Glances in Immunology of HIV and HCV Infection

Since the identification of HIV and HCV much progress has been made in the understanding of their life cycle and interaction with the host immune system. Despite these viruses markedly differ in their virological properties and in their pathogenesis, they share many common features in their immune escape and survival strategy. Both viruses have developed sophisticated ways to subvert and antagonize host innate and adaptive immune responses. In the last years, much effort has been done in the study of the AIDS pathogenesis and in the development of efficient treatment strategies, and a fatal infection has been transformed in a potentially chronic pathology. Much of this knowledge is now being transferred in the HCV research field, especially in the development of new drugs, although a big difference still remains between the outcome of the two infections, being HCV eradicable after treatment, whereas HIV eradication remains at present unachievable due to the establishment of reservoirs. In this review, we present current knowledge on innate and adaptive immune recognition and activation during HIV and HCV mono-infections and evasion strategies. We also discuss the genetic associations between components of the immune system, the course of infection, and the outcome of the therapies

Interdipendenza regionale: un nuovo modello valutativo-interpretativo. Le relazioni tra anca e cingolo pelvico--revisione sistematica della letteratura

Obiettivo: valutare l’effetto del tilt pelvico rispetto all’antiversione del collo femorale, all’antiversione dell’acetabolo e all’adattamento dell’anca nei tre piani dello spazio secondo il concetto dell’interdipendenza regionale. Metodi: si sono scelti gli studi conformi con il P.E.O di ricerca: Popolazione = tutti, Esposizione = modificazioni del tilt pelvico, Outcome = aumento/diminuzione dell’antiversione dell’acetabolo, del collo femorale e del rom dell’anca nei tre piani dello spazio. Risultati: otto studi sono stati suddivisi in tre gruppi: Il primo gruppo permette di osservare l’effetto del tilt pelvico rispetto all’antiversione dell’acetabolo e alla mobilità dell’anca, facendo emergere che la retroversione del bacino aumenta l’antiversione acetabolare e l’estensione dell’anca. Nel secondo gruppo è stato evidenziato che l’aumento dell’antiversione femorale porta ad una rotazione interna dell’anca più pronunciata durante il cammino, ad una diminuzione dei bracci di leva abduttivi e ad un aumento delle forze di contatto. Il terzo gruppo di studio non ha riportato nessuna relazione tra antiversione femorale e acetabolare nei soggetti affetti da coxartrosi. D’altro canto, è possibile che la correlazione ricercata non sia stata trovata proprio perché il campione esaminato in questo studio presentava coxartrosi, elemento che potrebbe essere espressione di un non corretto adattamento tra anca e bacino. Conclusioni: la retroversione del bacino aumenta l’antiversione acetabolare e l’estensione dell’anca; l'aumento dell'antiversione del collo femorale è comunemente associato ad una maggiore rotazione interna dell'anca sia in stazione eretta che durante l'andatura, agendo come strategia compensativa per la diminuzione dei bracci di leva dei muscoli abduttori dell'anca. Non ci sono elementi per trarre conclusioni sulla relazione tra il grado di versione del bacino, l’antiversione del collo femorale e la mobilità dell’anca nel piano orizzontale e frontale

Review Article Glances in Immunology of HIV and HCV Infection

Since the identification of HIV and HCV much progress has been made in the understanding of their life cycle and interaction with the host immune system. Despite these viruses markedly differ in their virological properties and in their pathogenesis, they share many common features in their immune escape and survival strategy. Both viruses have developed sophisticated ways to subvert and antagonize host innate and adaptive immune responses. In the last years, much effort has been done in the study of the AIDS pathogenesis and in the development of efficient treatment strategies, and a fatal infection has been transformed in a potentially chronic pathology. Much of this knowledge is now being transferred in the HCV research field, especially in the development of new drugs, although a big difference still remains between the outcome of the two infections, being HCV eradicable after treatment, whereas HIV eradication remains at present unachievable due to the establishment of reservoirs. In this review, we present current knowledge on innate and adaptive immune recognition and activation during HIV and HCV mono-infections and evasion strategies. We also discuss the genetic associations between components of the immune system, the course of infection, and the outcome of the therapies

Observed Differences between Males and Females in Surgically Treated Carpal Tunnel Syndrome Among Non-manual Workers: A Sensitivity Analysis of Findings from a Large Population Study

Objectives: We aimed at assessing whether differences among males and females in carpal tunnel syndrome (CTS) epidemiology might be attributable to segregation with respect to occupational biomechanical exposures or differential access to care by sex. Methods: We analysed surgically treated cases of CTS occurring among non-manual workers in Tuscany between 1997 and 2000. We conducted a Monte Carlo simulation to estimate the difference in occupational biomechanical exposures between males and females necessary to explain the observed incidence rate ratios. We also accounted for the sex-specific probability of receiving surgery after the diagnosis of CTS, as women were reported to be more likely to undergo surgery in a subset of our study population. We quantified the hypothetical biomechanical overload through the hand activity level (HAL) metric proposed by the American Conference of Governmental Industrial Hygienists. To quantify the effect of HAL on CTS risk, we assumed a prior distribution based on findings from two large cohort studies of industrial workers. Results: After adjustment for the probability of receiving surgery, women showed a 4-fold incidence of CTS as compared with men. To explain this association among non-manual workers, women should have an average value of HAL at least 5 points higher. Conclusions: Our analysis does not support the hypothesis that the difference in CTS incidence between males and females is entirely attributable to occupational risk factors or to differential access to surgery. The causal pathway between sex and CTS might include more determinants such as hormonal factors, anthropometric characteristics, and non-occupational exposure to biomechanical overload (e.g. household tasks)

Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms

Statins and histone deacetylase inhibitors affect lamin A/C - histone deacetylase 2 interaction in human cells

We recently identified lamin A/C as a docking molecule for human histone deacetylase 2 (HDAC2) and showed involvement of HDAC2-lamin NC complexes in the DNA damage response. We further showed that lamin NC-HDAC2 interaction is altered in Hutchinson-Gilford Progeria syndrome and other progeroid laminopathies. Here, we show that both inhibitors of lamin A maturation and small molecules inhibiting HDAC activity affect lamin NC interaction with HDAC2. While statins, which inhibit prelamin A processing, reduce protein interaction, HDAC inhibitors strengthen protein binding. Moreover, treatment with HDAC inhibitors restored the enfeebled lamin NC-HDAC2 interaction observed in HGPS cells. Based on these results, we propose that prelamin A levels as well as HDAC2 activation status might influence the extent of HDAC2 recruitment to the lamin A/C-containing platform and contribute to modulate HDAC2 activity. Our study links prelamin A processing to HDAC2 regulation and provides new insights into the effect of statins and histone deacetylase inhibitors on lamin NC functionality in normal and progeroid cells

Statins and Histone Deacetylase Inhibitors Affect Lamin A/C – Histone Deacetylase 2 Interaction in Human Cells

We recently identified lamin A/C as a docking molecule for human histone deacetylase 2 (HDAC2) and showed involvement of HDAC2-lamin A/C complexes in the DNA damage response. We further showed that lamin A/C-HDAC2 interaction is altered in Hutchinson-Gilford Progeria syndrome and other progeroid laminopathies. Here, we show that both inhibitors of lamin A maturation and small molecules inhibiting HDAC activity affect lamin A/C interaction with HDAC2. While statins, which inhibit prelamin A processing, reduce protein interaction, HDAC inhibitors strengthen protein binding. Moreover, treatment with HDAC inhibitors restored the enfeebled lamin A/C-HDAC2 interaction observed in HGPS cells. Based on these results, we propose that prelamin A levels as well as HDAC2 activation status might influence the extent of HDAC2 recruitment to the lamin A/C-containing platform and contribute to modulate HDAC2 activity. Our study links prelamin A processing to HDAC2 regulation and provides new insights into the effect of statins and histone deacetylase inhibitors on lamin A/C functionality in normal and progeroid cells

dysferlin in a hyperckaemic patient with caveolin 3 mutation and in c2c12 cells after p38 map kinase inhibition

Dysferlin is a plasma membrane protein of skeletal muscle whose deficiency causes Miyoshi myopathy, limb girdle muscular dystrophy 2B and distal anterior compartment myopathy. Recent studies have reported that dysferlin is implicated in membrane repair mechanism and coimmunoprecipitates with caveolin 3 in human skeletal muscle. Caveolin 3 is a principal structural protein of caveolae membrane domains in striated muscle cells and cardiac myocytes. Mutations of caveolin 3 gene (CAV3) cause different diseases and where caveolin 3 expression is defective, dysferlin localization is abnormal. We describe the alteration of dysferlin expression and localization in skeletal muscle from a patient with raised serum creatine kinase (hyperCKaemia), whose reduction of caveolin 3 is caused by a CAV3 P28L mutation. Moreover, we performed a study on dysferlin interaction with caveolin 3 in C2C12 cells. We show the association of dysferlin to cellular membrane of C2C12 myotubes and the low affinity link between dysferlin and caveolin 3 by immunoprecipitation techniques. We also reproduced caveolinopathy conditions in C2C12 cells by a selective p38 MAP kinase inhibition with SB203580, which blocks the expression of caveolin 3. In this model, myoblasts do not fuse into myotubes and we found that dysferlin expression is reduced. These results underline the importance of dysferlin-caveolin 3 relationship for skeletal muscle integrity and propose a cellular model to clarify the dysferlin alteration mechanisms in caveolinopathies

Failure of lamin A/C to functionally assemble in R482L mutated familial partial lipodystrophy fibroblasts: altered intermolecular interaction with emerin and implications for gene transcription

Familial partial lipodystrophy is an autosomal dominant disease caused by mutations of the LMNA gene encoding alternatively spliced lamins A and C. Abnormal distribution of body fat and insulin resistance characterize the clinical phenotype. In this study, we analyzed primary fibroblast cultures from a patient carrying an R482L lamin A/C mutation by a morphological and biochemical approach. Abnormalities were observed consisting of nuclear lamin A/C aggregates mostly localized close to the nuclear lamina. These aggregates were not bound to either DNA-containing structures or RNA splicing intranuclear compartments. In addition, emerin did not colocalize with nuclear lamin A/C aggregates. Interestingly, emerin failed to interact with lamin A in R482L mutated fibroblasts in vivo, while the interaction with lamin C was preserved in vitro, as determined by coimmunoprecipitation experiments. The presence of lamin A/C nuclear aggregates was restricted to actively transcribing cells, and it was increased in insulin-treated fibroblasts. In fibroblasts carrying lamin A/C nuclear aggregates, a reduced incorporation of bromouridine was observed, demonstrating that mutated lamin A/C in FPLD cells interferes with RNA transcription