Impact of total body water fluctuations on estimation of body fat from body density

The purpose was to investigate the possibility that variability in body weight in females due to water retention causes differences in body density (Db) values determined by hydrostatic weighing (HW). Determination of total body water (TBW) and Db were concurrently measured in seven females who experienced considerable fluctuations in body weight (1.5-4.5 kg) and seven males, ages 19-24. Females were measured when they felt they were at their lowest (LO) and highest (HI) body weights (BW) during a menstrual cycle. Males were randomly tested approximately 3 wk apart. Mean values of selected variables were compared in the LO vs HI testing sessions by paired t-tests. Significant mean differences were found in the females (P less than 0.01) for the following variables: BW (kg) (LO = 58.9, HI = 61.1), Db (g.cc-1) (LO = 1.0430, HI = 1.037), and percent body fat (%BF) as determined by HW alone (LO = 24.8%, HI = 27.6%). Variables significant at the P less than 0.05 level were TBW(l) (LO = 33.6, HI = 35.1) and %TBW of the fat-free body (LO = 74.5, HI = 75.9). However, changes in TBW could not entirely account for observed changes in Db. Only mean BW (kg) was significant (P less than 0.01) in the males (LO = 74.3, HI = 74.6). It is concluded that changes in TBW can in part result in significantly different Db values obtained from HW in females who did experience perceptible changes in BW during a menstrual cycle. The remaining differences may be due to changes in fat and protein content or methodological errors.     

AIDS-related cholangitis: radiographic findings in nine patients

Acalculous inflammation of the biliary tract is a recently reported complication of the acquired immunodeficiency syndrome (AIDS). In a 33-month period, nine men with AIDS were evaluated because of right upper quadrant and/or epigastric pain, jaundice, or abnormal liver function test results. Each patient underwent ultrasonography and endoscopic retrograde cholangiopancreatography; seven also underwent computed tomography. In eight of nine patients the imaging studies disclosed intrahepatic and extrahepatic bile duct changes identical to those seen in sclerosing cholangitis (strictures, focal dilatation, thickened duct walls). Isolated papillary stenosis and ductal dilatation were present in one patient, while eight patients had some stricturing of the distal common duct. The combination of papillary stenosis and intrahepatic ductal strictures appears unique to AIDS-related cholangitis. Endoscopic papillotomy provided variable relief to symptoms and biochemical abnormalities. Cholangitis caused by cytomegalovirus and/or Cryptosporidium infection is the proposed pathophysiologic mechanism.     

The National Marrow Donor Program

As the number of successful marrow transplants has increased, the lack of HLA-identical sibling donors for 60 to 70 percent of transplant candidates has become a serious problem. Pilot studies established that marrow transplantation between phenotypically HLA-identical, unrelated individuals can be accomplished successfully. Therefore, the National Marrow Donor Program was established to develop a large file of volunteer marrow donors and to serve as a center for the coordination of the donor search and donor-recipient matching processes. By November 1991, 63 months after the program was established, 457,205 potential marrow donors typed for HLA-A and -B antigens had agreed to be listed in the marrow donor registry. A donor search had been initiated for 8481 patients. At least one potential donor matched for at least three of the four HLA-A and -B antigens was located for 99.8 percent of patients. Among the 3156 searches that were completed, 940 (29.8%) resulted in a transplant. The median time in which to locate a matched donor, complete all predonation evaluations, and obtain donor consent was 208 days. The most common diagnosis in patients who underwent transplantation was chronic myelogenous leukemia (42.0%). When this analysis was completed in November 1991, the National Marrow Donor Program was operating a national network of 99 donor centers and 53 transplant centers. The donor file was increasing rapidly, and a follow- up system was in place to determine the effects of donation on the donors and the outcome in the patients who underwent transplantation. This national network of donor and transplant centers exists and is now facilitating unrelated-donor marrow transplants. The National Marrow Donor Program made it possible to locate donors for many patients in need of a transplant and helped to determine the role of unrelated- donor marrow transplants in the treatment of many diseases.     

Thermodynamic extent of counterion release upon binding oligolysines to single-stranded nucleic acids.

A major contribution to the binding free energy associated with most protein-nucleic acid complexes is the increase in entropy due to counterion release from the nucleic acid that results from electrostatic interactions. To examine this quantitatively, we have measured the thermodynamic extent of counterion release that results from the interaction between single-stranded homopolynucleotides and a series of oligolysines, possessing net charges z = 2-6, 8, and 10. This was accomplished by measuring the salt dependence of the intrinsic equilibrium binding constants--i.e., (delta log Kobs/delta log[K+])--over the range from 6 mM to 0.5 M potassium acetate. These data provide a rigorous test of linear polyelectrolyte theories that have been used to interpret the effects of changes in bulk salt concentration on protein-DNA binding equilibria, since single-stranded nucleic acids have a lower axial charge density than duplex DNA. Upon binding to poly(U), the thermodynamic extent of counterion release per oligolysine charge, z, is 0.71 +/- 0.03, which is significantly less than unity and less than that measured upon binding duplex DNA. These results are most simply interpreted using the limiting law predictions of counterion condensation and cylindrical Poisson-Boltzmann theories, even at the high salt concentrations used in our experiments. Accurate estimates of the thermodynamic extent of counterion binding and release for model systems such as these facilitate our understanding of the energetics of protein-nucleic acid interactions. These data indicate that for simple oligovalent cations, the number of ionic interactions formed in a complex with a linear nucleic acid can be accurately estimated from a measure of the salt dependence of the equilibrium binding constant, if the thermodynamic extent of ion release is known.     

Escherichia coli helicase II (UvrD) protein initiates DNA unwinding at nicks and blunt ends.

The Escherichia coli uvrD gene product, helicase II, is required for both methyl-directed mismatch and uvrABC excision repair and is believed to function by unwinding duplex DNA. Initiation of unwinding may occur specifically at either a mismatch or a nick, although no direct evidence for this has previously been reported. It has recently been shown that helicase II can unwind fully duplex linear and nicked circular DNA with lengths of at least approximately 2700 base pairs in vitro; hence, a flanking region of single-stranded DNA is not required to initiate DNA unwinding. In studies with uniquely nicked duplex DNA, we present EM evidence that helicase II protein initiates DNA unwinding at the nick, with unwinding proceeding bidirectionally. We also show that helicase II protein initiates DNA unwinding at the blunt ends of linear DNA, rather than in internal regions. These data provide direct evidence that helicase II protein can initiate unwinding of duplex DNA at a nick, in the absence of auxiliary proteins. We propose that helicase II may initiate unwinding from a nick in a number of DNA repair processes.     

Relationship between albuminuria and cardiovascular disease in Type 2 diabetes

Impaired renal function and albuminuria, common among people with type 2 diabetes, are strong predictors of atherosclerotic cardiovascular events. However, the relationships among albuminuria and measures of calcified atherosclerotic plaque are unknown. Coronary and carotid artery calcified plaque were measured using fast-gated helical computed tomography, and B-mode ultrasonography measured common carotid artery intima-medial thickness (IMT) in 588 white participants with type 2 diabetes from 325 families ascertained for the presence of multiple siblings with type 2 diabetes. Measured risk factors included age, gender, BP, body mass index, GFR, glycosylated hemoglobin, LDL cholesterol, HDL cholesterol, smoking, and medications that affect urine albumin:creatinine ratio (ACR). Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for an association among coronary artery calcified plaque, carotid artery calcified plaque, carotid IMT, and ACR while adjusting for measured risk factors. Participants had a mean +/- SD (median) age of 61.2 +/- 9.2 yr (61.0 yr), ACR of 106.2 +/- 590 mg/g (12.9 mg/g), GFR of 93.3 +/- 33.2 ml/min (87.4 ml/min), coronary artery calcium mass score of 1394 +/- 2685 (323), carotid artery calcium mass score of 295 +/- 652 (51), and IMT of 0.66 +/- 0.12 mm (0.65 mm). Adjusting for the measured covariates, ACR was strongly and positively associated with coronary artery calcium (P = 0.004) and carotid artery calcium (P = 0.0004). Albuminuria is strongly associated with calcified plaque in the coronary and carotid arteries in white individuals with type 2 diabetes and relatively preserved renal function.     

Weight lifted in strength training predicts bone change in postmenopausal women

PURPOSE: The aim of this study was to examine the relationship between weight lifted in 1 yr of progressive strength training and change in bone mineral density (BMD) in a group of calcium-replete, postmenopausal women. METHODS: As part of a large clinical trial, 140 calcium-supplemented women, 44-66 yr old, were randomized to a 1-yr progressive strength-training program. Half of the women were using hormone replacement therapy. Three times weekly, subjects completed two sets of six to eight repetitions in eight core exercises at 70-80% of one repetition maximum. BMD was measured at baseline and 1 yr. RESULTS: In multiple linear regression, the increase in femur trochanter (FT) BMD was positively related to total weight lifted (0.001 g.cm (-2)) for a SD of weight lifted, P< 0.01) after adjusting for age, baseline factors, HRT status, weight change, cohort, and fitness center. The weighted squats showed the strongest (0.002 g.cm(-2)) for a SD of weight lifted, P< 0.001), whereas the back extension exhibited the weakest (0.0005 g.cm(-2)) for a SD of weight lifted, P< 0.26) association with change in FT BMD. The amount of weight lifted in the weighted march exercise was significantly related to total body BMD (0.0006 g.cm(-2)) for a SD of weight lifted, P< 0.01). The associations between weight lifted and BMD for the femur neck or lumbar spine were not significant. CONCLUSION: Evidence of a linear relationship between BMD change and total and exercise-specific weight lifted in a 1-yr strength-training program reinforces the positive association between this type of exercise and BMD in postmenopausal women.     

A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents

OBJECTIVE: In adolescents with substance use disorder (SUD), comorbid attention-deficit/hyperactivity disorder (ADHD) is associated with greater severity of substance abuse, conduct problems, and worse treatment outcomes. Although many controlled trials have established the efficacy of psychostimulants, including pemoline, for ADHD in children and adolescents, none have been conducted in adolescents with SUD. This randomized, placebo-controlled trial, conducted between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance abuse and conduct problems. METHOD: Sixty-nine adolescents (aged 13-19) with conduct disorder (CD), SUD, and ADHD were recruited from the community and randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as tolerated. RESULTS: Pemoline had greater efficacy than placebo for ADHD as determined by significantly more Clinician's Global Impression-Improvement (CGI-I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent-rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study completers compared to placebo-treated completers (pemoline, n = 17; placebo, n = 16; p <.01), but no difference between groups in the intent-to-treat analysis (n = 68; p <.13). Substance use did not decline in either group, and there was no difference between groups in baseline to study endpoint change in substance use or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. CONCLUSIONS: Pemoline was efficacious for ADHD but did not have an impact on CD or substance abuse in the absence of specific treatment for SUD.     

The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function

The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (> or =65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean +/- SD dpm/10(6) cells) were 18,554 +/- 9,070 (n=257), 14,847 +/- 7,082 (n=86), and 12,155 +/- 6,334 (n=11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.