Stressful life events and adolescent substance use and depression: conditional and gender differentiated effects

Stressful life circumstances have myriad influences on human health and behavior. Early research focused on the variable distribution of stress and its effects by socioeconomic status, race, and gender. More recent research indicates that variation by age is also an important consideration. For example, adolescent reactions to stressful life events are often inconsistent with adult reactions to similar life situations and transitions. Moreover, since most studies assess only a single outcome--usually depression--they risk classification bias since analyses exclude other potential stress-related outcomes. This paper assesses the gender distinct effects of stressful life events on two outcomes among adolescents, substance use and depressive symptoms. The results of a second-order regression model indicate that life events affect female, but not male, depressive symptoms, especially when self-esteem is low or mastery is high. Furthermore, life events affect substance use when peer drug use is high, or when parental support is low, but this latter effect is limited to female adolescents.     

Disruption of redox homeostasis in the transforming growth factor-alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis

In previous studies we have demonstrated that transforming growth factor (TGF)-alpha/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that may be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors. By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2',7'-dichlorofluorescin diacetate, was significantly elevated in TGF-alpha/c-myc transgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However, hepatic tumors which developed in TGF-alpha/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathione peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-alpha and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-alpha/c-myc mouse model.     

Keloids and end-stage renal disease

We determined the angiotensin-converting enzyme (ACE) insertion/deletion genotype in 209 hypertensive individuals and in 100 matched normotensive controls. A significant association was detected between hypertension and the deletion/deletion (D/D) genotype of the ACE gene when the relation was adjusted for age, sex, and body mass index.     

Patterns of general health care and STD services use among high-risk youth in Denver participating in community-based urine chlamydia screening

BACKGROUND: In the United States, youth are at highest risk for STDs, and innovative programs have been called for to increase their access to essential STD-related services. To guide the development of such programs, locally relevant information is needed on current use of general health care and STD services in this population. GOAL: To study access to and use of general health care and STD services in a purposive sample of high-risk youth in inner-city Denver. STUDY DESIGN: An interview-based survey conducted as part of a community program for urine chlamydia screening targeting black and Hispanic youth 13 years to 25 years. RESULTS: Of 221 sexually experienced youth in the survey, 72% had accessed general health services in the past year and 39% reported an STD evaluation at any time in the past. Community and school clinics were reported by 50% as a source for general health care and by 62% as a source for STD services. STD clinics were reported by only 14% as a source for STD services. Routine checkups were the most important reasons to seek general health care, yet of those who went for a routine checkup, only 34% reported an STD evaluation. Although few barriers appeared to exist in accessing general health care, anticipated anxiety about procedures and results formed the major barrier to accessing STD services. CONCLUSIONS: Use of general health services was common in this population of high-risk adolescents; however, the provision of STD services as part of general health care visits appeared to be low. On the basis of these findings, a comprehensive STD prevention strategy may be envisioned, which would include provider interventions to increase the provision of STD prevention services in general health care settings; community interventions to enhance access to general health care and STD services; and community-based screening programs for those not able or willing to seek clinic-based services.     

Structural determinants of the bifunctional corn Hageman factor inhibitor: x-ray crystal structure at 1.95 A resolution

Corn Hageman factor inhibitor (CHFI) is a bifunctional 127 residue, 13.6 kDa protein isolated from corn seeds. It inhibits mammalian trypsin and Factor XIIa (Hageman Factor) of the contact pathway of coagulation as well as alpha-amylases from several insect species. Among the plasma proteinases, CHFI specifically inhibits Factor XIIa without affecting the activity of other coagulation proteinases. We have isolated CHFI from corn and determined the crystallographic structure at 1.95 A resolution. Additionally, we have solved the structure of the recombinant protein produced in Escherichia coli at 2.2 A resolution. The two proteins are essentially identical. The proteinase binding loop is in the canonical conformation for proteinase inhibitors. In an effort to understand alpha-amylase inhibition by members of the family of 25 cereal trypsin/alpha-amylase inhibitors, we have made three-dimensional models of several proteins in the family based on the CHFI coordinates and the coordinates determined for wheat alpha-amylase inhibitor 0.19 [Oda, Y., Matsunaga, T., Fukuyama, K., Miyazaki, T., and Morimoto, T. (1997) Biochemistry 36, 13503-13511]. From an analysis of the models and a structure-based sequence analysis, we propose a testable hypothesis for the regions of these proteins which bind alpha-amylase. In the course of the investigations, we have found that the cereal trypsin/alpha-amylase inhibitor family is evolutionarily related to the family of nonspecific lipid-transfer proteins of plants. This is a new addition to the group which now consists of the trypsin/alpha-amylase inhibitors, 2S seed storage albumins, and the lipid-transfer family. Apparently, the four-helix conformation has been a successful vehicle in plant evolution for providing protection from predators, food for the embryo, and lipid transfer.     

MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily

The DNA glycosylase MutY, which is a member of the Helix-hairpin-Helix (HhH) DNA glycosylase superfamily, excises adenine from mispairs with 8-oxoguanine and guanine. High-resolution crystal structures of the MutY catalytic core (cMutY), the complex with bound adenine, and designed mutants reveal the basis for adenine specificity and glycosyl bond cleavage chemistry. The two cMutY helical domains form a positively-charged groove with the adenine-specific pocket at their interface. The Watson-Crick hydrogen bond partners of the bound adenine are substituted by protein atoms, confirming a nucleotide flipping mechanism, and supporting a specific DNA binding orientation by MutY and structurally related DNA glycosylases.     

Urokinase receptor-dependent upregulation of smooth muscle cell adhesion to vitronectin by urokinase

The plasminogen activator system has been implicated in the modulation of the response to vascular injury. Although urokinase-type plasminogen activator (uPA) and its receptor (uPAR) may enhance matrix degradation as well as migration and invasion by smooth muscle cells (SMCs), their roles in cell adhesion are uncertain. Therefore, we examined the ability of uPA and uPAR to modulate adhesion of cultured human vascular SMCs to various matrices. We demonstrated a dose-dependent stimulation of adhesion by single-chain uPA (scuPA) to vitronectin (maximum 1.55-fold [+/-0. 04-fold] increase, 10 nmol/L, P<0.002) but not to laminin, collagen I, or collagen IV. Baseline adhesion to vitronectin was completely inhibited by both EDTA and RGD peptide but was restored to >40% of control in the presence of scuPA (P=0.001 and 0.046, respectively). Adhesion to vitronectin was also significantly enhanced by the amino-terminal fragment of uPA (P=0.007) and two-chain, high-molecular-weight uPA (P<0.01) but not by the low-molecular-weight fragment of uPA, which lacks the receptor-binding domain. Aprotinin, a plasmin inhibitor, had no effect on baseline or scuPA-stimulated adhesion, suggesting a plasmin-independent process. Preincubation of scuPA with soluble uPAR inhibited scuPA stimulation of adhesion by 88+/-14% (P=0.01), as did pretreatment of SMCs with phosphatidylinositol-specific phospholipase C, which removes glycophosphatidylinositol-anchored proteins, including uPAR. Antibodies to both alphavbeta3 and alphavbeta5 integrin inhibited baseline adhesion but not scuPA stimulation. Finally, coating plates with scuPA alone enabled cell adhesion, which could be inhibited by both soluble uPAR and anti-uPAR antibodies. These data suggest that uPA stimulates adhesion of SMCs specifically to vitronectin and that it is mediated by an interaction with uPAR. Upregulation of both proteins after vascular injury may facilitate migration through stimulation of both matrix degradation and cell adhesion.     

Biomechanical evaluation of the schuhli nut

The schuhli out is a device designed to lock an AO 4.5-mm cortical screw to a 4.5-mm dynamic compression plate independent of bony contact with the plate. The nut engages the screw below the plate, elevating the plate, and locking the screw at a 90 degrees angle, thus preventing toggling. Photoelastic modeling and biomechanical testing on sheep tibias were done to determine the mechanical properties of constructs using schuhli nuts. Use of schuhli nuts was shown to decrease stress in the bone below the plate. The initial axial stiffness of a construct fixed with schuhli nuts is less than a construct with standard screws, but the rate of loss of stiffness with cyclic loading is similar. When a cortical defect is present at the near cortex and the screw engages the far cortex only, the use of a schuhli nut significantly improves the stability of the construct compared with a standard screw alone, and behaves mechanically the same as a standard construct with intact cortices. This indicates that the schuhli nut acts as a substitute for a deficient cortex. The schuhli nut can be useful in osteoporotic bone because it prevents the screw from stripping the threads in the bone as the screw is advanced. It also serves to lock the screw to help prevent the screw from backing out. The schuhli nut may be a useful tool to improve stability in the treatment of complex fractures, reconstructions, or in pathologic bone.     

Meningococcal meningitis presenting as stroke in an afebrile adult

We describe a healthy, afebrile 26-year-old man who presented to the emergency department with left hemiparesis and cranial nerve deficits caused by meningococcal meningitis. The results of the computed tomographic scan of the head were negative. Magnetic resonance imaging showed lesions in the basal ganglia and caudate consistent with ischemic infarcts. The neurologic deficits initially progressed but improved to near-resolution after 1 month. This case was unusual in that the patient was afebrile despite a high bacterial load and significant neurologic deficits. His presentation thus mimicked a straightforward stroke. Close attention to the physical examination findings led to a comprehensive evaluation that yielded the correct diagnosis.