8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder

neurogenetics - A de novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis....     

Medial Prefrontal Cortex Has a Causal Role in Selectively Enhanced Consolidation of Emotional Memories after a 24-Hour Delay: A TBS Study

Previous research points to an association between retrieval-related activity in the medial prefrontal cortex (mPFC) and preservation of emotional information compared with co-occurring neutral information following sleep. Although the role of the mPFC in emotional memory likely begins at encoding, little research has examined how mPFC activity during encoding interacts with consolidation processes to enhance emotional memory. This issue was addressed in the present study using transcranial magnetic stimulation in conjunction with an emotional memory paradigm. Healthy young adults encoded negative and neutral scenes while undergoing concurrent TMS with a modified short intermittent theta burst stimulation (sTBS) protocol. Participants received stimulation to either the mPFC or an active control site (motor cortex) during the encoding phase. Recognition memory for scene components (objects and backgrounds) was assessed after a short delay (30 min) and a long delay [24 h (including a night of sleep)] to obtain measures of specific and gist-based memory processes. The results demonstrated that, relative to control stimulation, sTBS to the mPFC enhanced memory for negative objects on the long delay test (collapsed across specific and gist-based memory measures). mPFC stimulation had no discernable effect on memory for objects on the short delay test nor on the background images at either test. These results suggest that mPFC activity occurring during encoding interacts with consolidation processes to preferentially preserve negatively salient information.SIGNIFICANCE STATEMENT Understanding how emotional information is remembered over time is critical to understanding memory in the real world. The present study used noninvasive brain stimulation [repetitive transcranial magnetic stimulation (rTMS)] to investigate the interplay between mPFC activity that occurs during memory encoding and its subsequent interactions with consolidation processes. rTMS delivered to the mPFC during encoding enhanced memory for negatively valenced pictures on a test following a 24 h delay, with no such effect on a test occurring shortly after the encoding phase. These results are consistent with the hypothesis that emotional aspects of memories are differentially subjected to consolidation processes, and that the mPFC might contribute to this “tag-and-capture” mechanism during the initial formation of such memories.     

Mortality and revision rate of cemented and uncemented hemiarthroplasty after hip fracture: an analysis of the Dutch Arthroplasty Register (LROI)

Background and purpose — Femoral neck fractures are commonly treated with cemented or uncemented hemiarthroplasties (HA). We evaluated differences in mortality and revision rates in this fragile patient group.Patients and methods — From January 1, 2007 until December 31, 2016, 22,356 HA procedures from the Dutch Arthroplasty Register (LROI) were included. For each HA, follow-up until death, revision, or end of follow-up (December 31, 2016) was determined. The crude revision rate was determined by competing risk analysis. Multivariable Cox regression analyses were performed to evaluate the effect of fixation method (cemented vs. uncemented) on death or revision. Age, sex, BMI, Orthopaedic Data Evaluation Panel (ODEP) rating, ASA grade, surgical approach, and previous surgery were included as potential confounders.Results — 1-year mortality rates did not differ between cemented and uncemented HA. 9-year mortality rates were 53% (95% CI 52–54) in cemented HA compared to 56% (CI 54–58) in uncemented HA. Multivariable Cox regression analysis showed similar mortality between cemented and uncemented HA (HR 1.0, CI 0.96–1.1). A statistically significantly lower 9-year revision rate of 3.1% (CI 2.7–3.6) in cemented HA compared with 5.1% (CI 4.2–6.2) in the uncemented HA was found with a lower hazard ratio for revision in cemented compared with uncemented HA (HR 0.56, CI 0.47–0.67).Interpretation — Long-term mortality rates did not differ between patients with a cemented or uncemented HA after an acute femoral neck fracture. Revision rates were lower in cemented compared with uncemented HA.

The number of hemiarthroplasties (HA) after displaced femoral neck fracture increases as a result of global aging, and inferior results and high risk of reoperation after internal fixation. Although the literature on the decision to use cemented or uncemented HA may favor a cemented implant, both techniques are currently used. The use of bone cement is associated with bone cement implantation syndrome (BCIS) characterized by hypoxia, hypotension, loss of consciousness around the time of bone cementation, and intraoperative death (Olsen et al. 2014, Rutter et al. 2014). More intraoperative complications including intraoperative death were found in cemented HA in the Norwegian register (Gjertsen et al. 2012, Talsnes et al. 2013). However, no differences in mortality were found after 1 week (Costain et al. 2011, Yli-Kyyny et al. 2014). More studies including randomized controlled trials (Deangelis et al. 2012, Taylor et al. 2012) and registry studies (Costa et al. 2011, Ekman et al. 2019) did not show differences in mortality between cemented and uncemented HA. Randomized controlled trials (Taylor et al. 2012, Langslet et al. 2014, Inngul et al. 2015) and register studies (Gjertsen et al. 2012, Yli-Kyyny et al. 2014) have shown that the use of uncemented implants could result in a higher risk of periprosthetic fractures. A meta-analysis by Li et al. (2013) concluded that differences in several outcome parameters indicated cemented hemiarthroplasty to be superior to the uncemented counterpart. However, a serious flaw in this analysis is that several studies were included using an outdated stem like the Austin Moore (Sonne-Holm et al. 1982, Emery et al. 1991, Parker et al. 2010) and the experimental uncemented Thomson stem (Sadr and Arden 1977). The use of a prosthesis without Orthopaedic Data Evaluation Panel (ODEP) rating > 3A could influence outcome and is therefore discouraged (Grammatopoulos et al. 2015). A recent review by Rogmark and Leonardsson (2016) included 5 randomized studies comparing modern uncemented and cemented hemiarthroplasties. They found no differences in mortality, but more periprosthetic fractures in uncemented cases. We compared cemented and uncemented HA after an acute hip fracture with primary outcome mortality and revision rate. Data from the Dutch Arthroplasty Register (LROI) were used and the cohort of cemented HAs was compared with uncemented HAs, accounting for the ODEP rating and other confounders.     

Management of a large post-traumatic skin and bone defect using an Ilizarov frame

The authors report the case of a 28-year old male who presented with a compound diaphyseal fracture of the tibia, which was treated with intramedullary nailing. Postoperatively he required an extensive fasciotomy for an acute compartment syndrome. The fracture evolved towards post-traumatic osteomyelitis, growing methicillin-resistant Staphylococcus aureus (MRSA), combined with a large overlying soft tissue gap. An Ilizarov frame was used to treat both the bone and the skin defect. The infected fracture was treated by resection and longitudinal bone transport. Meanwhile, the skin was gradually closed using extra rods on the frame, allowing for a transverse 'skin transport'. Both the bone and the soft tissues healed without further complications.     

Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers

Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE‐preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 ± 2 and 34 ± 6 mmol potassium and took up 25 ± 9 and 24 ± 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE‐preserved livers took up a mean of 19 ± 3 mmol potassium, while controls released 8 ± 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE‐preserved livers while levels increased after reperfusion of SCS‐preserved liver, delta potassium levels were ‐0.77 ± 0.20 vs. +0.64 ± 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS‐preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient.     

The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP,Not Pyrophosphate

The plasma membrane protein ankylosis homologue (ANKH, mouse ortholog: Ank) prevents pathological mineralization of joints by controlling extracellular levels of the mineralization inhibitor pyrophosphate (PPi). It was long thought that ANKH acts by transporting PPi into the joints. We recently showed that when overproduced in HEK293 cells, ANKH mediates release of large amounts of nucleoside triphosphates (NTPs), predominantly ATP, into the culture medium. ATP is converted extracellularly into PPi and AMP by the ectoenzyme ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We could not rule out, however, that cells also release PPi directly via ANKH. We now addressed the question of whether PPi leaves cells via ANKH using HEK293 cells that completely lack ENPP1. Introduction of ANKH in these ENPP1-deficient HEK293 cells resulted in robust cellular ATP release without the concomitant increase in extracellular PPi found in ENPP1-proficient cells. Ank activity was previously shown to be responsible for about 75% of the PPi found in mouse bones. However, bones of Enpp1^−/− mice contained <2.5% of the PPi found in bones of wild-type mice, showing that Enpp1 activity is also a prerequisite for Ank-dependent PPi incorporation into the mineralized bone matrix in vivo. Hence, ATP release precedes ENPP1-mediated PPi formation. We find that ANKH also provides about 25% of plasma PPi, whereas we have previously shown that 60% to 70% of plasma PPi is derived from the NTPs extruded by the ABC transporter, ABCC6. Both transporters that keep plasma PPi at sufficient levels to prevent pathological calcification therefore do so by extruding NTPs rather than PPi itself. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Altered movement during single leg hop test after ACL reconstruction: implications to incorporate 2-D video movement analysis for hop tests

Purpose

There is a lack of objective factors which can be used in guiding the return to sport (RTS) decision after an anterior cruciate ligament reconstruction (ACLR). The purpose of the current study was to conduct qualitative analysis of the single leg hop (SLH) in patients after ACLR with a simple and clinical friendly method and to compare the possible difference in movement pattern between male and female patients.

Methods

Sixty-five patients performed the single leg hop (SLH) test at 6.8?±?1.0 months following isolated ACLR. Digital video camcorders recorded frontal and sagittal plane views of the patient performing the SLH. Knee flexion at initial contact (IC), peak knee flexion, knee flexion range of motion (RoM), and knee valgus RoM were calculated. In addition, limb symmetry index (LSI) scores were calculated.

Results

No differences were found in movement pattern between males and females. Movement analysis revealed that males had a decrease in knee flexion at IC (p?=?0.018), peak knee flexion (p?=?0.002), and knee flexion RoM (p?=?0.017) in the injured leg compared to the non-injured leg. Females demonstrated a decrease in peak knee flexion (p?=?0.011) and knee flexion RoM (p?=?0.023) in the injured leg compared to the non-injured leg. Average LSI scores were 92.4% for males and 94.5% for females.

Conclusions

Although LSI scores were >?90%, clinical relevant altered movement patterns were detected in the injured leg compared to the non-injured leg. Caution is warranted to solely rely on LSI scores to determine RTS readiness.

Clinical trial registry name and registration

The University of Groningen, ID 2012.362.

Level of evidence

III.

     

Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease

Purpose

The cannabinoid type 2 receptor (CB₂R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB₂R is primarily found on microglia. CB₂R upregulation has been reported in animal models of Alzheimer’s disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB₂R tracer [¹¹C]NE40 in healthy controls (HC) and in patients with Alzheimer’s disease (AD) to investigate whether higher CB₂R availability regionally colocalized to Aβ deposits is present in vivo.

Methods

Dynamic 90-min [¹¹C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [¹¹C]PIB scan 40 min after injection. In four HC, a retest scan with [¹¹C]NE40 PET was performed within 9 weeks to investigate test–retest characteristics.

Results

[¹¹C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time–activity curves best; both binding potential (BP_ND) and distribution volume (V _T) parameters could be used. Brain uptake was generally low with an average K ₁ value of 0.07 ml/min/ml tissue. V _T and BP_ND were in the range of 0.7 – 1.8 and 0.6 – 1.6, respectively. Test values in HC were about 30 % for V _T and BP_ND. AD patients showed overall significantly lower CB₂R binding. No relationship was found between regional or global amyloid load and CB₂R availability.

Conclusion

Kinetic modelling of [¹¹C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [¹¹C]NE40 PET shows lower CB₂R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [¹¹C]NE40 binds to CB₂R with lower affinity and/or selectivity than to CB₁R.

     

Long-Term Results from the MAJESTIC Trial of the Eluvia Paclitaxel-Eluting Stent for Femoropopliteal Treatment: 3-Year Follow-up

Purpose

To report the 3-year results of the MAJESTIC first-in-human study of the Eluvia Drug-Eluting Vascular Stent System for treating femoropopliteal artery lesions.

Methods

The prospective, single-arm, multicenter clinical trial enrolled 57 patients with symptomatic lower limb ischemia (Rutherford category 2, 3, or 4) and lesions in the superficial femoral artery or proximal popliteal artery. Mean lesion length was 70.8 ± 28.1 mm, and 46% of lesions were occluded. Efficacy measures at 2 years included primary patency, defined as duplex ultrasound peak systolic velocity ratio of ≤2.5 and the absence of target lesion revascularization (TLR) or bypass. Safety monitoring through 3 years included adverse events and TLR.

Results

Primary patency was estimated as 83.5% (Kaplan–Meier analysis) at 24 months, and 90.6% (48/53) of patients maintained an improvement in Rutherford class. At 36 months, the Kaplan–Meier estimate of freedom from TLR was 85.3%. No stent fractures were identified, and no major target limb amputations occurred.

Conclusion

MAJESTIC results demonstrated long-term treatment durability among patients whose femoropopliteal arteries were treated with the paclitaxel-eluting Eluvia stent.

Level of Evidence

Level 2b, cohort study

     

Artefacts induced by coiled intracranial aneurysms on 3.0-Tesla versus 1.5-Tesla MR angiography—An in vivo and in vitro study

Objective

To compare metal-induced artefacts from coiled intracranial aneurysms on 3.0-Tesla and 1.5-Tesla magnetic resonance angiography (MRA), since concerns persist on artefact enlargement at 3.0 Tesla.

Materials and methods

We scanned 19 patients (mean age 53; 16 women) with 20 saccular aneurysms treated with coils only, at 1.5 and 3.0 Tesla according to standard clinical 3D TOF-MRA protocols containing a shorter echo-time but weaker read-out gradient at 3.0 Tesla in addition to intra-arterial digital subtraction angiography (IA-DSA). Per modality two neuro-radiologists assessed the occlusion status, measured residual flow, and indicated whether coil artefacts disturbed this assessment on MRA. We assessed relative risks for disturbance by coil artefacts, weighted kappa's for agreement on occlusion levels, and we compared remnant sizes. For artefact measurements, a coil model was created and scanned with the same protocols followed by 2D MR scans with variation of echo-time and read-out gradient strength.

Results

Coil artefacts disturbed assessments less frequently at 3.0 Tesla than at 1.5 Tesla (RR: 0.3; 95%CI: 0.1–0.8). On 3.0-Tesla MRA, remnants were larger than on 1.5-Tesla MRA (difference: 0.7 mm; 95%CI: 0.3–1.1) and larger than on IA-DSA (difference: 1.0 mm; 95%CI: 0.6–1.5) with similar agreement on occlusion levels with IA-DSA for both field strengths (κ 0.53; 95%CI: 0.23–0.84 for 1.5-Tesla MRA and IA-DSA; κ 0.47; 95%CI: 0.19–0.76 for 3.0-Tesla MRA and IA-DSA). Coil model artefacts were smaller at 3.0 Tesla than at 1.5 Tesla. The echo-time influenced artefact size more than the read-out gradient.

Conclusions

Artefacts were not larger, but smaller at 3.0 Tesla because a shorter echo-time at 3.0 Tesla negated artefact enlargement. Despite smaller artefacts and larger remnants at 3.0 Tesla, occlusion levels were similar for both field strengths.