Looking for resilience: Understanding the longitudinal trajectories of responses to stress

Taking advantage of two large, population-based, and longitudinal datasets collected after the 1999 floods in Mexico (n = 561) and the September 11, 2001 terrorist attacks in New York (n = 1267), we examined the notion that resilience may be best understood and measured as one member of a set of trajectories that may follow exposure to trauma or severe stress. We hypothesized that resistance, resilience, recovery, relapsing/remitting, delayed dysfunction, and chronic dysfunction trajectories were all possible in the aftermath of major disasters. Semi-parametric group-based modeling yielded the strongest evidence for resistance (no or mild and stable symptoms), resilience (initially moderate or severe symptoms followed by a sharp decrease), recovery (initially moderate or severe symptoms followed by a gradual decrease), and chronic dysfunction (moderate or severe and stable symptoms), as these trajectories were prevalent in both samples. Neither Mexico nor New York showed a relapsing/remitting trajectory, and only New York showed a delayed dysfunction trajectory. Understanding patterns of psychological distress over time may present opportunities for interventions that aim to increase resilience, and decrease more adverse trajectories, after mass traumatic events.     

Effect of intravenous sedation on the outcome of transvaginal oocyte retrieval: a comparative study of propofol- and methohexital-based techniques

This study retrospectively compares patients who underwent outpatient transvaginal follicle aspiration with either a propofol- or methohexital-based intravenous sedation technique. Data collected from patient charts (n = 212) over a 46-month period were analyzed to determine the effects of each sedation technique on procedure and recovery times, number of retrieved ova, as well as rates of nausea, fertilization, cleavage, pregnancy, and delivery. All patients were included in the study, regardless of age or diagnosis. procedure time was lower in the propofol group (51 t 18 min) than in the methohexital group (61 I 20 min) (p > 0.01). Patients in the methohexital group (139 2 51 min) spent more time in the recovery room than did those in the propofol group (71 ? 34 min) (p > 0.01). The nausea rates were significantly lower in the propofol group compared with the methohexital group (1.9% vs. 14.4%, respectively) (p > 0.02). Fertilization rate in the propofol group was 77.7% and was 62.9% in the methohexital group (p > 0.01). The numbers of retrieved ova and the cleavage rates were similar in both groups. The rate of pregnancy in patients sedated with propofol (46.1%) was higher than the methohexital group (26.9%) (p > 0.02). Delivery rate was 38.5% in the propofol group and 20.6% in the methohexital group (p > 0.02). In summary, propofol intravenous sedation for transvaginal follicle aspiration was associ- ated with an improved outcome. Pregnancy and delivery rates were higher while nausea, an unpleasant side effect, was sharply reduced.     

Resistance exercise training and alendronate reverse glucocorticoid-induced osteoporosis in heart transplant recipients.

BACKGROUND: Immunosuppression therapy with bolus glucocorticoids causes regional osteoporosis in the axial skeleton of heart transplant recipients (HTR). No preventive strategy is generally accepted for steroid-induced bone loss. METHODS: To determine the efficacy of an anti-osteoporosis regimen that combined a bisphosphonate agent (alendronate sodium) with the osteogenic stimulus of mechanical loading, 25 HTRs were randomly assigned either to a group that received alendronate (10 mg/day) for 6 months (ALEN; n = 8), a group that received alendronate (10 mg/day) and performed specific resistance exercises for 6 months (ALEN + TRN; n = 8) or to a non-intervention control group (CONTR; n = 9). Alendronate was initiated at 2 months after transplantation. Bone mineral density (BMD) of the total body, femur neck and lumbar spine (L-2 and L-3) was measured by dual-energy X-ray absorptiometry before and 2, 5 and 8 months after transplantation. Resistance training consisted of lumbar extension exercise (MedX) performed 1 day/week and 8 variable resistance exercises (MedX) performed 2 days/week. RESULTS: Pre-transplantation BMD values did not differ among the 3 groups. BMD of the total body, femur neck and lumbar vertebra were significantly decreased below baseline at 2 months after transplantation in CONTR (-2.6 +/- 0.9%, -5.1 +/- 1.8%, -12.5 +/- 4.2%, respectively), ALEN (-2.8 +/- 0.8%, -5.3 +/- 1.6%, -12.0 +/- 3.9%) and ALEN + TRN groups (-2.7 +/- 1.0%, -5.6 +/- 2.1%, -11.2 +/- 3.7%). CONTR had further significant losses of BMD after 3 and 6 months. ALEN had no further regional BMD losses after initiation of alendronate therapy. ALEN + TRN restored BMD of the whole body, femur neck and lumbar vertebra to within 0.9%, 2.1%, and 3.4% of pre-transplantation levels, respectively. CONCLUSIONS: Resistance exercise plus alendronate was more efficacious than alendronate alone in restoring BMD in HTRs. Our results indicate that anti-osteoporosis therapy in this population should include both an anti-resorptive agent as well as an osteogenic stimulus, such as mechanical loading.     

Preclinical pharmacologic studies of the new antitumor agent carmethizole (NSC-602668) in the mouse and beagle dog

Summary The chemical breakdown of carmethizole [1-methyl-2-methylthio-4,5-bis-(hydroxymethyl)imidazole-4,5-bis(N-methylcarbamate)hydrochloride] and its pharmacokinetics in the mouse and beagle dog were studied. Carmethizole was relatively unstable in aqueous media, having a half-life of 1 h in 0.9% sodium chloride, human whole blood, human plasma, and dog urine at 37°C. Its major breakdown product in 0.9% sodium chloride and pH 5.0 sodium phosphate buffer was carmethizole diol. When carmethizole was added to pH 7.0 or pH 9.0 sodium phosphate buffer, the major breakdown product was carmethizole diol-4-monophosphate. Carmethizole reacted directly with glutathione at pH 8.0, forming a glutathione adduct of carmethizole monocarbamate. Elimination of the drug from the plasma of the beagle dog following i.v. bolus doses of 22.4 and 4.3 mg/kg was biphasic. At these doses the terminal half-life was 39 and 46 min, respectively, and the respective total body clearance was 4.6 and 7.7 ml/min per kg. The 22.4 mg/kg dose was lethal to the beagle dog by day 4. Elimination of carmethizole from the plasma of mice following an i. v. bolus dose of 115 mg/kg was monoexponential, with a half-life of 11.6 min and a total body plasma clearance of 43.6 ml/min per kg. When the drug was infused at 230 mg/kg over 8 h into mice, the total body clearance was 40.8 ml/min per kg. Following the i.v. bolus administration of carmethizole to mice, 30% of the total dose was excreted in urine over 3 h as carmethizole diol, 10%, as carmethizole diol-sulfate, 3.4%, as carmethizole 4-monocarbamate, and 2.4%, as unchanged drug.     

Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks,chromosomal instability,and reduced life span in mice

The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(lex1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51.     

Holt-Oram syndrome associated with the hypoplastic left heart syndrome

We present the first case of Holt-Oram syndrome associated with the lethal congenital heart defect of hypoplastic left heart syndrome. The possible pathophysiological link is explored and the need for careful genetic and cardiologic evaluation in these patients is reiterated.     

Physical Deletion of the p53 Gene in Bladder Cancer: Detection by Fluorescence in Situ Hybridization

To understand better the role of physical p53 deletion in bladder cancer, 106 formalin-fixed and 45 unfixed bladder tumors were examined using fluorescence in situ hybridization. Probes for centromere 17 and the p53 locus were hybridized simultaneously to interphase tumor cells to analyze p53 and chromosome 17 copy number on a cell by cell basis. 17p deletion was found in four of 43 pTa tumors, 18 of 43 pT1 tumors and 29 of 58 pT2-4 tumors (P = 0.0001). 17p deletion was also highly correlated with grade (P = 0.0001) and with p53 immunostaining (P = 0.0005). Chromosome 17 polysomy was associated with stage, grade, 17p deletions, and p53 immunostaining (P = 0.0001). The strong difference in centromere 17 copy number and 17p deletions between pTa and pT1 tumors supports a relevant biological distinction between pTa and pT1 tumors.