so that immobilization in plaster may be avoided. When compared with other systems of intramedullary fixation, the anchor nail is more effective than the Rush nail from a mechanical point of view, and the Kuntscher nail from a biological one.

The Ilizarov method for the treatment of non-union in the humerus.

The authors report 7 cases of septic and aseptic pseudoarthrosis in the humerus, with or without tissue loss, treated with the Ilizarov apparatus. The method proved to be therapeutically effective, guaranteeing a short amount of time required for consolidation, with bone callus of the periosteal type which was abundant and mechanically effective, immediate functional recovery, and no important complications.

Autogenous patella as replacement for a resected femoral or tibial condyle. A report on 19 cases.

The size and shape of the patella make it suitable for the partial replacement of a femoral or tibial condyle resected for tumour, or destroyed by trauma. It can provide a good articular surface and may give satisfactory knee function. Nineteen cases of patellar grafts are presented, with follow-up from two to nine years. Good consolidation of the graft and fair stability of the joint were obtained; the range of movement was 90 degrees or more in 79% of cases. In contrast with an allograft of a femoral or tibial condyle, the technique described does not need an allograft bank, has a lower risk of infection, and allows better and quicker consolidation and revascularisation of the grafts, as well as a better range of movement at the knee, probably because of the lack of fibrosis from immunological reaction. Merle d'Aubigné's technique, using a patellar graft with a vascular muscle pedicle, is useful only for some cases, requires a longer period of immobilisation and weakens the extensor apparatus. Our series shows that consolidation and revascularisation of a patellar graft can occur in the absence of a pedicle.

The treatment of pulmonary metastases in osteosarcoma. Preliminary observations on 30 cases.

Thirty cases of pulmonary metastases in osteosarcoma are analysed from the point of view of evaluating the indications for localised excision, and also to report the results obtained. This group is compared with 42 analogous cases in which the metastases were not treated surgically. The results of pulmonary surgery is shown to be effective in the multidisciplinary treatment of osteosarcoma with pulmonary metastases.

Endoprosthesis of the humerus: description of a new model and its application.

A new type of endoprosthesis of the humerus is presented. It is indicated in resection of the proximal humerus for primary and secondary neoplasms. After describing its construction and the technique for fitting it, the writers analyse the clinical results in thirteen cases. They emphasize the advantages over prostheses of other kinds: simplicity of fitting, wide possibilities of adaptation to individual cases, and the very satisfactory aesthetic and functional aspect.

Aneurysmal bone cyst (a study of 127 cases, 72 with longterm follow up).

127 cases of aneurysmal bone cyst are analysed, seventy two of which were followed up from one to fifteen years after treatment. Statistics on sex, age, site and localisation are reported. Symptoms, radiographic features, histological appearances and differential diagnosis are discussed. In half the cases the cyst was clearly shown to be of subperiosteal origin. The aetiology is unknown, but the pathogenesis seems to consist of a haemorrhagic and hyperplastic (not neoplastic) process which is progressive but has a tendency to become stabilised on reaching a certain point of maturation. Local excision is indicated or, in cases where this is difficult to carry out, radiotherapy. Recurrences occurred in 12 per cent of the cases, always within one year after operation. All cases were eventually cured and there was no evidence of malignant transformation.