Mitochondrial Transfer Ameliorates Cognitive Deficits, Neuronal Loss, and Gliosis in Alzheimer's Disease Mice.

Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer's disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-ß intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD.

Direct Transcatheter Valve Deployment via Sternotomy for Complex Aortic Valve Reoperation.

Reoperative aortic valve replacement is associated with increased morbidity. Valve-in-valve transcatheter aortic valve replacement offers a less invasive alternative to traditional reoperation. However, cases of valve failure after valve-in-valve transcatheter aortic valve replacement represent a complex surgical challenge. We present a case requiring a complex reoperative aortic valve replacement due to structural valve deterioration after multiple previous valve-in-valve transcatheter aortic valve replacements. We performed removal of 3 previous valve-in-valve transcatheter aortic valves, bioprosthetic leaflet excision, and intentional bioprosthetic fracture under direct vision for annular enlargement. This facilitated direct insertion of a new transcatheter aortic valve for expedient and successful management of recurrent aortic stenosis in a very high-risk patient. Creative use of leaflet excision, intentional bioprosthetic fracture, and insertion of a new transcatheter aortic valve under direct vision, proved efficient and successful in a high-risk patient with few surgical options.

Mutations in ERGIC1 cause Arthrogryposis multiplex congenita, neuropathic type.

Arthrogryposis multiplex congenita (AMC) is heterogeneous group of disorders characterized by non-progressive joint contractures from birth that involve more than 1 part of the body. There are various etiologies for AMC including genetic and environmental depends on the specific type, however, for most types, the cause is not fully understood. We previously reported large Israeli Arab kindred consisting of 16 patients affected with AMC neuropathic type, and mapped the locus to a 5.5 cM interval on chromosome 5qter. Using whole exome sequencing, we have now identified homozygous pathogenic variant in the ERGIC1 gene within the previously defined linked region. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. We further show that this mutation was absent in more than 200 samples of healthy unrelated individuals of the Israeli Arab population. Thus, our findings expand the spectrum of hereditary AMC and suggest that abnormalities in protein trafficking may underlie AMC-related disorders.

Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.

Septic Shock and Multiple Organ Failure After Office Endometrial Sampling.

BACKGROUND: Office endometrial biopsy with a Pipelle cannula is the main method for sampling the endometrial lining. The Pipelle biopsy is safe, efficient, and cost effective. This office endometrial sampling method is also an accurate and safe procedure for endometrial sampling of patients with endometrial carcinoma. It is associated with minimal pain and does not require anesthesia. CASE: Pipelle is the most common method used for sampling the endometrial lining. No data are available of infectious complications related to endometrial biopsy. The incidence is presumed to be negligible. We present an unusual case of a 52-year-old woman who experienced septic shock and multiple organ failure following Pipelle endometrial sampling. CONCLUSION: Lower abdominal pain is the cardinal presenting symptom in woman with pelvic infection. Our case emphasizes that an atypical symptom such as abdominal pain after endometrial biopsy could be a sign of infectious complications.

Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy.

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/ß-tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re-polymerization. Morpholino-mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone-associated tubulinopathy, and provide insights into the phenotype of this disorder.

SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum.

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

Standardization of radiological evaluation of dynamic contrast enhanced MRI: application in breast cancer diagnosis.

Dynamic contrast enhanced MRI is applied as an adjuvant tool for breast cancer detection, diagnosis, and follow-up of therapy. Despite improvements through the years in achieving higher spatial and temporal resolution, it still suffers from lack of scanning and processing standardization, and consequently, high variability in the radiological evaluation, particularly differentiating malignant from benign lesions. We describe here a hybrid method for achieving standardization of the radiological evaluation of breast dynamic contrast enhanced (DCE)-magnetic resonance imaging (MRI) protocols, based on integrating the model based three time point (3TP) method with principal component analysis (PCA). The scanning and image processing procedures consisted of three main steps: 1. 3TP standardization of the MRI acquisition parameters according to a kinetic model, 2. Applying PCA to test cases and constructing an eigenvectors' base related to the contrast-enhancement kinetics and 3. Projecting all new cases on the eigenvectors' base and evaluating the clinical outcome. Datasets of overall 96 malignant and 26 benign breast lesions were recorded on 1.5T and 3T scanners, using three different MRI acquisition parameters optimized by the 3TP method. The final radiological evaluation showed similar detection and diagnostic ability for the three different MRI acquisition parameters. The area under the curve of receiver operating characteristic analysis yielded a value of 0.88 ± 0.034 for differentiating malignant from benign lesions. This 3TP+PCA hybrid method is fast and can be readily applied as a computer aided diagnostic tool of breast cancer. The underlying principles of this method can be extended to standardize the evaluation of malignancies in other organs.

Outcomes of delayed sternal closure after complex aortic surgery.

OBJECTIVE: Open chest management during complex proximal aortic surgery may sometimes be necessary. Infectious complications such as mediastinitis and late aortic graft infection remain a concern. The objective of this study was to report our experience with open chest management and delayed sternal closure after complex proximal aortic surgery. METHODS: Between 1991 and 2007, 12 patients (1.2%, 12/1011) required open chest management and delayed sternal closure. Eight patients were men (67%), with a mean age of 56 years (range 28-83 years). Four cases involved redo-median sternotomy (33%) and seven cases (58%) involved acute dissection. All procedures were performed using total cardiopulmonary bypass with profound hypothermic circulatory arrest. Reasons for open chest management included hemodynamic instability, mediastinal edema, bleeding, and respiratory compromise. RESULTS: In-hospital mortality was 16.7% (2/12). Delayed sternal closure was achieved in 92% of patients (11/12). Mean time to closure was 3 days (range 1-9 days). Five patients (42%) required one or more mediastinal explorations prior to final closure. Mean length of stay was 51 days (range 1-186 days). Significant predictors of open chest management were pump time (p<0.0001) and intra-operative blood transfusions (p<0.002). Mean follow-up was 60 months (range 8-106 months). No patients developed mediastinitis or aortic graft infection during postoperative follow-up. CONCLUSIONS: Open chest management with delayed sternal closure after complex aortic repairs may be performed with acceptable mortality. Open chest management does not appear to increase the risk of infectious complications (mediastinitis or graft infections) during complex proximal aortic replacement.

Intraoperative skeletal muscle ischemia contributes to risk of renal dysfunction following thoracoabdominal aortic repair.

OBJECTIVE: Renal dysfunction is among the most commonly occurring morbidities following descending thoracic and thoracoabdominal aortic repair. We hypothesized that myoglobin nephrotoxicity might arise from leg ischemia caused by femoral artery cannulation, which is required for distal aortic perfusion. Lacking complete historical laboratory data on myoglobinemia, we studied somatosensory evoked potential (SSEP) changes in the leg (a functional marker of leg ischemia), as a surrogate predictor of acute postoperative renal failure. METHODS: Intraoperative leg SSEP function and preoperative glomerular filtration rate (GFR - an essential covariate) were available for 299 patients. Change in SSEP was defined as 10% increase in latency or 50% decrease in amplitude. Postoperative renal dysfunction was 1mg/dl/day increase in creatinine for 2 days, clinical diagnosis of ARF or need for dialysis postoperatively. RESULTS: Change in SSEP in the cannulated leg occurred in 108/299 (36%) of cases intraoperatively. All recovered normal SSEP function at decannulation. Patients with SSEP changes had 41/108 (38%) postoperative renal failure compared to 49/191 (26%) without (odds ratio 1.8, p<0.03). Modeled with GFR, aneurysm extent, and chronic obstructive pulmonary disease (COPD), SSEP changes had an adjusted odds ratio of 1.9, p<0.03. Pre-op GFR was also a highly significant predictor of postoperative renal failure (OR 0.98/ml; p<0.0001). CONCLUSION: This is the first study to show a relationship between intraoperative leg ischemia and postoperative renal failure. It provides epidemiological evidence that the ischemic leg may be an important contributor to rhabdomyolysis-like renal morbidity after thoracoabdominal aortic surgery.

Multilevel somatosensory evoked potentials and cerebrospinal proteins: indicators of spinal cord injury in thoracoabdominal aortic aneurysm surgery.

OBJECTIVE: Multilevel somatosensory evoked potentials (SSEP) and the release of biochemical markers in cerebrospinal fluid (CSF) were investigated to identify patients with spinal cord ischemia during thoracoabdominal aortic repair and/or a vulnerable spinal cord during the postoperative period. METHODS: Thirty-nine consecutive patients undergoing elective aneurysm repair using distal aortic perfusion and cerebrospinal fluid drainage were studied. Continuous SSEP were monitored using nerve stimulation of the right and left posterior tibial nerves with signal recording at the level of both common peroneal nerves, the cervical cord and at the cortical level. CSF concentrations of the markers glial fibrillary acidic protein (GFAp), the light subunit of neurofilament triplet protein (NFL), and S100B were determined at different time points from before surgery until 3 days postoperatively. RESULTS: SSEP indicated spinal cord ischemia in two patients leading to additional intercostal artery reattachments. In one of them the signal loss was permanent and the patient woke up with paraplegia. In the other the signal returned but the patient later developed delayed paraplegia. Three patients without SSEP indications of spinal cord ischemia during surgery later developed delayed paraplegia. The patients with spinal cord symptoms had significant increases, during the postoperative period of CSF biomarkers GFAp (571-fold), NFL (14-fold) and S100B (18-fold) compared to asymptomatic patients. GFAp increased before or in parallel to onset of symptoms in the patients with delayed paraplegia. CONCLUSIONS: Peroperative multilevel SSEP has a high specificity in detecting spinal cord ischemia but does not identify all patients with a postoperative vulnerable spinal cord. Biochemical markers in CSF increase too late for intraoperative monitoring but GFAp is promising for identifying patients at risk for postoperative delayed paraplegia.

Update on outcomes of acute type B aortic dissection.

BACKGROUND: The optimal treatment of acute type B aortic dissection remains controversial. This study reports early clinical outcomes of medical management for acute type B aortic dissection. METHODS: Between January 2001 and April 2006, data on 159 consecutive patients (55 women [35%]) with the confirmed diagnosis of acute type B aortic dissection were prospectively collected and analyzed. Mean age was 62 years (range, 29 to 94). On admission, all patients were initiated on an acute type B aortic dissection protocol with the intent to manage all patients medically. Indications for surgical intervention included rupture, aortic expansion, retrograde dissection, malperfusion (visceral, peripheral), and intractable pain. All patients were followed up after discharge with serial clinical and radiographic examinations. RESULTS: Overall hospital mortality was 8.8% (14/159): 17% (4/23) with procedural intervention, and 7.4% (10/136) when medical management was maintained. Early intervention was required in 23 patients (14.5%), of which 21 (13.2%) were open vascular/aortic procedures, and two (1.3%) were percutaneous aortic interventions. Morbidity included rupture (5.0%), stroke (5.0%), paraplegia (8.2%), bowel ischemia (5.7%), acute renal failure (20.1%), dialysis requirement (13.8%), and peripheral ischemia (3.8%). Mortality associated with complicated dissection (74/159) was 17%, and mortality associated with uncomplicated dissection (85/159) was 1.2% (p < 0.0003). Late vascular related procedures were performed in 11 (7.6%) of 144 cases (9 aortic, 2 peripheral vascular). The only independent risk factors for hospital mortality by multiple logistic regression analysis was rupture (p < 0.0009). Independent risk factors for mid-term death were history of chronic obstructive pulmonary disease (p < 0.002) and glomerular filtration rate at admission (p < 0.0001). CONCLUSIONS: Medical management, especially for uncomplicated acute type B aortic dissection, is associated acceptable outcomes. This study provides current data for initial medical management of acute type B aortic dissection. Alternative strategies for the treatment of acute Type B aortic dissection should be compared with these results.

Acute type A aortic dissection complicated by stroke: can immediate repair be performed safely?

OBJECTIVE: Emergency surgical intervention for acute type A aortic dissection complicated by stroke remains controversial. The urgency of immediate repair in this setting is tempered by the concern that cerebral reperfusion may worsen neurologic outcome. The purpose of this study was to report and analyze our results with acute type A aortic dissection complicated by stroke. METHODS: Between September 1999 and March 2005, 151 consecutive patients presented with acute type A aortic dissection. Of this group, 16 (10.6%) patients had sustained a preoperative stroke. Mean age was 56 years (range 43-73 years), with 6 (38%) women. Right hemispheric, left hemispheric, and bilateral strokes occurred in 81%, 13%, and 6%, respectively. Computed tomographic scan or transesophageal echocardiography diagnosed aortic dissection; clinical examination, computed tomographic scan, or transcranial Doppler ultrasound diagnosed stroke. Aortic repair was performed with cardiopulmonary bypass, profound hypothermic circulatory arrest, and retrograde cerebral perfusion. One patient with complete neurologic devastation (coma) was not operated on. RESULTS: Overall hospital mortality was 18.8% (3/16). Mortality in 2 patients who did not undergo surgery (1 patient who was neurologically devastated, and 1 patient whose aorta ruptured while awaiting surgery) was 100% (2/2). Operative mortality was 7% (1/14). Among patients undergoing surgery, neurologic status completely recovered in 2 (14%) patients, improved in 6 (43%) patients, remained the same in 6 (43%) patients, and worsened in none. Median time from onset of stroke to surgery was 9 hours (range 1-240 hours). Eighty percent of patients who underwent surgical repair within 10 hours had improvement in neurologic status, where as none operated on beyond 10 hours improved (P < .02). CONCLUSIONS: In our experience, surgical repair of acute type A aortic dissection can be performed in the setting of preoperative stroke with acceptable mortality. Moreover, no worsening of neurologic condition was observed after surgical repair. Immediate surgical repair is warranted even if acute type A aortic dissection is complicated by stroke.

The hybrid elephant trunk procedure: a single-stage repair of an ascending, arch, and descending thoracic aortic aneurysm.

Surgical repair of extensive aortic aneurysms requires a two-stage approach. We present the case of a single-stage repair using a hybrid procedure. This case demonstrates the technical feasibility of repairing properly selected extensive aortic aneurysms in a single procedure.

Outcomes of medical management of acute type B aortic dissection.

BACKGROUND: Currently, the optimal treatment of acute type B aortic dissection remains controversial. The purpose of this study was to report early clinical outcomes of medical management for acute type B aortic dissection. METHODS AND RESULTS: Between January 2001 and March 2005, 129 consecutive patients with the confirmed diagnosis of acute type B aortic dissection were studied. Mean age was 61 years (range, 29 to 94), with 33.3% (43/129) female. Acute type B aortic dissection protocol was instituted with the intent to manage all patients medically. Indications for surgical intervention included rupture, aortic expansion, malperfusion, and intractable pain. All patients were followed-up after discharge. Hospital mortality was 10.1% (13/129), 19% (4/21) when vascular intervention was required, and 8.3% (9/108) when medical management was maintained. Early intervention was required in 21 cases (16.2%), 19 (14.7%) open vascular/aortic cases and 2 cases (1.6%) of percutaneous aortic interventions. Morbidity included rupture (4.7%), stroke (4.7%), paraplegia (8.5%), bowel ischemia (7%), acute renal failure (21%), dialysis requirement (13%), and peripheral ischemia (4.7%). Late vascular-related procedures were performed in 5.2% (6/116) of cases. Univariate risk factors for early mortality were rupture (P<0.0001), need for laparotomy (P<0.008), acute renal failure (P<0.0001), need for dialysis (P<0.0001), and lower extremity ischemia (P<0.0004). The only independent risk factors for hospital mortality by multiple logistic regression was rupture (P<0.0009), and independent risk factors for midterm death were history of chronic obstructive pulmonary disease (P<0.002) and low glomerular filtration rate (<57 mL/min; P<0.0001). CONCLUSIONS: Medical management for acute type B aortic dissection is associated acceptable outcomes. Outcomes of other management strategies, eg, endovascular stenting, for acute type B aortic dissection need to be compared with these results.

Cochlear nerve size evaluation in children with sensorineural hearing loss by high-resolution magnetic resonance imaging.

PURPOSE: To determine differences in size of cochlear nerves among subjects with deafness due to connexin 26 (Cx26) mutations, subjects with deafness of unknown origin, and normal hearing subjects by sagittal high-resolution magnetic resonance (HRMR) imaging of the temporal bone. MATERIALS AND METHODS: Cross-sectional and surface areas and volumetric measurements of the cochlear nerve and modiolus were made on HRMR images of the internal auditory canal (IAC) and inner ear in the 3 groups of children (groups 1, 2, and 3). Three-way comparisons of in vivo cochlear nerve measurements on HRMR imaging were made among 17 children with sensorineural hearing loss (SNHL) and no obvious etiology for the hearing loss (group 1), 7 children with profound SNHL due to a Cx26 mutation (group 2), and 10 normal hearing children (group 3). RESULTS: Children with profound SNHL of unknown cause and children with profound SNHL due to a connexin mutation displayed hypoplastic cochlear nerves as compared with normal controls. HRMR imaging of the temporal bone was accurately delineated potential problems with cochlear nerves in 2 of 17 instances where high-resolution computed tomography did not do so. CONCLUSIONS: Accurate and specific measurements of the cochlear nerve and related structures is possible on HRMR imaging of the temporal bone. The size of the cochlear nerve is mildly hypoplastic in children with profound SNHL of unknown causes or children with a deafness-causing Cx26 mutation. HRMR imaging is superior to high-resolution computed tomography in the investigation of profound SNHL in children.

Robotic replacement of the descending thoracic aorta: an alternative to endovascular therapy?

BACKGROUND: : Replacement of the descending thoracic aorta is traditionally performed via a left thoracotomy. Endovascular treatment of descending thoracic aortic aneurysms has recently evolved as an alternative treatment for selected patients, yet no long-term results are available. The authors replaced the descending thoracic aorta in a group of pigs with an interposition Dacron graft using a closed-chest, totally robotic technique. METHODS: : Ten pigs, weighing 25 to 45 kg, underwent surgery using the DaVinci robotic surgical system. Under single-lung ventilation and CO2 insufflation, the descending thoracic aorta was completely mobilized. Proximal and distal cross-clamps were applied through separate accessory stab wounds. The mid-descending thoracic aorta was excised. An interposition Dacron graft was robotically sewn in an end-to-end fashion to the descending thoracic aorta using interrupted nitinol clips. RESULTS: : All animals survived the procedure. Mean aortic clamp time was 55 ± 14 minutes. All anastomoses were completed without difficulty with a mean total anastomotic time of 42 ± 11 minutes. The anastomoses were challenged for bleeding by administrating α1-adrenergic receptor agonists to a systolic blood pressure of 200 mm Hg with no evidence of leak. DISCUSSION: : Robotic replacement of the thoracic aorta is feasible and reproducible. This procedure provides the standard Dacron graft repair with its known long-term results. The added value of robotic technology to the therapeutic armamentarium in the treatment of thoracic aortic aneurysms may be worth the effort required for procedural development. Furthermore, it may serve as a valid alternative to endovascular treatment of thoracic aortic aneurysms.

Surgical repair of extensive aortic aneurysms.

We present our 14-year experience in the management of extensive aortic aneurysms. Significant progress has been made in reducing the morbidity and mortality associated with these procedures. Our strategies for organ protection, operative techniques, including the elephant trunk technique, and surgical results are discussed.