Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Do radiolucent lines and stress shielding of the humeral shaft really matter in shoulder arthroplasty?

The purpose of this study is to evaluate at a mid-term follow up, the radiological survival of an uncemented humeral stem in shoulder arthroplasty. One hundred and twenty-six replacements including hemi (HA), total (TSA) and reverse (RSA) implanted from 1999 to 2008 were reviewed at a mean follow up of 7.2 years (48-144 months). The same uncemented triconical stem (SMR, Lima Corporate) was implanted. There were: 23 HSA, 43 TSA, 60 RSA. An independent observer evaluated all the patients with Constant Score. A radiologic analysis by an expert radiologist and an orthopaedic surgeon was performed: humeral component-bone interface was divided in seven zones. They judged a mobilisation if a migration or tilt of the humeral implant or if≥ 2 mm radiolucent line in at least three zones was present. Chi-squared test, Fisher test and analysis of variance were performed and a p<0.05 was considered statistically significant. No major radiological signs of loosening and no tilt or migration of the humeral component were found. Only 23 (18.2%) patients had no RL around the humeral implant. In the remaining 103 (81.7%) implants: 96 (76.1%) presented RL less than 2 mm, particularly 75 (59.5%) in less than 3 zones and 21 (16.6%) in more than 3 zones. Of the remaining 7 (5.5%) implants the presence of RL of 2 mm or greater in only one zone was seen. Apart from sepsis no revision was performed for humeral component loosening. Although a high rate of RL, uncemented humeral stem has an excellent survivorship at a mid-term follow up. Relationship between presence, position and depth of RL and internal stress shielding is commonly observed but does not appear t

Griscelli syndrome type 2: long-term follow-up after unrelated donor bone marrow transplantation

Griscelli syndrome (GS) is a rare autosomal recessive disease characterized by silvery hair ('partial albinism'). Three forms exist; GS type 2 (GS2), the most common one, is characterized by severe primary immunodeficiency with acute episodes of hemophagocytic lymphohistiocytosis (HLH) which may be fatal in the absence of hematopoietic stem cell transplantation. A 5-year-old boy with HLH was referred to us because of silvery-gray hair present since birth. Abnormal pigment clumps were observed in the medulla of hair shafts on light microscopy. Electron microscopy of a skin biopsy revealed melanosomes in melanocytes, but not in keratinocytes. Leukocytes were devoid of intracytoplasmic granules on blood smear. Neurological signs were absent. Genotyping revealed a homozygous haplotype for polymorphic markers linked to the RAB27A locus, but no RAB27A mutation. A diagnosis of GS2 was established. The patient received bone marrow transplantation (BMT) from an unrelated donor, and after 72 months he did not show relapse of HLH. The long, uneventful follow-up supports the use of BMT from an unrelated donor if transplantation from a relative is not possible

A previously unreported function of beta1B integrin isoform in caspase-8-dependent integrin-mediated keratinocyte death

Integrins regulate adhesive cell-matrix interactions and mediate survival signals. On the other hand, unligated or free cytoplasmic fragments of integrins induce apoptosis in many cell types (integrin-mediated death). We have previously shown that b1 integrins expression protects keratinocyte stem cells from anoikis, while the role of the b1B integrin isoform has never been clarified. Here we report that suspended keratinocytes undergo apoptosis via the activation of caspase-8, independently of Fas/Fas Ligand system. Indeed, anti-b1 integrin neutralizing antibodies induced apoptosis in short-hairpin-RNA-Fas-Associated-Death-Domain treated cells. Moreover, before and during suspension, caspase-8 directly associated with b1 integrin, that in turn internalized and progressively degraded, shedding the cytoplasmic domain. b1B was expressed only in the cytoplasm in a perinuclear fashion and remained unaltered during suspension. At 24 hrs, as b1A located close to the nucleus, b1B co-localized with b1A and co-immunoprecipitated with caspase-8. Caspase-8 was activated earlier in b1B integrin transfected keratinocytes, and these cells underwent a higher rate of apoptosis than mock cells. By contrast, caspase-8 was not activated in siRNA b1B transfected cells. These results indicate that when b1A is unligated, b1B is responsible for “integrin-mediated death” in human keratinocytes

Solar retinopathy: a new setting of red, green, and blue channels

PURPOSE: To introduce a new color imaging technique using improved settings of red, green, and blue channels for improved delineation of retinal damage in patients with solar retinopathy. METHODS: A retrospective case series of patients with poor vision secondary to solar retinopathy were analyzed. All patients underwent visual acuity, refraction, and dilated fundus examination. A spectral domain–optical coherence tomography of the macula and color fundus imaging using optimized red, green, and blue color setting was performed. Patients were reviewed over a 6-month period. The data were analyzed for statistical significance using an independent t test and a receiver operating characteristic curve. RESULTS: In total, 20 eyes of 10 patients were included between 2009 and 2017. The mean age was 24.9 ± 18.1 years. Best corrected visual acuity at first consultation was 0.78 ± 0.11 and after 6 months was 0.83 ± 0.09. Spectral domain–optical coherence tomography demonstrated retinal abnormalities at the myoid zone, ellipsoid zone, and the outer segment of photoreceptors. Receiver operating characteristic curve analysis showed an improving effect (area under the curve = 0.62; 95% confidence interval = 0.42–0.79). The color channels parameters, which improve visualization of the lesions were found to be 67-0.98-255 for the R-guided setting, 19-0.63-121 for the B-guided setting, and 7-1.00-129 for the G-guided setting. The ideal red, green, and blue setting was in 24-0.82-229. CONCLUSIONS: The use of a new setting of red, green, and blue channels could improve the diagnosis and monitoring of solar retinopathy, hence improving patient care

The ERA-EDTA Registry Annual Report 2018: a summary

Background The European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Registry collects data on kidney replacement therapy (KRT) via national and regional renal registries in Europe and countries bordering the Mediterranean Sea. This article summarizes the 2018 ERA-EDTA Registry Annual Report, and describes the epidemiology of KRT for kidney failure in 34 countries. Methods Individual patient data on patients undergoing KRT in 2018 were provided by 34 national or regional renal registries and aggregated data by 17 registries. The incidence and prevalence of KRT, the kidney transplantation activity and the survival probabilities of these patients were calculated. Results In 2018, the ERA-EDTA Registry covered a general population of 636 million people. Overall, the incidence of KRT for kidney failure was 129 per million population (p.m.p.), 62% of patients were men, 51% were ≥65 years of age and 20% had diabetes mellitus as cause of kidney failure. Treatment modality at the onset of KRT was haemodialysis (HD) for 84%, peritoneal dialysis (PD) for 11% and pre-emptive kidney transplantation for 5% of patients. On 31 December 2018, the prevalence of KRT was 897 p.m.p., with 57% of patients on HD, 5% on PD and 38% living with a kidney transplant. The transplant rate in 2018 was 35 p.m.p.: 68% received a kidney from a deceased donor, 30% from a living donor and for 2% the donor source was unknown. For patients commencing dialysis during 2009–13, the unadjusted 5-year survival probability was 42.6%. For patients receiving a kidney transplant within this period, the unadjusted 5-year survival probability was 86.6% for recipients of deceased donor grafts and 93.9% for recipients of living donor grafts

Prodromal frontotemporal dementia: clinical features and predictors of progression

Background: The prodromal phase of frontotemporal dementia (FTD) is still not well characterized, and conversion rates to dementia and predictors of progression at 1-year follow-up are currently unknown. // Methods: In this retrospective study, disease severity was assessed using the global CDR plus NACC FTLD. Prodromal FTD was defined to reflect mild cognitive or behavioural impairment with relatively preserved functional independence (global CDR plus NACC = 0.5) as well as mild, moderate and severe dementia (classified as global CDR plus NACC = 1, 2, 3, respectively). Disease progression at 1-year follow-up and serum NfL measurements were acquired in a subgroup of patients. // Results: Of 563 participants, 138 were classified as prodromal FTD, 130 as mild, 175 as moderate and 120 as severe FTD. In the prodromal and mild phases, we observed an early increase in serum NfL levels followed by behavioural disturbances and deficits in executive functions. Negative symptoms, such as apathy, inflexibility and loss of insight, predominated in the prodromal phase. Serum NfL levels were significantly increased in the prodromal phase compared with healthy controls (average difference 14.5, 95% CI 2.9 to 26.1 pg/mL), but lower than in patients with mild FTD (average difference -15.5, 95% CI -28.4 to -2.7 pg/mL). At 1-year follow-up, 51.2% of patients in the prodromal phase had converted to dementia. Serum NfL measurements at baseline were the strongest predictors of disease progression at 1-year follow-up (OR 1.07, 95% CI 1.03 to 1.11, p < 0.001). // Conclusions: Prodromal FTD is a mutable stage with high rate of progression to fully symptomatic disease at 1-year follow-up. High serum NfL levels may support prodromal FTD diagnosis and represent a helpful marker to assess disease progression

Cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia: a case report.

Cryptococcosis is an opportunistic infection, the incidence of which is increased in the immunocompromised patients. Cryptococcus neoformans is an encapsulated fungus that mainly infects the lungs and the central nervous system, possibly involving different organs. Cutaneous cryptococcosis is classified into localized infection, usually occurring after traumatic inoculation (primary cutaneous cryptococcosis) and cutaneous manifestation due to hematogenous dissemination (secondary cutaneous cryptococcosis), mostly in patients with underlying immunosuppression. We report a case of cutaneous cryptococcosis in a patient affected by chronic lymphocytic leukaemia