Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons

Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9‐day survival and control of thrombocytopenia following GalT‐KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256–264.. © 2012 John Wiley & Sons A/S. Abstract: Background:  With standard miniature swine donors, survivals of only 3 days have been achieved in primate liver‐transplant recipients. The recent production of alpha1,3‐galactosyl transferase knockout (GalT‐KO) miniature swine has made it possible to evaluate xenotransplantation of pig organs in clinically relevant pig‐to‐non‐human primate models in the absence of the effects of natural anti‐Gal antibodies. We are reporting our results using GalT‐KO liver grafts. Methods:  We performed GalT‐KO liver transplants in baboons using an immunosuppressive regimen previously used by our group in xeno heart and kidney transplantation. Post‐operative liver function was assessed by laboratory function tests, coagulation parameters and histology. Results:  In two hepatectomized recipients of GalT‐KO grafts, post‐transplant liver function returned rapidly to normal. Over the first few days, the synthetic products of the donor swine graft appeared to replace those of the baboon. The first recipient survived for 6 days and showed no histopathological evidence of rejection at the time of death from uncontrolled bleeding, probably caused by transfusion‐refractory thrombocytopenia. Amicar treatment of the second and third recipients led to maintenance of platelet counts of over 40 000 per μl throughout their 9‐ and 8‐day survivals, which represents the longest reported survival of pig‐to‐primate liver transplants to date. Both of the last two animals nevertheless succumbed to bleeding and enterococcal infection, without evidence of rejection. Conclusions:  These observations suggest that thrombocytopenia after liver xenotransplantation may be overcome by Amicar therapy. The coagulopathy and sepsis that nevertheless occurred suggest that additional causes of coagulation disturbance must be addressed, along with better prevention of infection, to achieve long‐term survival.     

Closed femoral intramedullary nailing in the lateral decubitus position with the aid of intraoperative skeletal traction

The closed intramedullary nailing is the treatment of choice for femoral diaphyseal fractures. These procedures typically have been performed on a fracture table with either supine or lateral position. However, the use of a fracture table has a lot of disadvantages compared to a lateral position on radiolucent routine table. We reviewed one hundred and twenty-eight patients with femur fractures between 2005 and 2009, who were treated with closed femoral intramedullary nailing in lateral decubitus position on radiolucent routine table. Indirect reduction was facilitated by the aid of intraoperative skeletal traction. Clinical and radiologic results were evaluated. There were no rotational or length malreductions that required surgical revision. There were no injuries to the perineum or contralateral leg, nerve palsies, or fracture table–related complications. There were three cases of non-union and two cases of interlocking screw loosening. Lateral decubitus position obviates the need for fracture table, making it easier to establish an entry point for an intramedullary device. Closed femoral intramedullary nailing in lateral decubitus position with the aid of intraoperative skeletal traction is safe and an effective technique with a low incidence of complications compared to the use of fracture table.     

Outcomes of interlaminar and transforminal spinal injections

Epidural spinal injections can be administered via a translaminar or transforaminal route, depending on the clinical scenario. When it is more desirable to target a specific nerve root, a transforaminal approach is typically used, and when the target is more diffuse, a translaminar method is chosen. Both are commonly used and can be utilized similarly in the lumbar or cervical spine. However, it is essential that the clinician understand the risks and benefits of these injections. In the lumbar spine, both translaminar epidural steroid injections (TLESI) and transforaminal epidural steroid injections (TFESI) have been shown to provide up to 6 months of pain relief, though long-term benefits are less reliable. In the cervical spine, translaminar injections may provide longer relief and have a lower complication rate than cervical transforaminal injections. Proper technique is essential to minimize the rate of these rare but occasionally severe complications.     

Combined tadalafil and α-blocker therapy for benign prostatic hyperplasia in patients with erectile dysfunction: a multicenter, prospective study

This prospective study evaluated the safety of tadalafil 5 mg taken once a day in terms of hypotensive side effects and whether it improves lower urinary tract symptoms (LUTS) and restores sexual function in patients with erectile dysfunction who are receiving concomitant α-blocker (AB) therapy for benign prostatic hyperplasia (BPH). A total of 158 LUTS/BPH patients receiving AB therapy for ≥3 months were given tadalafil 5 mg once a day. Before treatment with tadalafil (V1), and 4 weeks (V2) and 12 weeks (V3) after starting tadalafil, blood pressure, heart rate, International Prostate Symptom Score (IPSS), maximal urine flow rate (Qmax), postvoiding residual urine volume, and International Index of Erectile Function (IIEF-5) score were measured. Of the 158 LUTS/BPH patients, a total of 119 completed the trial. Blood pressure (systolic and diastolic) and heart rate did not change. IPSS and IIEF-5 scores improved significantly, but Qmax and postvoiding residual urine volume did not; however, in the 39 men with a low baseline Qmax (≤10 mL/s), Qmax rose significantly from 7.97 ± 1.44 mL/s (baseline) to 8.91 ± 1.60 mL/s (V3; P = .012). The remaining patients (baseline Qmax >10 mL/s) did not change. At V2 and V3, adverse side effects were observed in 10 men (7.30%) and 6 men (5.04%), respectively. Facial flushing was the most common adverse side effect (6 men at V2 and 4 men at V3), followed by headache (2 men each at V2 and V3) and dizziness (2 men at V2). Two patients dropped out of the study because of adverse side effects. In conclusion, tadalafil 5 mg once a day in combination with AB appeared to have few adverse effects on hypotensive events and can improve LUTS and restore sexual function.     

Surgical correction for supination loss following malunited radial fractures

We evaluated fourteen patients who had restricted supination as a major impairment related with a malunited radius fracture. All patients underwent an opening wedge corrective osteotomy, bone grafting, and volar plate fixation. Clinical results were assessed based on range of motion, visual analogue scale for pain, grip power, and a Modified Mayo Wrist Score. The mean supination increased from 24 degrees preoperatively to 71 degrees postoperatively (p < 0.01). Dorsiflexion range, grip power and pain score improved significantly after the operation. The mean value for the Modified Mayo Wrist score improved from 58.6 points to 83.9 points (p < 0.01). Radiological measurements showed that the degree of dorsal angulation decreased from a mean of 9.0 degrees to -2.5 degrees after the corrective osteotomy. This study demonstrated that a malunited radius fracture with dorsal angulation, even if the latter appears mild, can induce functional impairment due to limited range of supination. Supination can be restored by an appropriately performed corrective osteotomy.     

Factors related to the development of myelopathy in patients with cervical ossification of the posterior longitudinal ligament

This study evaluates factors related to myelopathic symptoms in patients with ossification of the posterior longitudinal ligament (OPLL). A total of 87 patients with OPLL were included. Of these, 53 (Group I) had no symptoms or presented with neck pain and radiculopathy and 34 (Group II) had myelopathic symptoms. Gender, age, and history of trauma were evaluated in the two groups. The range of movement of the cervical spine was measured using plain radiographs. The number of involved segments, type of OPLL, and maximal compression ratio were analysed using CT and signal change in the spinal cord was evaluated using MRI. The patients' age was found to be significant (p = 0.001). No difference was found between gender and the range of movement in the two groups. The maximum compression of the spinal canal showed a difference (p = 0.03). The signal change of the spinal cord was different between the two groups. In patients with OPLL of the cervical spine, myelopathic symptoms are not related to the range of movement or the number of involved segments.     

Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial

Background

Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.

Objective

To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.

Design, setting, and participants

The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).

Intervention

Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.

Measurements

Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.

Results and limitations

In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.

Conclusions

Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.     

Anesthetic and recovery profiles of lidocaine versus mepivacaine for spinal anesthesia in patients undergoing outpatient orthopedic arthroscopic procedures

Study ObjectiveTo compare isobaric lidocaine and mepivacaine in outpatient arthroscopic surgery.DesignProspective, randomized, double-blinded study.SettingAmbulatory surgery center affiliated with an academic tertiary-care hospital.Patients84 adult, ASA physical status 1, 2, and 3 ambulatory patients, age 18-70 years, undergoing arthroscopic knee surgery.InterventionPatients were randomized to receive a combination spinal-epidural anesthetic using 80 mg of either isobaric 2% mepivacaine or isobaric 2% lidocaine. Patients also received a femoral 3-in-1 block with 0.5% bupivacaine applied to the affected extremity.MeasurementsDemographic data and level and duration of the block were recorded. The use of supplemental epidural anesthesia was noted along with frequency of bradycardia, hypotension, and episodes of nausea and vomiting. Duration of block and times to ambulation and voiding were recorded. Delayed variables, including fatigue, difficulty urinating, back pain, and transient neurologic symptoms (TNS) were obtained.Main ResultsNo demographic differences were noted between groups, and surgical duration was similar. Satisfactory anesthesia was achieved in all cases, with no differences noted in hypotension, bradycardia, nausea, or vomiting. Onset of sensory and motor block was similar. Duration of block before epidural supplementation was 94 ± 21 minutes with lidocaine versus 122 ± 23 minutes for mepivacaine (P < 0.011). Times to ambulation and voiding were longer in patients receiving mepivacaine but did not affect PACU stay. Twenty-four and 48-hour recovery was similar with no TNS symptoms reported.ConclusionNo major differences were noted between lidocaine and mepivacaine spinal anesthesia. Time to ambulation and voiding were longer in patients who received mepivacaine as was time to first dose of epidural catheter. Neither group had TNS symptoms. Lidocaine and mepivacaine are both appropriate spinal anesthetics for ambulatory orthopedic lower extremity procedures.     

Novel extraneural role of neurite outgrowth inhibitor A: modulation of osteoclastogenesis via positive feedback regulation of nuclear factor of activated T cell cytoplasmic 1

Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte lineage precursors upon receptor activator of NF-κB ligand (RANKL) stimulation. In a proteomic approach to identify proteins involved in osteoclastogenesis, we observed a dramatic increase in the expression of neurite outgrowth inhibitor A (Nogo-A) upon RANKL stimulation of mouse bone marrow macrophages (BMMs) in a nuclear factor of activated T cell cytoplasmic 1 (NFATc1)-dependent manner. The knockdown of Nogo-A in BMMs significantly reduced RANKL-dependent osteoclast differentiation accompanied by diminished NFATc1 induction, suggesting that a positive feedback mechanism is involved. Conversely, Nogo-A overexpression in BMMs as well as in RAW264.7 macrophages greatly augmented osteoclastogenesis, with concomitant increase in the NFATc1 induction. Both the mitogen-activated protein kinase (MAPK) pathway and calcium oscillation, which are central to RANKL-dependent NFATc1 activation and induction, were enhanced by Nogo-A. Finally, Nogo-A knockdown in mouse calvariae prevented interleukin 1 (IL-1)-induced bone loss. These findings not only reveal an unprecedented extraneural role of Nogo-A in osteoclastogenesis but also suggest a novel drug target against bone-lytic diseases.     

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte- and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption.