The cholinomimetic agent carbachol induces headache in healthy subjects

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 µg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (V_MCA) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) ( P  = 0.042) and in the postinfusion period (30–90 min) ( P  = 0.027). Carbachol infusion caused a drop in V_MCA ( P  = 0.003) and an increase in STA diameter ( P  = 0.006), but no increase in the RA diameter ( P  = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.     

Implementation of an in vitro fertilization program

The establishment of an in vitro fertilization program is described. Organization of the physical laboratory, media formulation, and preliminary mouse embryo culture are discussed. Parameters of patient eligibility, ovarian stimulation, and laporoscopy are also defined. At the conclusion of Phase I, 17 patients were induced; 10 went to laparoscopy, and at least one four-cell embryo was returned to 7, resulting in one continuing pregnancy.     

Functional outcome after isolated acetabular fractures

OBJECTIVE: To evaluate objectively the effectiveness of current surgical management of displaced acetabular fractures. To provide insight into how these evaluation methods can be used to identify areas in which improvements in surgery and rehabilitation can be pursued to improve patient outcomes. DESIGN: Consecutive case series. SETTING: University medical center. PATIENTS: Fifteen patients were studied, each with an isolated, displaced acetabular fracture treated with a Kocher-Langenbeck approach. MAIN OUTCOME MEASURES: Primary outcome measures included hip muscle strength, including work (Joules/minute) and maximum torque (30 degrees/second) for abductors/adductors and flexors/extensors. Gait analysis of patients and able-bodied cohorts, including stride length, speed, and cadence, were also assessed. Motion analysis during gait was also studied for each body segment, including the trunk, pelvis, hip, knee, and ankle, in the sagittal, frontal, and axial planes. Motion data for the affected side was compared with motion data for the unaffected side, and linear gait findings for the study patients were compared to able-bodied cohorts. An assessment of clinical outcome was performed by completion of a validated Musculoskeletal Function Assessment (MFA) questionnaire and the were results correlated with muscle strength and gait analysis. Secondary outcome measures included adequacy of fracture reduction, radiographic grade, the presence and severity of heterotopic ossification at the time of the most recent follow-up, and passive range of motion of the affected and unaffected hips. RESULTS: No statistical differences in muscle strength for each of the major muscle groups were found when the affected limb was compared with the unaffected limb. No statistical differences were found between the study patients and the able-bodied cohorts with regards to stride length, gait speed, and cadence. The only significant difference found in body segment position was trunk inclination. When the study patients were compared with able-bodied cohorts, the patients tended to walk with greater forward inclination of their trunks; this was true for all phases of gait. Total MFA scores averaged 22 (range, 0-57). Patients could be separated into two separate groups based on their total MFA score. One group (n = 6) had an average MFA score of 7 (range, 0-10), while a second group (n = 9) had an average MFA score of 32 (range, 12-57). The scores of study patients as a whole, and those of each individual group of patients, were compared with known MFA scores for nonpatients and patients in the Orthopaedic Trauma Association/Association for the Study of Internal Fixation (OTA/AO) injury group (hip and thigh). When the muscle strengths of these two groups of patients were compared, all hip flexion and extension variables were significantly weaker in the group with an average MFA score of 32, whereas none of the gait variables were different between the two groups. At an average follow-up of 24 months, seven patients had an excellent radiographic grade, four patients had a good grade, two patients had a fair grade, and two patients had a poor grade. These radiographic grades were in contrast to achieving an anatomic reduction in eleven patients, a satisfactory reduction in three patients, and an unsatisfactory reduction in one patient. Heterotopic ossification was found in eight patients, four patients had Grade 1, and four patients, had Grade 2. No statistically significant differences were observed when each MFA group was compared with each of these radiographic variables. Passive hip range of motion was not statistically different when the affected hip was compared with the unaffected hip. CONCLUSIONS: Standardized muscle strength determination, gait, and motion analysis, and completion of an MFA questionnaire provided a thorough and revealing evaluation of patients who have undergone open reduction and internal fixation (ORIF) of a displaced acetabular fracture. Minimal alterations in body posture and affected limb motion were present in patients displaying relatively normal gait parameters, including stride length, speed, and cadence. Despite dissection of the hip musculature during surgery, normal muscle strength recovery was possible after operative repair of these acetabular fractures. However, functional outcome, as determined by MFA scores, was considerably poorer in those patients with significantly weaker hip flexion and extension strength, compared with those of patients with more desirable MFA scores. Based on the current data, it appears that the use of these and similar evaluation instruments can allow determination of factors that negatively affect outcome (hip flexion and extension strength), which otherwise may remain unknown. It is possible that identification and treatment of these factors will improve the quality of life for patients after this type of injury.     

Assessment of articular fragment displacement in acetabular fractures: a comparison of computerized tomography and plain radiographs

OBJECTIVES: Quantitatively evaluate plain radiographs, relative to computed tomography (CT) scans, for assessment of articular fragment displacement (step and gap) in displaced acetabular fractures and in canine osteotomized acetabular specimens. DESIGN: Retrospective evaluation of a consecutive series of CT scans and plain radiographs of patients with displaced acetabular fractures and canine acetabulae osteotomized to represent acetabular fractures with displacement. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: Computed tomography scans and plain radiographic images of 62 consecutive patients with displaced acetabular fractures were reviewed; 20 patients met the inclusion criteria regarding location, fracture pattern, availability of plain radiographs and CT scans, and the position of the femoral head at the time of radiographic assessment. The hemipelvi of five adult mongrels underwent osteotomy of the acetabulum and similar radiographic evaluation. INTERVENTION: Three independent reviewers measured step and gap deformity on plain radiographs and CT scans utilizing a standardized measurement technique. MAIN OUTCOME MEASUREMENTS: Sensitivity and specificity of plain radiographs for detecting step and gap displacement (2 mm and 4 mm) relative to CT scans were determined. Intraclass correlation coefficient and intraobserver reliability was also calculated. For the canine specimens, sensitivities of each imaging method were determined relative to actual fragment displacement measurements. RESULTS: In the clinical images, when compared to CT, plain radiographs showed poor sensitivity at detecting step deformity (sensitivity = 25%). When analyzed by fracture type, plain radiographs were particularly poor at detecting step deformities in fractures involving a single column of the acetabulum (sensitivity = 0%). Excellent intraobserver and intraclass reliability existed among the three reviewers. Computed tomography scans were considerably more accurate in measuring step and gap displacement relative to actual measurements than plain radiographs in the canine specimens. CONCLUSIONS: 1) Plain radiographs showed poor sensitivity for the detection of step and gap deformities in patients with acetabular fractures and in osteotomized canine specimens, relative to CT scans; 2) differences between CT and plain radiographs in both specimen types were greatest with the most clinically relevant deformity-i.e., step; and 3) CT scans are essential and should continue to be used in conjunction with plain radiographs in the preoperative evaluation of displaced acetabular fractures and perhaps should be considered in the postoperative assessment of fracture reduction.     

Molecular modelling of CYP2B6 based on homology with the CYP2C5 crystal structure: analysis of enzyme-substrate interactions

The results of homology modelling of CYP2B6 based on the CYP2C5 crystal structure is described in terms of substrates and inhibitors binding within the putative active site. In general these results are in agreement with currently available evidence from substrate metabolism, mode of inhibitor action and site-directed mutagenesis experiments within the CYP2B subfamily of enzymes. Consequently, the model based on the CYP2C5 template represents an advance on those models produced from bacterial P450s, such as CYP101 and CYP102. Quantitative Structure-Activity Relationships (QSARs) for substrates binding to CYP2B6 indicate a key role for hydrogen bonding, and lipophilic character, as determined by the log P parameter (where P is the octanol/water partition coefficient), is also of importance for explaining the variation in experimental binding affinity for CYP2B6 substrates. It is possible to estimate the binding energies for typical CYP2B6 substrates based on their properties and interactions with the enzyme, which show good concordance with experimental data in the form of apparent Km values.