Prosthetic Impingement in Total Hip Arthroplasty—The Trigger for Adverse Wear

Development of total hip arthroplasty (THA) now spans more than 5 decades encompassing combinations of metal-on-metal (MOM), ceramic-on-metal (COM), metal-on-plastic (MOP), ceramic-on-plastic (COM), and ceramic-on-ceramic (COC). In every arena of extensive technical development, there exists a data set that when viewed in isolation seemed of little import, but when assembled in-toto may produce a generational shift in perception. Our review focused on two such THA events. Firstly, COC retrieval studies (1999-2001) noted habitual wear patterns on heads and peripheral wear stripes, along with femoral-neck impingement, and ceramic surfaces stained gray by metal debris. These COC data indicated THA risks included, 1) cup edge-loading (E/L) on heads producing “stripe wear”, 2) component impingement releasing metal particles resulting in 3) tissues contaminated by metal debris. A corresponding MOM impingement-debris mechanism was only perceived by Howie (2005) in a McKee-Farrar retrieval study. Our anticipation at LLUMC was that MOM retrievals would provide superior wear details to those seen on COC retrievals. We noted stripe wear in the polar zone of CoCr heads and basal stripes in the non-wear areas. The basal-polar stripe combinations were found in all MOM retrievals. Basal-polar stripe combinations followed cup-rim profiles in our LLUMC simulations of prosthetic impingement. LPUH videos demonstrated the formation of stripe wear in functional-standing and functional-sitting postures for both impingement and subluxation episodes using THA and RA designs. The stripes on CoCr heads revealed the large scratches we now term “microgrooves”. Microgroove width varied from 40 - 400 um with 100 um being typical. The longitudinal striations in microgrooves, the raised jagged lips, scratches with shallow entry and exit termini, were all indicative of a classic 3rd-body wear mechanism. The THA impingement simulations denoted four sites of edge-loading, i.e. neck-E/L, inferior cup-E/L, superior cup-E/l and head-E/L, and ingress of Ti64 particles as a contaminating-roughness effect. Individual MOM cases referred to LLUMC demonstrated dramatic evidence of neck notching. At one end of the debris spectrum, a Ti64-notch model predicting a 6 mm3 annual wear-rate represented the release of 5700 particles of 126 um-size (approximating daily release of 16 particles). At the other end of the spectrum, if metal particles were crushed between MOM surfaces to the equivalent nanometer size found in tissues, our notch model represented approximately 22-trillion Ti64 particles annually deposited in tissues. The anatomical THA models represented in LPUH videos demonstrated that even 1-degree of head subluxation from a rigid cup created a cup “lift-off” scenario (CLO) that would open a gap of 250 - 400 microns between femoral head and cup. This would void all lubrication potential and focus the total hip-joint force along the beveled cup rim, i.e. stripe wear. It is therefore interesting that MOM impingement/debris predictions by Howie et al. have not been confirmed until now or discussed in contemporary literature. Therefore, this review of 50 years of THA data demonstrated that hip impingement was always the trigger for adverse wear and that metal-backed cups represent the potential for release of metal debris at extremes of functional standing and sitting postures.

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimi-zing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.

Subclinical proximal tubulopathy in hepatitis B:The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity,such as estimated glomerular filtration rate(eGFR)and phosphatemia,are late markers of proximal tubulopathy.Multiple early markers are available,but no consensus exists on their use.AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy(SPT),as defined with early biomarkers,in treated vs untreated hepatitis B virus(HBV)-monoinfected patients.METHODS A prospective,non-randomized,multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted.The patients were separated into three groups:Naïve,starting entecavir(ETV)treatment,or starting tenofovir disoproxil(TDF)treatment.Data on the early markers of SPT,the eGFR and phosphatemia,were collected quarterly.SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%.The prevalence and cumulative incidence of SPT at month 24(M24)were calculated.Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests,whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data.Multivariate analyses were used to adjust for any potential confounding factors.RESULTS Of the 196 patients analyzed,138(84 naïve,28 starting ETV,and 26 starting TDF)had no SPT at inclusion.At M24,the prevalence of SPT was not statistically different between naïve and either treated group(21.1%vs 30.7%,P<0.42 and 50.0%vs 30.7%,P=0.32 for ETV and TDF,respectively);no patient had an eGFR lower than 50 mL/min/1.73 m²or phosphatemia less than 0.48 mmoL/L.In the multivariate analysis,no explanatory variables were identified after adjustment.The cumulative incidence of SPT over 24 mo(25.5%,13.3%,and 52.9%in the naïve,ETV,and TDF groups,respectively)tended to be higher in the TDF group vs the naïve group(hazard ratio:2.283,P=0.05).SPT-free survival at M24 was 57.6%,68.8%,and 23.5%for the naïve,ETV,and TDF groups,respectively.The median survival time without SPT,evaluated only in the TDF group,was 5.9 mo.CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients.SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Hereditary spastic paraplegia type 56:what a mouse can tell-a narrative review

Hereditary spastic paraplegia type 56(SPG56-HSP)is a rare autosomal recessive disorder caused by loss of function mutations in CYP2U1,leading to an early-onset limbs spasticity,often complicated by additional neurological or extra-neurological manifestations.Given its low prevalence,the molecular bases underlying SPG56-HSP are still poorly understood,and effective treatment options are still lacking.Recently,through the generation and characterization of the SPG56-HSP mouse model,we were able to take few important steps forward in expanding our knowledge of the molecular background underlying this complex disease.Leveraging the Cyp2u1-/-mouse model we were able to identify several new diagnostics biomarkers(vitamin B2,coenzyme Q,neopterin,and interferon-alpha),as well as to highlight the key role played by the folate pathway in SPG56-HSP pathogenesis,providing a potential treatment option.In this review,we discuss the major role played by the Cyp2u1-/-model in dissecting clinical and biological aspects of the disease,opening the way to a series of new research paths ranging from clinical trials,biomarker testing,and to the expansion of the underlying genetic and molecular,emphasizing how basic mouse model characterization could contribute to advance research in the context of rare disorders.