Citations

Background and Purpose— Early hematoma expansion in spontaneous intracerebral hemorrhage (ICH) is associated with worse clinical outcome. We hypothesized that hemodynamic parameters are associated with the increase in hematoma volume owing to their relationship to blood vessel wall stresses. Methods— We performed a post hoc analysis of clinical and computed tomography (CT) data from patients enrolled in a prospective observational study of ICH patients presenting within 3 hours from symptom onset. Hematoma volumes were measured at hospital arrival and at 1 and 20 hours from presentation. Blood pressure and heart rate, recorded at 19 time points between presentation and 20 hours, were used to derive hemodynamic variables. Multivariable logistic-regression models were constructed to assess the relation between hemodynamic parameters and hematoma growth, adjusted for clinical covariates. Results— From the original study, 98 patients underwent baseline and 1-hour CT scans; of these, 65 had 20-hour CT scans. Substantial hematoma growth was observed in 28% within the first hour. Of the 65 patients not undergoing surgery within 20 hours, 37% experienced hematoma growth by 20 hours. Neither baseline or peak hemodynamic parameters nor changes in hemodynamic parameters were significantly associated with hematoma growth at either 1 or 20 hours. Conclusions— We found no blood pressure or heart rate parameters, individually or in combination, that were associated with hematoma growth. Our data suggest the influence of hemodynamic parameters on vessel wall stress to be an unlikely target for intervention in reducing the risk of early hematoma growth in ICH.

Abstract Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, γ-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor. (Cancer Res 2006; 66(12): 5993-6)

The splanchnic bed produces cortisol at rates approximating extraadrenal tissues by converting cortisone to cortisol via the 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 pathway. It is not known whether splanchnic cortisol production is regulated by nutrient ingestion and/or by the accompanying changes in hormone secretion. To address this question, 18 healthy humans were randomized to ingest either a mixed meal or to receive an intravenous saline infusion while total-body, splanchnic, and d3 cortisol production (an index of 11β-HSD type 1 activity) were measured using the combined hepatic catheterization and d4 cortisol infusion methods. Fasting glucose and insulin concentrations did not differ on the meal and saline study days. Glucose and insulin concentrations increased after meal ingestion, peaking at 11.0 ± 1.0 mmol/l and 451 ± 64 pmol/l, respectively, at 45 min, then fell to baseline thereafter. In contrast, glucose and insulin concentrations slowly fell to 5.1 ± 0.1 mmol/l and 27 ± 6 pmol/l during the 6 h of observation on the saline study day. Fasting cortisol concentration did not differ on the meal and saline study days. Cortisol increased (P < 0.05) to a peak of 353 ± 55 nmol/l after meal ingestion but did not change after saline infusion. The increase in cortisol after meal ingestion was associated with an increase in both total body cortisol (from 748 ± 63 to 1,620 ± 235 nmol/min; P < 0.01) and total body d3 cortisol (from 99 ± 11 to 143 ± 11 nmol/min; P < 0.01) production, whereas there was no change in either on the saline study day. The increase in total-body cortisol and d3 cortisol production after meal ingestion originated in extrasplanchnic tissues since splanchnic cortisol production (mean 0–360 min: 254 ± 83 vs. 262 ± 36 nmol/min) and splanchnic d3 cortisol production (mean 0–360 min: 72 ± 22 vs. 77 ± 14 nmol/min) did not differ on the meal and saline study days. We conclude that ingestion of a mixed meal does not alter either splanchnic cortisol production or the conversion of d4 cortisol to d3 cortisol or, therefore by implication, flux via the splanchnic 11β-HSD type 1 pathway.

Abstract Hip scans of U.S. adults aged 20–99 years acquired in the Third National Health and Nutrition Examination Survey (NHANES III) using dual-energy X-ray absorptiometry (DXA) were analyzed with a structural analysis program. The program analyzes narrow (3 mm wide) regions at specific locations across the proximal femur to measure bone mineral density (BMD) as well as cross-sectional areas (CSAs), cross-sectional moments of inertia (CSMI), section moduli, subperiosteal widths, and estimated mean cortical thickness. Measurements are reported here on a non-Hispanic white subgroup of 2719 men and 2904 women for a cortical region across the proximal shaft 2 cm distal to the lesser trochanter and a mixed cortical/trabecular region across the narrowest point of the femoral neck. Apparent age trends in BMD and section modulus were studied for both regions by sex after correction for body weight. The BMD decline with age in the narrow neck was similar to that seen in the Hologic neck region; BMD in the shaft also declined, although at a slower rate. A different pattern was seen for section modulus; furthermore, this pattern depended on sex. Specifically, the section modulus at both the narrow neck and the shaft regions remains nearly constant until the fifth decade in females and then declined at a slower rate than BMD. In males, the narrow neck section modulus declined modestly until the fifth decade and then remained nearly constant whereas the shaft section modulus was static until the fifth decade and then increased steadily. The apparent mechanism for the discord between BMD and section modulus is a linear expansion in subperiosteal diameter in both sexes and in both regions, which tends to mechanically offset net loss of medullary bone mass. These results suggest that aging loss of bone mass in the hip does not necessarily mean reduced mechanical strength. Femoral neck section moduli in the elderly are on the average within 14% of young values in females and within 6% in males.

Abstract IGFBP-4 is an inhibitor of IGF-I in bone. We show that TGF-β regulates IGFBP-4 and enhances IGF-I-stimulated growth of cultured human bone cells through increased expression of an IGFBP-4 protease, PAPP-A. This effect of TGF-β on IGF-I bioavailability may promote local bone formation. Insulin-like growth factor binding protein (IGFBP-4) proteolysis is implicated in the regulation of local insulin-like growth factor (IGF)-I bioavailability during bone remodeling. The IGFBP-4 protease secreted by normal adult human osteoblastic (hOB) cells in culture is a novel metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). We have recently identified an inhibitor of PAPP-A, the precursor form of major basic protein (proMBP). Very little is known about the molecular regulation of this IGFBP-4 protease system. In the present study, we determined the effect of transforming growth factor (TGF)-β and IGF-II, the two most abundant growth factors in human bone, on PAPP-A and proMBP expression in primary cultures of hOB cells. Treatment with TGF-β resulted in time- and dose-dependent increases in PAPP-A mRNA expression, with a maximal 12-fold increase after 24 h of stimulation with 10 ng/ml TGF-β. Increased PAPP-A levels in hOB cell-conditioned medium paralleled PAPP-A gene expression. In addition, TGF-β completely suppressed proMBP expression. Treatment of hOB cells with IGF-II had no effect on PAPP-A or proMBP gene expression. However, IGFBP-4 proteolysis in cell-free assay was dependent on IGF-II, and there was increased IGF-II-dependent IGFBP-4 protease activity in conditioned medium from hOB cells that were treated with TGF-β. IGF-I stimulation of hOB cell proliferation was markedly enhanced by pretreatment with TGF-β and [Leu27]IGF-II, and this enhancement was prevented with protease-resistant IGFBP-4. In summary, TGF-β regulates IGFBP-4 proteolysis in hOB cells through increased expression of the protease, PAPP-A, and decreased expression of the inhibitor, proMBP. However, functional activation of the IGFBP-4 protease system is dependent on IGF-II, which acts at a post-translational level. These data support a model whereby local TGF-β and IGF-II in the bone microenvironment coordinately amplify IGF-I bioavailability through controlled IGFBP-4 proteolysis, which may be a means to promote bone formation.

Numerous reports in the literature associate head trauma with high-frequency hearing losses, often mimicking "4K notches" attributed to noise exposure. We have observed that some patients with a positive history for head trauma may show midfrequency notches in their audiometric configurations.

Nonfatal penetrating injuries to the brainstem offer a unique opportunity to assess subcortical auditory pathway function. A case study of a patient suffering a severe nailgun accident is presented. Hearing sensitivity and acoustic reflexes were normal bilaterally, but word recognition was reduced for one ear. Auditory brainstem response results indicated waves I–IV were present bilaterally, but wave V was absent bilaterally. Results of vestibular findings indicated central pathology also. Results of audiologic, vestibular, radiologic, neurologic, and physical medicine examinations are discussed.

Widespread applications of totally laparoscopic aortic reconstructions have been limited by the long cross-clamp time required to suture the aortic anastomosis despite improvement in instrumentation. The authors' hypothesis was that a “one-step anastomosis concept” using an intraluminal stapler would allow shorter cross-clamp time but similar patency and imperviousness as videoscopic suturing techniques. An intraluminal stapler (Endopath-ILS, Ethicon) with a modified anvil was used to perform videoscopic-assisted thoracic aorta-to-iliac artery bypass with a 21 mm by 8 mm polytetrafluoroethylene (PTFE) graft in 22 sheep through a minimally invasive approach using a 5 cm thoracotomy. The graft-to-iliac artery anastomoses were hand sutured through a flank incision. Twelve sheep were used to establish the technique and 10 subsequent animals constituted the study group. Aortic cross-clamp time, imperviousness, and need for additional sutures were recorded and compared to previously reported data using videoscopic suturing in pigs. Patency was assessed by comparing lower limb arterial pressures. Macroscopic and microscopic examinations of the anastomoses were performed at different time-points within the first 3 months. Videoscopic-assisted stapled anastomoses were also performed on atherosclerotic aortas of 3 human cadavers. Stapled anastomoses between the thoracic aorta and PTFE graft were completed in 8 of 10 animals. Two animals were euthanized after stapler failure and anastomotic bleeding. Sutures to strengthen the anastomosis had to be used in 4 cases. Mean aortic cross-clamp time in 8 successful cases was 4.3 ±2.9 minutes (range 2–11 minutes) and was significantly shorter than clamp time of videoscopic suturing technique (48.7 ±9.4 minutes, p<0.0001). Imperviousness was good or excellent in 4 animals and fair in 4 animals. All anastomoses were patent at the end of the procedure. Examination of the anastomosis of the 2 failed interventions showed medial aortic tear surrounding the anastomosis in 1 case and misfired staples in the other. No graft occlusion was noted during follow-up ranging from 0 to 12 weeks. At the time of harvest, no bleeding was noted after epinephrine and volume infusion to increase mean arterial pressure to 200 mm Hg for 15 minutes. Macroscopic examination of the anastomoses revealed adequate healing with circumferential stapling of the prosthesis to the aortic wall and no stenosis or thrombus except in 1 false aneurysm (1/7, 14%). Surface electron microscopy showed cells coverage of the anastomosis surface. When applied on human cadaver thoracic and abdominal aorta with atherosclerotic changes, clamping times of less than 5 minutes were achieved. However, imperviousness tested with saline was poor. An automatic stapling device allows performance of a graft-to-aorta anastomosis through a minimally invasive approach with shorter clamping time than a videoscopic suturing technique. However, the current technique of aortic stapling is unreliable and further improvements are needed.