Editorial Commentary: Measurements for Successful High Tibial Osteotomy: Understanding Supine Versus Standing and Intraoperative Fluoroscopic Alignment Is Required

A high tibial osteotomy (HTO) that is used to correct varus malalignment, such as with medial arthrosis or before cartilage restoration or posterolateral reconstructions, represents an important and required surgery for clinical success. A major problem that occurs with HTO planning is that the preoperative measurements, with either lower limb supine or standing weight-bearing radiographs, will invariably show abnormal medial or lateral tibiofemoral compartment opening resulting from soft-tissue laxity or injury. It is imperative that this tibiofemoral joint opening be accounted for in the osteotomy correction calculations. There are well-described methods available that affect operative planning, such as the use of preoperative stress radiographs to determine the millimeters of tibiofemoral opening or closure. The use of intraoperative fluoroscopy with application of axial loading to the lower limb and verification of closure of the tibiofemoral joint is recommended. A careful fluoroscopic examination of the tibiofemoral compartments allows a final adjustment of the osteotomy correction and confirms the final weight-bearing line percent measurement and limb alignment. Postoperative radiographs are required to detect outliers resulting from unexpected soft-tissue laxity or inadequate correction.     

CCN1/Cyr61 Is Required in Osteoblasts for Responsiveness to the Anabolic Activity of PTH

CCN1/Cyr61 is a dynamically expressed matricellular protein that serves regulatory functions in multiple tissues. Previous studies from our laboratory demonstrated that CCN1 regulates bone maintenance. Using an osteoblast and osteocyte conditional knockout mouse model (Ccn1^OCN), we found a significant decrease in trabecular and cortical bone mass in vivo, in part through suppression of Wnt signaling since the expression of the Wnt antagonist sclerostin (SOST) is increased in osteoblasts lacking CCN1. It has been established that parathyroid hormone (PTH) signaling also suppresses SOST expression in bone. We therefore investigated the interaction between CCN1 and PTH-mediated responses in this study. We find that loss of Ccn1 in osteoblasts leads to impaired responsiveness to anabolic intermittent PTH treatment in Ccn1^OCN mice in vivo and in osteoblasts from these mice in vitro. Analysis of Ccn1^OCN mice demonstrated a significant decrease in parathyroid hormone receptor-1 (PTH1R) expression in osteoblasts in vivo and in vitro. We investigated the regulatory role of a non-canonical integrin-binding domain of CCN1 because several studies indicate that specific integrins are critical to mechanotransduction, a PTH-dependent response, in bone. These data suggest that CCN1 regulates the expression of PTH1R through interaction with the αvβ3 and/or αvβ5 integrin complexes. Osteoblasts that express a mutant form of CCN1 that cannot interact with αvβ3/β5 integrin demonstrate a significant decrease in mRNA and protein expression of both PTH1R and αv integrin. Overall, these data suggest that the αvβ3/β5-binding domain of CCN1 is required to endow PTH signaling with anabolic activity in bone cells. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Electroencephalographic Burst Suppression Is Not Required to Elicit Maximal Neuroprotection from Pentobarbital in a Rat Model of Focal Cerebral Ischemia

Background: Barbiturates have previously been demonstrated to reduce focal cerebral ischemic brain damage. However, the dose of drug required to elicit maximal neuroprotection has not been defined. The authors' hypothesized that doses of pentobarbital substantially lower than those required to cause electroencephalographic burst suppression would result in maximal magnitudes of reduction of cerebral infarct volume.

Methods: Wistar rats underwent 90 min of filament occlusion of the middle cerebral artery while either awake (control), or anesthetized with intravenous sodium pentobarbital administered to preserve an active electroencephalogram (15-23 mg *symbol* kg sup -1 *symbol* h sup -1) or a pattern of burst suppression (45-60 mg *symbol* kg sup -1 *symbol* h sup -1; n = 17). During ischemia and for the first 6 h of recirculation, brain temperature was rigorously controlled at 38.0+/-0.2 degree Celsius. Rats were allowed a recovery interval of 7 days after which neurologic function and cerebral infarct volume were assessed. In nonischemic rats undergoing a similar anesthetic protocol, the cerebral metabolic rate of glucose utilization was measured at each anesthetic depth.

Results: Relevant physiologic values were similar between groups. Total infarct volume (mean+/-SD) was smaller in the active electroencephalogram group than in the control group (124+/-68 mm sup 3 versus 163+/-66 mm3; P < 0.05). Increasing the dose of pentobarbital (burst suppression) did not further decrease infarct volume (128+/-54 mm3). Neurologic score and infarct volume were positively correlated (P < 0.001). Cerebral metabolic rate of glucose utilization was reduced by 56% in the burst suppression group versus 43% in the active electroencephalogram pentobarbital group (P < 0.001).     

CCR5 Is Required for Regulation of Alloreactive T-Cell Responses to Single Class II MHC-Mismatched Murine Cardiac Grafts

The effector CD4 T-cell response in wild-type C57BL/6 recipients of single class II MHC-disparate B6.H-2^bm12 cardiac allografts is restricted by CD4⁺CD25⁺ regulatory T cells (Tregs) resulting in long-term allograft survival. To investigate the role chemokine receptors might play in Treg function, this study tested the requirement for CCR5 on Tregs to suppress the alloimmune response in C57BL/6 recipients of B6.H-2^bm12 cardiac allografts. In contrast to the long-term survival of B6.H-2^bm12 allografts in wild-type recipients (>100 days), the allografts were acutely rejected within 25 days in CCR5^−/− recipients with intense infiltration of CD4 T cells. Numbers and duration of donor-reactive CD4 T cells producing IFN-γ and IL-4 were markedly increased in spleens of B6.CCR5^−/− versus wild-type recipients. Wild-type and B6.CCR5^−/− mice had equivalent numbers of splenic FoxP3⁺ Tregs before and following transplantation, and these Tregs were equivalently suppressive in vitro . However, diminished numbers of FoxP3⁺ Tregs infiltrated B6.H-2^bm12 allografts in B6.CCR5^−/− recipients. Adoptive transfer of wild-type, but not CCR5-deficient, CD4⁺CD25⁺ Tregs to CCR5^−/− recipients restored long-term survival of B6.H-2^bm12 cardiac grafts. Collectively, these results indicate that CCR5 expression is required for the regulatory functions of Tregs that restrict alloreactive CD4 T-cell responses to single class II MHC-mismatched cardiac allografts.     

What Sample Sizes are Required for Pooling Surgical Case Durations among Facilities to Decrease the Incidence of Procedures with Little Historical Data?

Background: Better predictions of each case's duration would reduce operating room labor costs and patient waiting times. A barrier to using historical case duration data to predict the duration of future cases is the absence for some cases of previous data for the same scheduled procedure from the same facility. The authors examined sample size requirements for pooling case duration data from several facilities to create a 90% chance of having case duration data for almost all procedures.

Methods: Four academic medical centers provided data, totaling 200,401 cases classified by the scheduled Current Procedural Terminology codes.

Results: The 12% of cases in which procedures occurred once or twice accounted for 79% of procedures or combinations of procedures. When a procedure was being performed for the first time at a facility, that same procedure had been performed previously at least once at one or more of the other three facilities only 13-25% of the time. More than 1 million cases would be needed to have a 90% chance of having at least 3 cases for each procedure observed in the original 200,401 cases. However, with N = 200,401 cases in our initial data set, we observed less than one third of the estimated total number of possible procedures.     

Is Transabdominal Repair of Mild to Moderate Cystocele Necessary for Correction of Prolapse during a Modified Burch Procedure?

A nonconcurrent cohort study by chart review of cases was carried out at the Urogynecology Unit of Mount Sinai Hospital in Toronto, Canada, in 380 patients with stress urinary incontinence (SUI) undergoing Burch retropubic urethropexy (RPU) with or without transabdominal internal anterior repair (TIAR). There were 191 subjects (group A) who had both RPU and TIAR, and 189 (group B) who had RPU alone. The main outcome measures were postoperative recurrence of cystocele and SUI. Statistical analysis was performed using multiple regression analysis; P<0.05 was considered statistically significant. Of patients with preoperative cystocele grade 1 and 2 (mild to moderate) followed-up at 1 year, recurrence in groups A and B, respectively, was found in 13/114 (11.4%) vs. 4/99 (4.0%) (P<0.05). Regression analysis showed this trend of greater recurrence with TIAR to persist at 5 years, although a significant number of patients were lost to follow-up. There was no statistically significant difference in the cure of SUI between the groups. There was a 2.1% incidence of inadvertent cystotomy during TIAR (with no bladder injuries in group B), although this complication was always recognized and repaired without sequelae. In patients with both SUI and mild to moderate cystocele, TIAR may not be a necessary addition to RPU for treatment of the cystocele, although a randomized clinical trial is needed to determine the optimal transabdominal treatment in such cases. There is no detrimental effect of TIAR on the Burch procedure’s success in curing SUI.     

High-dose amrinone is required to accelerate rewarming from deliberate mild intraoperative hypothermia for neurosurgical procedures

BACKGROUND: Since the time available to provide the cooling and rewarming is limited during deliberate mild hypothermia, the technique to accelerate the cooling and rewarming rate of core temperature has been studied. Amrinone has been reported to accelerate the cooling rate but not the rewarming rate of core temperature during deliberate mild hypothermia. The failure of amrinone effect on the rewarming rate might be due to an insufficient dose of amrinone during hypothermic conditions. The authors therefore tested whether higher doses of amrinone can accelerate the rewarming rate of core temperature during deliberate mild hypothermia for neurosurgery. METHODS: After institutional approval and informed consent, 30 patients were randomly assigned to one of three groups. Patients in the control group (n = 10) did not receive amrinone; patients in the AMR 15 group (n = 10) received 15 microg x kg(-1) x min(-1) amrinone with a 1.0-mg/kg loading dose of amrinone at the beginning of cooling; and patients in the ReAMR group (n = 10) received 5 microg x kg(-1) x min(-1) amrinone with 1.0-mg/kg loading and reloading doses of amrinone at the beginning of cooling and rewarming, respectively. Administration of amrinone was started just after the induction of cooling and continued until the end of anesthesia. Anesthesia was maintained with nitrous oxide in oxygen, propofol, and fentanyl. After induction of anesthesia, patients were cooled, and tympanic membrane temperature was maintained at 34.5 degrees C. After completion of the main surgical procedures, patients were actively rewarmed and extubated in the operating room. RESULTS: The cooling and rewarming rates of core temperature were both significantly faster in both amrinone groups than in the control group. During the cooling and rewarming periods, forearm minus fingertip temperature gradient was significantly smaller in both amrinone groups than in the control group. During the rewarming period, heart rate and mean arterial pressure in the AMR 15 group were significantly faster and lower, respectively, than in the control group. Systemic vascular resistance in the AMR 15 group was smaller than in the control group throughout the study; on the other hand, only the value after the start of rewarming in the ReAMR group was smaller than in the control group. CONCLUSIONS: Amrinone at an infusion rate of 15 or 5 microg x kg(-1) x min(-1) with a reloading at the beginning of rewarming accelerated the rewarming rate of core temperature during deliberate mild hypothermia. This suggests that high-dose amrinone is required to accelerate rewarming from deliberate mild intraoperative hypothermia for neurosurgical procedures.     

Is accurate self-monitoring necessary for people with acquired neurological problems to benefit from the use of differential reinforcement methods?

Challenging behaviour exhibited by people with acquired neurological problems must be managed if their maximum rehabilitation potential is to be achieved. Differential reinforcement of low rates of responding (DRL) appears to be an effective method for this. The effectiveness of DRL in the presence of severe cognitive deficits, including disorders of attention and memory, is nevertheless surprising. Indeed, such difficulties may prevent individuals with brain injury benefiting from operant conditioning procedures because of impairment of the central executive component of working memory. Consequently, use of other behavioural techniques such as response cost and self-monitoring training (SMT) have been adopted, as it has been argued they circumvent neuropsychological constraints to learning by directing attention to aspects of behaviour not being monitored. DRL, however, may be more desirable as it involves minimal intrusion; is concerned with establishment of pro-social behaviour; and treatment gains can occur rapidly and be maintained for long periods following withdrawal. Whether DRL is dependent upon accurate self-monitoring is addressed through the study of three people participating in rehabilitation. This shows DRL can be effective, despite severe cognitive impairments, but SMT facilitates greater improvements in selective attention. How DRL may circumvent cognitive impairment is discussed.