Patterns of Cerebrospinal Fluid Alzheimer’s Dementia Biomarkers in People Living with HIV: Cross-Sectional Study on Associated Factors According to Viral Control,Neurological Confounders and Neurocognition

People living with HIV (PLWH) age with an excess burden of comorbidities that may increase the incidence of age-related complications. There is controversy surrounding the hypothesis that HIV can accelerate neurodegeneration and Alzheimer’s dementia (AD). We performed a retrospective study to analyze the distribution of cerebrospinal fluid (CSF) AD biomarkers (beta amyloid 1–42 fragment, tau, and phosphorylated tau) in adult PLWH (on cART with undetectable viremia, n = 136, with detectable viremia, n = 121, and with central nervous system CNS disorders regardless of viremia, n = 72) who underwent a lumbar puncture between 2008 to 2018; HIV-negative controls with AD were included (n = 84). Five subjects (1.5%) presented CSF biomarkers that were compatible with AD: one was diagnosed with AD, whereas the others showed HIV encephalitis, multiple sclerosis, cryptococcal meningitis, and neurotoxoplasmosis. Regardless of confounders, 79.6% of study participants presented normal CSF AD biomarkers. Isolated abnormalities in CSF beta amyloid 1–42 (7.9%) and tau (10.9%) were associated with age, biomarkers of intrathecal injury, and inflammation, although no HIV-specific feature was associated with abnormal CSF patterns. CSF levels of AD biomarkers very poorly overlapped between HIV-positive clinical categories and AD controls. Despite the correlations with neurocognitive performance, the inter-relationship between amyloid and tau proteins in PLWH seem to differ from that observed in AD subjects; the main driver of the isolated increase in tau seems represented by non-specific CNS inflammation, whereas the mechanisms underlying isolated amyloid consumption remain unclear.     

Targeted IL‐4 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis

F8‐IL‐4 is a recently developed immunocytokine that delivers IL‐4 to sites of inflammation by targeting the neovasculature. We previously reported that F8‐IL‐4, in combination with dexamethasone (DXM), provides a durable therapy in mice with collagen‐induced arthritis (CIA). Therefore, the objective of this study was to identify the mechanism by which IL‐4 and DXM combination therapy provides long‐lasting disease remission. F8‐IL‐4 alone attenuated inflammation in CIA and this was associated with increased T_H2 and decreased T_H17 cell numbers in the joints. Similarly, DXM alone had an antiinflammatory effect associated with lower T_H17 cell numbers. In both cases, these therapeutic benefits were reversed once treatment was stopped. On the other hand, combination therapy with F8‐IL‐4 plus DXM led to a synergistic increase in the percentage of regulatory T (Treg) cells and antiinflammatory macrophages in the arthritic joint and spleen as well as IL‐10 levels in serum and spleen. The net result of this was a more pronounced attenuation of inflammation and, more importantly, protection from arthritis relapse post therapy retraction. In conclusion, F8‐IL‐4 plus DXM is a durable treatment for arthritis that acts by promoting Treg cells in a synergistic manner, and by producing a sustained increase in antiinflammatory macrophages.     

Primary therapy with ECF in combination with a GnRH analog in premenopausal women with hormone receptor-positive T2-T4 breast cancer

Patients with hormone receptor-positive tumors less often show a pathological complete response (pCR) than do those with hormone receptor-negative tumors. The addition of endocrine therapies may improve the clinical benefits of primary therapies in these patients. We investigated the efficacy of the epirubicin+cisplatin+fluorouracil (ECF) as continuous infusion) regimen in association with a gonadotropin-releasing hormone (GnRH) analog in 36 premenopausal women with T2-T4a-d N0-2 M0 ER and/or PgR-positive breast cancer. Median age was 39.5 years (range 26-53). Clinical response (complete or partial) was observed in 27 out of 36 patients (75% 95% CI 57.8-87.9%) and a pCR was observed in four patients (11%). Nine (25%) patients had stable disease and no progression was observed. Twenty-one patients (58%) were submitted for breast-conserving surgery and 15 had a radical mastectomy. No baseline clinical and biological characteristics significantly correlated with response. Thirty out of 31 patients evaluable for endocrine assessment had documented ovarian suppression, which occurred after a median of 28 days (range 20-43). We conclude that the combination of ECF and a GnRH analog is associated with a high response rate in the primary treatment of breast cancer. Further studies combining chemotherapy and endocrine agents are warranted in patients with hormone receptor-positive tumors.     

Ca’ Granda,an avant-garde hospital between the Renaissance and Modern age: a unique scenario in European history

The Ospedale Maggiore, known as Ca’ Granda, was founded in 1456 by will of Francesco Sforza, Duke of Milan, and was considered for almost five centuries a model for Milanese, Italian and even European healthcare. Attracting patients from all over Europe, the Ca’ Granda distinguished itself for the introduction of new treatments and innovative health reforms. In the burial ground of the hospital still lie the bodies of the deceased patients, who came from the poorest strata of the population. The study of their remains aims to give back a general identity and a story to each of these persons as well as reconstruct a fraction of the sixteenth century population of Milano as concerns lifestyle and disease and examine practises and therapy of this exceptional hospital. It is estimated that about two million commingled bones and articulated skeletons rest in the crypt, together with other types of findings (e.g., ceramic, coins, clothing). These remains are the object of a large project involving various disciplines ranging from humanities to hard sciences. The aim of this paper is to bring this historical gem to the attention of scholars and provide a glimpse of what its contents have already revealed.     

Incidence of epilepsy in extremely low-birthweight infants (<1,000 g): A population study of central and southern Sardinia

Purpose:   With the development of intensive care, the survival of extremely low-birthweight (ELBW) infants (<1,000 g) has greatly improved. The aim of our study was to report the incidence of epilepsy after a follow-up of >7 years in a population of ELBW children, born in central and southern Sardinia between 1991 and 2000.
Methods:   We analyzed data of 104 children. All infants had had serial cranial ultrasound echography (CUE) in the neonatal period and some also had magnetic resonance imaging (MRI). At last follow-up we evaluated the occurrence of epilepsy through a review of clinical charts and a structured telephone interview.
Results:   In 11 (10.6%) of 104 of children we observed febrile seizures (FS). Epilepsy occurred in 9 (8.6%) of 104 ELBW children, and in these patients a frequent positive family history for epilepsy and/or FS was present. In four epilepsy patients CUE was highly pathologic, showing intraventricular hemorrhage (IVH) of grade IV and in two mildly abnormal (IVH of grade I–II). In three additional children with normal neonatal ultrasound scan, a later magnetic resonance imaging (MRI) study revealed lesions related to neonatal insult.
Discussion:   In our ELBW population, epilepsy had an incidence clearly superior to that expected in infancy (8.6% vs. 0.6–0.8% ) . A frequent positive familiar history for epilepsy and/or FS suggests that a genetic predisposition may also play a role. Subjects with highly abnormal CUE are a subgroup with high risk for seizures; however, epilepsy can occur even with normal CUE.     

Psychometric properties of the Italian version of the Cognitive Reserve Scale (I-CRS)

The original definition of cognitive reserve (CR) refers to the individual differences in cognitive performance after a brain damage or pathology. Several proxies were proposed to evaluate CR (education, occupational attainment, premorbid IQ, leisure activities). Recently, some scales were developed to measure CR taking into account several cognitively stimulating activities. The aim of this study is to adapt the Cognitive Reserve Scale (I-CRS) for the Italian population and to explore its psychometric properties. I-CRS was administered to 547 healthy participants, ranging from 18 to 89 years old, along with neuropsychological and behavioral scales to evaluate cognitive functioning, depressive symptoms, and apathy. Cronbach’s α, corrected item-total correlations, and the inter-item correlation matrix were calculated to evaluate the psychometric properties of the scale. Linear regression analysis was performed to build a correction grid of the I-CRS according to demographic variables. Correlational analyses were performed to explore the relationships between I-CRS and neuropsychological and behavioral scales. We found that age, sex, and education influenced the I-CRS score. Young adults and adults obtained higher I-CRS scores than elderly adults; women and participants with high educational attainment scored higher on I-CRS than men and participants with low education. I-CRS score correlated poorly with cognitive and depression scale scores, but moderately with apathy scale scores. I-CRS showed good psychometric properties and seemed to be a useful tool to assess CR in every adult life stage. Moreover, our findings suggest that apathy rather than depressive symptoms may interfere with the building of CR across the lifespan.     

Incidental Papillary Thyroid Carcinoma: Diagnostic Findings in a Series of 287 Carcinomas

The recent increase in the detection of papillary thyroid carcinoma (PTC) has been influenced by the finding of incidental tumours. To this group, carcinomas measuring less than 1 cm (the so-called microcarcinomas) as well as those above 1 cm belong. Analyzing a case series from our own experience, this paper focuses on the current pre-operative diagnostic challenges that can lead to PTC incidental discovery. For this retrospective study, 287 patients with a PTC diagnosis were selected. For each, the following variables were analysed: sex, age, ultrasound (US) appearance, number of thyroid nodules, PTC size, PTC variants and presence of other associated pathology. Pre-operative fine needle aspiration (FNA) results were classified according to the five-tiered SIAPEC system. For 281 patients, the US-guided FNA results were available. Cytohistological correlation was evaluated in terms of FNA sensitivity and false negative rate. An incidental PTC was found in 45.2 % of patients. The majority of these were due to unsuccessful US detection of malignant nodules (103 cases); incorrect cytological diagnosis was responsible for the other 24 cases. The most powerful clinical confounding factors were: multinodular background versus single nodule presentations (p?p?2 cm) due to tumour heterogeneity. Although with limitations related to the tumour’s intrinsic features and the thyroid background, US-guided FNA, especially if performed by a dedicated multidisciplinary team, is a powerful diagnostic tool for detecting malignant thyroid nodules. To the state of the art, we propose a practical clinical-pathological cut-off for this procedure, setting it at 5 mm.