Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

Gait analysis outcomes of percutaneous medial hamstring tenotomies in children with cerebral palsy.

BACKGROUND: Hamstring lengthening procedures are commonly performed on children with cerebral palsy (CP) to improve gait. The purpose of this study was to determine the efficacy of percutaneous hamstring tenotomy surgery for children with ambulatory CP. METHODS: In this retrospective study, subjects were included if they had a diagnosis of CP and had computerized gait analysis data collected before and after surgery. Subjects were not included in the study if they had any open hamstring lengthening on the same side. Other concomitant lower extremity surgeries were not exclusionary. Short- and long-term follow-up groups were established: if the time from their surgery to their gait laboratory was less than 18 months, they were placed in the short-term follow-up group, and if the time from their surgery to their gait laboratory was greater than 18 months, they were placed in the long-term follow-up group. RESULTS: The results demonstrated that for short- and long-term groups on preoperative to postoperative analysis, there was significantly improved knee extension at initial contact, increased velocity, increased stride length, improved overall gait as indicated by a decrease in a 16 variable multivariate index (Gillette Gait Index), and a decreased popliteal angle. For the short-term group only, additional significant findings included increased peak knee extension in stance and reduced plantar flexion at initial contact. The absolute values of peak knee extension in stance and plantar flexion at initial contact were equivalent at follow-up for the short- and long-term groups. Increased anterior pelvic tilt was also significant for the short-term follow-up group only. CONCLUSIONS: The findings of this study demonstrate that the minimally invasive technique of percutaneous hamstring tenotomy is effective in improving key dynamic gait parameters for individuals with CP for a short period, and these benefits are maintained in the long term. LEVEL OF EVIDENCE: Level IV.

Range of motion measures under anesthesia compared with clinical measures for children with cerebral palsy.

The purpose of this study was to determine whether there is a difference in range of motion at the ankle and knee when measured in the clinic versus under anesthesia for ambulatory children with cerebral palsy. Dorsiflexion and popliteal angle were measured on 70 limbs in the clinic and under surgical anesthesia with the assessor blinded. For the group of patients under 11 years of age, dorsiflexion with the knee flexed significantly increased a mean of 9.5 degrees (P<0.05) and with the knee extended significantly increased 8.5 degrees when patients were under anesthesia compared with the clinical measures. Dorsiflexion angles did not change significantly between the two conditions for the group of patients older than 11 years of age. Mean popliteal angle did not change significantly between the two conditions for either age group.

Role of the triradiate cartilage in predicting curve progression in adolescent idiopathic scoliosis.

Braces are commonly used to treat progressive adolescent idiopathic scoliosis. Several previous studies have reported a correlation between the success of brace treatment and skeletal maturity markers. These studies have not focused on the status of the triradiate cartilage (TRC) as it relates to successful brace treatment for adolescent idiopathic scoliosis. The authors retrospectively evaluated all patients at their institution from 1990 to 1997 with a diagnosis of adolescent idiopathic scoliosis who were treated in a Boston brace. Sixty-two patients met inclusion criteria. At presentation, the average age was 12.87 years, the average Risser sign was 0.56, and 45% of patients had an open TRC. The average follow-up was 2.92 years. Greater than 5 degrees of progression at discontinuation of bracing was considered a failure. Curves with a closed TRC failed bracing 21% of the time, whereas those with an open TRC failed 54% of the time (P = 0.0069). Those curves with a closed TRC progressed 3.12 degrees on average, whereas curves with an open TRC progressed 6.86 degrees. Curves associated with a closed TRC at initiation of bracing progressed less frequently and to a lesser degree than those associated with an open TRC (P = 0.027). Although the TRC is not an independent predictor of curve stability, it is an additional indicator of skeletal maturity and may prove most useful in patients with otherwise borderline indications for brace treatment.

The pediatric outcomes data collection instrument detects improvements for children with ambulatory cerebral palsy after orthopaedic intervention.

The purpose of this study was to assess whether the Pediatric Outcomes Data Collection Instrument (PODCI) was able to detect changes in function, as perceived by the parents of children and adolescents with cerebral palsy who had undergone lower limb soft tissue and/or bony surgeries. This was a retrospective study of 80 ambulatory patients who were seen in the motion laboratory and classified with the Gross Motor Functional Classification System (GMFCS). Significant changes (P < 0.05) were detected in the PODCI scores for upper extremity function, transfers and mobility, physical function and sports, and global function after surgery, by approximately 4% to 5%, whereas comfort (pain-free) did not significantly change. There was a significant difference in the PODCI scores preoperatively between GMFCS levels I, II, and III for upper extremity function, transfers and mobility, physical function and sports, and global function. Postoperative improvements were of equal magnitude for each GMFCS level. This suggests that the PODCI did not have a ceiling effect for high-functioning children. Age (+/-10 years) and surgery (soft tissue/soft tissue plus bony) were not significant factors for any of the subcategories preoperative to postoperative. In conclusion, the PODCI detected improvement as perceived by the parents in ambulatory children with cerebral palsy after lower-limb soft tissue and/or bony surgeries in 4 areas by a magnitude of approximately 4% to 5%.

Comprehensive outcomes of surgically treated idiopathic toe walkers.

The treatment of idiopathic toe walking in children can include surgical lengthening of the gastrocnemius/soleus complex after conservative options have been ineffective. Previous outcome reports of surgery for idiopathic toe walkers have largely been limited to assessing the sagittal plane motion of dorsiflexion/plantar flexion with minimal quantitative preoperative and postoperative analysis. The purpose of this study was to comprehensively assess the outcome of idiopathic toe walkers that had been treated surgically. Fourteen children seen in our motion analysis laboratory that underwent gastrocnemius or tendo-Achilles lengthening for idiopathic toe walking were retrospectively reviewed. Preoperatively, this group had significantly greater anterior pelvic tilt than normal, decreased peak knee flexion in swing, greater external foot progression, and the expected increased plantar flexion (P < 0.01). Postoperatively, anterior pelvic tilt decreased by a mean of about 4 degrees (P < 0.01), only for the group that had tendo-Achilles lengthening because the gastrocnemius group was close to normal preoperatively, and peak knee flexion normalized. The foot progression angle of this group did not change from preoperative values and remained significantly more external than normal, although dorsiflexion in stance significantly improved after surgery (indicating the goal of the surgery was achieved). Increased external foot progression in idiopathic toe walkers is apparently due to increased external tibial torsion and/or external hip rotation but was unaffected by gastrocnemius/soleus surgical lengthening. Significant improvement occurred on an overall index of gait variables, indicating surgery can be an effective treatment of idiopathic toe walkers.

Proximal rectus femoris release surgery is not effective in normalizing hip and pelvic variables during gait in children with cerebral palsy.

The purpose of this study was to determine the efficacy of the proximal rectus femoris release to treat hip flexor contractures and hip and pelvic gait deviations in children with spastic cerebral palsy. This study was a retrospective repeated-measures analysis of data collected on two matched groups of patients, those with and without proximal rectus femoris release surgery, seen in our Motion Analysis Laboratory. Proximal rectus release surgery did not improve hip extension, did not decrease anterior pelvic tilt, and did not improve temporal-distance measures of gait in children with cerebral palsy. A multivariate measure, the Hip Flexor Index, was also unchanged. The group of patients without any hip flexor surgery was not different from the rectus femoris release group on hip or pelvic variables before or after surgery. The findings of this study offer no evidence that the proximal rectus femoris release is successful in achieving desired gait outcomes at the hip and pelvis in children with cerebral palsy.

Resting energy expenditure and respiratory quotient in adolescents following spinal fusion surgery.

STUDY DESIGN: Prospective, 2-factor design. The first factor was the group with 2 levels, spine surgery and control. The second factor was timing with 3 levels, baseline, 1-week follow-up, and 6-week follow-up. OBJECTIVES: The purpose of this study was to assess changes in caloric requirements and the body's nutritional substrate utilization following spinal surgery in adolescents. SUMMARY OF BACKGROUND DATA: In an effort to optimize recovery from and assure best possible outcomes after spinal surgery in adolescents, the nutritional requirements of spine surgery patients were evaluated. METHODS: Indirect calorimetry was used to measure resting energy expenditure, a measure of caloric requirements, and respiratory quotient, an indication of percentages of fat, protein, and carbohydrate utilization. Twenty-three patients undergoing spinal fusion surgery were evaluated immediately before surgery, at an average of 4.8 days after surgery, and at an average 53 days follow-up. A control group of 15 patients completed the same series of 3 tests: baseline, 1-week later, and 6-weeks later. RESULTS: Resting energy expenditure increased significantly by 150 kcal/day (2.7 kcal/kg/day) following spinal fusion surgery in adolescents. By 6 weeks postoperation, patient's caloric requirements returned to baseline level. No changes in resting energy expenditure occurred in the control group between the 3 test periods. Anterior/posterior surgeries and single surgeries had similar kcal/kg/day requirements after surgery. Respiratory quotient decreased significantly following surgery (0.79 to 0.70), indicating a shift to fat oxidation after surgery. At 6 weeks postoperation, the respiratory quotient returned to baseline level. The control group demonstrated no change in the respiratory quotient during the 3 testing periods. CONCLUSIONS: Substrate utilization shifts to fat oxidation in adolescents following spinal surgery, indicating lipids would be the alimentation of choice immediately after surgery. Caloric requirements increase 9% above the baseline measurements. Anterior/posterior surgeries and single surgeries (anterior or posterior alone) have the same increase in kcal/kg/day. Because of the substrate utilization change by the body after surgery, a preponderance of these calories should initially be given as lipids. After approximately 6 weeks, both resting energy expenditure and respiratory quotient returned to preoperative levels following spinal surgery in adolescents, indicating special nutrition is not required beyond 6 weeks.

Outcomes in surgical treatment of "idiopathic-like" scoliosis associated with syringomyelia.

Patients with "idiopathic-like" spinal deformities associated with syringomyelia were retrospectively reviewed. Ten patients had surgical stabilization of their curvatures with at least a 2-year follow-up, and an additional five patients were evaluated for deformity pattern with <2 years of follow-up. Paralytic curve patterns, scoliosis associated with spina bifida, congenital scoliosis, or other associated syndromes were discarded. All 10 patients with surgery who were followed for an average of 46 months lost 10 degrees correction above, through, or below the instrumented segments. A total of 50% lost correction through the instrumented segments. Anterior fusion stabilized the instrumented portion of the spine better than posterior instrumentation alone. Eighty percent of the 15 patients had thoracic kyphosis >40 degrees. Only one patient was lordoscoliotic. Syringomyelia deformities tend to be kyphoscoliotic in 80% of cases and behave more like paralytic curvatures postoperatively. MRI is recommended for apparent idiopathic scoliotic curvatures that are kyphoscoliotic and not lordoscoliotic.