Neuroactive pregnanolone isomers during pregnancy

The pregnanolone isomers (PI) allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), isopregnanolone (3beta-hydroxy-5alpha-pregnan-20-one), epipregnanolone (3beta-hydroxy-5beta-pregnan-20-one), progesterone, and estradiol were measured in 138 pregnant women. The sampling was carried out from the first through the 10th month of pregnancy. Gas chromatography-mass spectrometry analysis and RIA were used for the measurement of steroid levels. The ratios of individual PI were similar to those found previously around parturition: about 25:10:7:1 for allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone, respectively. All the PI showed a significant increase during pregnancy, which was more pronounced in the 3alpha-steroids. The results indicated changing ratios between 3alpha- and 3beta-PI and between 5alpha- and 5beta-PI throughout pregnancy. The constant allopregnanolone/isopregnanolone ratio found through pregnancy weakened the hypothesis of the role of isopregnanolone in the onset of parturition. The ratio of estradiol (stimulating uterine activity) to 5alpha-PI and epipregnanolone exhibited significant changes during pregnancy in favor of estradiol up to the sixth or seventh month, in contrast to the constant estradiol/pregnanolone ratio. A pregnancy-stabilizing role of pregnanolone, counterbalancing the stimulating effect of estradiol on the onset of parturition, was suggested.     

Quantification ofN-acetyl-l-aspartic acid in urine by isotope dilution gas chromatography-mass spectrometry

Summary A method for quantification ofN-acetyl-l-aspartic acid by isotope dilution gas chromatography-mass spectrometry using¹⁵ N-[²H₃]acetyl-l-aspartic acid is described. The method is sufficiently sensitive to be used with solvent extraction techniques commonly employed for urinary organic acid analysis. The mean concentration ofN-acetyl-l-aspartic acid in 80 normal and abnormal control urine specimens was 19.7±10.8 mg/g creatinine (12.7±7.8 mmol/mol creatinine). Seven patients, ages 9 months to 7 years, with Canavan-van Bogaert syndrome had urinaryN-acetyl-l-aspartic acid levels from 606 to 4760 mg/g creatinine. The method can also be used with cerebrospinal fluid, in which the concentration ofN-acetyl-l-aspartic acid is about one-tenth of that in urine.     

Massive Lindane Overdose with Toxicokinetics Analysis

Background

Lindane is a possible carcinogen with known teratogenicity and immunologic and neurotoxic properties. Despite reports of seizures, coma, and death associated with its use as well as banning of its environmental use by the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) still allows treatment with lindane as a second-line scabicide and pediculicide. We present a case of a massive suicidal ingestion of lindane in which the patient survived the ingestion, though he did expire shortly thereafter from an unrelated cause pre-discharge.

Methods

Pharmacokinetic analysis of serum lindane concentrations was performed with Phoenix® WinNONLIN®. The estimated distribution half-life for lindane was 10.3 h, and the terminal half-life was 162.9 h, much longer than the previously reported terminal half-life of 25–36 h. Because of this long half-life, repeated lindane exposures may lead to accumulation of lindane in the tissues.

Result

After overdose, toxicity may be delayed and full recovery may be prolonged.     

A comparison of the psychosocial functioning of children with drug-versus alcohol-dependent fathers

The present study compared the psychosocial functioning of children whose fathers primarily abused illicit drugs other than alcohol (n = 51 ) to children from a demographically matched sample of families whose fathers abused alcohol (n = 51). Children with drug-abusing (DA) fathers exhibited significantly more negative child behaviors on a standardized child-rating scale than did children from homes with alcohol-abusing fathers. In addition, a significantly greater proportion of children with DA fathers met clinical cutoffs indicative of psychosocial impairment (n = 23: 45%) than did children whose fathers abused alcohol (n = 5; 10%). Mediation analyses indicated that severity of drug, legal, medical, employment, and family problems partially mediated the relationship between type of family (i.e., families with fathers who had an alcohol problem versus families with fathers who had a drug problem) and children's psychosocial adjustment.     

Myocardial gene expression of glucose transporter 1 and glucose transporter 4 in response to uteroplacental insufficiency in the rat

Uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and subsequent low birth weight, which predisposes the affected newborn towards adult Syndrome X. Individuals with Syndrome X suffer increased morbidity from adult ischemic heart disease. Myocardial ischemia initiates a defensive increase in cardiac glucose metabolism, and individuals with Syndrome X demonstrate reduced insulin sensitivity and reduced glucose uptake. Glucose transporters GLUT1 and GLUT4 facilitate glucose uptake across cardiac plasma membranes, and hexokinase II (HKII) is the predominant hexokinase isoform in adult cardiac tissue. We therefore hypothesized that GLUT1, GLUT4 and HKII gene expression would be reduced in heart muscle of growth-retarded rats, and that reduced gene expression would result in reduced myocardial glucose uptake. To prove this hypothesis, we measured cardiac GLUT1 and GLUT4 mRNA and protein in control IUGR rat hearts at day 21 and at day 120 of life. HKII mRNA quantification and 2-deoxyglucose-uptake studies were performed in day-120 control and IUGR cardiac muscle. Both GLUT1 and GLUT4 mRNA and protein were significantly reduced at day 21 and at day 120 of life in IUGR hearts. HKII mRNA was also reduced at day 120. Similarly, both basal and insulin-stimulated glucose uptake were significantly reduced in day-120 IUGR cardiac muscle. We conclude that adult rats showing IUGR as a result of uteroplacental insufficiency express significantly less cardiac GLUT1 and GLUT4 mRNA and protein than control animals (which underwent sham operations), and that this decrease in gene expression occurs in parallel with reduced myocardial glucose uptake. We speculate that this reduced GLUT gene expression and glucose uptake contribute towards mortality from ischemic heart disease seen in adults born with IUGR.     

Novel effect of vasoactive intestinal polypeptide and peptide histidine isoleucine: inhibition of in vitro secretion of prolactin in the tilapia, Oreochromis mossambicus

The effects of vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) on the in vitro secretion of two prolactins (PRL) from the rostral pars distalis (RPD) and of growth hormone (GH) from the proximal pars distalis (PPD) of the pituitary of the tilapia (Oreochromis mossambicus) were studied. RPDs were incubated for 20 hr in hypoosmotic (280-300 mOsm) or hyperosmotic (340-350 mOsm) Krebs-Ringer bicarbonate medium with added peptide concentrations of 0 (control), 0.3, 3.0, 30, and 300 nM; similarly, PPDs were incubated with the same peptide concentrations in isoosmotic (325 mOsm) medium supplemented with cortisol. PRL and GH in the tissue and secreted into the medium were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by soft laser densitometry of the protein band(s). Neither VIP nor PHI has a detectable effect on the secretion of GH. Secretion of the two PRLs is significantly inhibited by VIP and PHI in both hyperosmotic and hypoosmotic medium. In hyperosmotic medium, 300 nM VIP inhibits secretion of both PRLs by 47%, whereas in hypoosmotic medium, 300 nM VIP inhibits their secretion by 27%. PHI inhibits their secretion by ca. 65% in hyperosmotic medium and by 40% in hypoosmotic medium. There is preliminary immunocytochemical evidence for some VIP-like immunoreactivity (IR), but no conclusive indication of PHI-like IR, in the hypothalamo-hypophysial area. The inhibitory actions of VIP and PHI on PRL secretion in tilapia are in contrast to the known stimulatory actions of VIP and PHI on PRL secretion in tetrapods.     

Weight-Bearing Dorsiflexion Range of Motion and Landing Biomechanics in Individuals With Chronic Ankle Instability

Context

People with chronic ankle instability (CAI) exhibit less weight-bearing dorsiflexion range of motion (ROM) and less knee flexion during landing than people with stable ankles. Examining the relationship between dorsiflexion ROM and landing biomechanics may identify a modifiable factor associated with altered kinematics and kinetics during landing tasks.

Objective

To examine the relationship between weight-bearing dorsiflexion ROM and single-legged landing biomechanics in persons with CAI.

Design

Cross-sectional study.

Setting

Laboratory.

Patients or Other Participants

Fifteen physically active persons with CAI (5 men, 10 women; age = 21.9 ± 2.1 years, height = 168.7 ± 9.0 cm, mass = 69.4 ± 13.3 kg) participated.

Intervention(s)

Participants performed dorsiflexion ROM and single-legged landings from a 40-cm height. Sagittal-plane kinematics of the lower extremity and ground reaction forces (GRFs) were captured during landing.

Main Outcome Measure(s)

Static dorsiflexion was measured using the weight-bearing–lunge test. Kinematics of the ankle, knee, and hip were observed at initial contact, maximum angle, and sagittal displacement. Sagittal displacements of the ankle, knee, and hip were summed to examine overall sagittal displacement. Kinetic variables were maximum posterior and vertical GRFs normalized to body weight. We used Pearson product moment correlations to evaluate the relationships between dorsiflexion ROM and landing biomechanics. Correlations (r) were interpreted as weak (0.00–0.40), moderate (0.41–0.69), or strong (0.70–1.00). The coefficient of determination (r²) was used to determine the amount of explained variance among variables.

Results

Static dorsiflexion ROM was moderately correlated with maximum dorsiflexion (r = 0.49, r² = 0.24), ankle displacement (r = 0.47, r² = 0.22), and total displacement (r = 0.67, r² = 0.45) during landing. Dorsiflexion ROM measured statically and during landing demonstrated moderate to strong correlations with maximum knee (r = 0.69–0.74, r² = 0.47–0.55) and hip (r = 0.50–0.64, r² = 0.25–0.40) flexion, hip (r = 0.53–0.55, r² = 0.28–0.30) and knee (r = 0.53–0.70, r² = 0.28–0.49) displacement, and vertical GRF (−0.47– −0.50, r² = 0.22–0.25).

Conclusions

Dorsiflexion ROM was moderately to strongly related to sagittal-plane kinematics and maximum vertical GRF during single-legged landing in persons with CAI. Persons with less dorsiflexion ROM demonstrated a more erect landing posture and greater GRF.Key Words: ankle sprain, drop landing, neuromuscular control, kinematics, kinetics

Key Points

• During a single-legged landing, persons with chronic ankle instability demonstrated moderate to strong relationships between dorsiflexion range of motion (ROM) and sagittal-plane kinematics at the knee and hip and vertical ground reaction forces.
• Persons with less dorsiflexion ROM exhibited a less flexed landing strategy that attenuated ground reaction forces less efficiently.
• Identifying dorsiflexion deficits may enable clinicians to implement interventions to increase ROM and potentially modify the landing biomechanics that persons with chronic ankle instability exhibit.

Ankle sprains are one of the most common injuries associated with athletics.¹ In addition, up to 73% of athletes who sustain ankle sprains experience recurrent ankle sprains, and 59% report functional loss and residual symptoms that have affected athletic performance.² Residual symptoms resulting from ankle sprains are often associated with a condition known as chronic ankle instability (CAI). This condition is characterized by repetitive ankle-sprain injuries, frequent episodes of the ankle “giving way,” and decreased self-reported function stemming from an acute ankle sprain.³ Persons with CAI have reported diminished health-related quality of life and are at greater risk for developing posttraumatic ankle osteoarthritis.^4,5 Based on the number of persons who develop CAI and the long-term consequences of the condition, a better understanding of the contributing factors is warranted to improve clinical intervention strategies.Chronic ankle instability may be associated with several mechanical impairments in ankle function,³ including a deficit in ankle-joint dorsiflexion range of motion (ROM).^3,6 Whereas the exact prevalence of dorsiflexion ROM deficits has not been determined, 30% to 74% of persons with CAI have at least a 5° deficit in weight-bearing dorsiflexion ROM compared with the contralateral limb.^7,8 The exact origin of dorsiflexion ROM deficits is unclear, but it likely results from arthrokinematic alterations and adaptive shortening of the triceps surae muscle group.^9,10 More importantly, dorsiflexion deficits may limit the ability to fully achieve a closed-packed, stable position of the ankle during dynamic activities, such as gait and landing, which may promote the pathomechanics associated with ankle-sprain mechanisms.^9,11,12 Therefore, a cascade of structural impairments leading to decreased dorsiflexion ROM may affect the ability to execute functional activities and ultimately contribute to the repeated ankle sprains and episodes of giving way related to CAI.Dorsiflexion ROM plays a prominent role in the biomechanics of tasks that require landing.¹³ Greater passive open chain dorsiflexion ROM has been associated with greater hip and knee flexion and lower ground reaction forces (GRFs) during a jump-landing task in healthy persons.¹³ Those with greater dorsiflexion ROM land with a less erect posture by using greater sagittal-plane displacement, which allows the body to attenuate forces more efficiently.¹³ Therefore, the available amount of dorsiflexion ROM may influence function not only at the ankle but also at more proximal structures in the lower extremity. Persons with CAI have demonstrated less dorsiflexion ROM during gait^11,14 and less knee flexion during landing than persons without CAI, but these findings have not been consistent in the literature.^15,16 Furthermore, persons with CAI have shown greater energy dissipation at the ankle and less energy dissipation at the knee.¹⁷ Cumulatively, these observations suggest that alterations exist in the distal to proximal linkage of the kinetic chain of the lower extremity in persons with CAI.¹⁷ Further examining a potential connection between dorsiflexion ROM and landing biomechanics may provide additional insight into these findings.Persons who have CAI and less dorsiflexion ROM may also exhibit more erect landing postures and greater GRF, which may have implications for sustaining future lower extremity injuries or episodes of giving way.^18,19 Examining this relationship may further support integrating clinical intervention strategies that target dorsiflexion ROM into the rehabilitation of persons with CAI.⁹ Therefore, the purpose of our study was to examine the relationship between dorsiflexion ROM and single-legged landing biomechanics in persons with CAI. We examined dorsiflexion ROM statically, using the weight-bearing–lunge test, and dynamically, using motion capture, to determine its relationship to landing biomechanics. In addition, we focused on the sagittal-plane kinematics of the lower extremity and GRFs to explore how dorsiflexion ROM may influence force attenuation in persons with CAI. Kinematics were examined in the sagittal plane because it is primarily responsible for force attenuation during landing tasks.²⁰ We hypothesized that persons with less dorsiflexion ROM would exhibit less sagittal-plane motion throughout the lower extremity and greater GRF during a single-legged drop-landing task.     

HIV Infection Among People Who Inject Drugs in the United States: Geographically Explained Variance Across Racial and Ethnic Groups

Objectives. We explored how variance in HIV infection is distributed across multiple geographical scales among people who inject drugs (PWID) in the United States, overall and within racial/ethnic groups.Methods. People who inject drugs (n = 9077) were recruited via respondent-driven sampling from 19 metropolitan statistical areas (MSAs) for the Centers for Disease Control and Prevention’s 2009 National HIV Behavioral Surveillance system. We used multilevel modeling to determine the percentage of variance in HIV infection explained by zip codes, counties, and MSAs where PWID lived, overall and for specific racial/ethnic groups.Results. Collectively, zip codes, counties, and MSAs explained 29% of variance in HIV infection. Within specific racial/ethnic groups, all 3 scales explained variance in HIV infection among non-Hispanic/Latino White PWID (4.3%, 0.2%, and 7.5%, respectively), MSAs explained variance among Hispanic/Latino PWID (10.1%), and counties explained variance among non-Hispanic/Latino Black PWID (6.9%).Conclusions. Exposure to potential determinants of HIV infection at zip codes, counties, and MSAs may vary for different racial/ethnic groups of PWID, and may reveal opportunities to identify and ameliorate intraracial inequities in exposure to determinants of HIV infection at these geographical scales.Since the mid-1990s, there has been an increase in studies evaluating whether features of the social, economic, physical, and political environment (i.e., place characteristics) affect health. This focus on place characteristics is evident in the development of theories conceptualizing place characteristics as health determinants,1–3 in the use of geospatial and systematic social observation methods to measure place characteristics,4–10 in the application of multilevel modeling to assess the potential impacts of place characteristics,11–18 and in the recognition that interventions should not solely encourage individual behavior change but also modify environmental features.3,16,19Literature emerging from this field of research demonstrates that place characteristics operationalized at different geographical scales influence psychosocial processes and individual behaviors that increase vulnerability to several health outcomes. With rare exception,20–24 however, studies of place and health typically assess the potential influence of place characteristics at a single geographical scale and do not simultaneously evaluate characteristics of other geographical scales. For example, several studies, including our own,25,26 sample participants from a single metropolitan statistical area (MSA) to assess the relationships of census tract characteristics to health, without sampling participants from multiple MSAs to simultaneously assess the relationships of tract-, county-, and MSA-level characteristics to health.25–32 The decision to focus on characteristics of a single geographical scale may arise because of data availability, cost constraints, or feasibility.Studies of place and health that focus on a single geographical scale, however, may misspecify relationships and hinder the exploration of causal pathways in 2 ways. First, studies that focus on features measured at a single geographical scale may overlook potential health determinants that are operationalized at other geographical scales. For instance, research assessing the relationships of features of neighborhoods (e.g., economic deprivation, racial/ethnic composition, policing practices, and “crackdowns”) cannot determine the influence of policies, laws, and governmental expenditures that are operationalized at county, MSA, and state levels, and shape neighborhood environments. Second, studies of features of a single geographical scale cannot determine whether relationships between characteristics operating at one geographical scale are confounded, mediated, or modified by characteristics of other geographic scales.3,16,33 The possibility that at least 1 of these mechanisms can occur has been demonstrated in research conducted by Warner and Gomez, which suggests that, among Black women diagnosed with breast cancer, residing in census blocks with high concentrations of Black residents is more protective against mortality in more racially segregated metropolitan areas than less racially segregated metropolitan areas.34In addition, research assessing the association of place-based factors with health outcomes rarely highlights the extent to which variance in health outcomes is explained by place and place-based factors. Determining whether health outcomes vary geographically can generate hypotheses about inequities in exposure to potential place-based determinants of health, and thereby inform how interventions and social policies are developed and spatially concentrated.35The present study illustrates the generative possibilities of extending research beyond a single geographical scale by achieving 2 primary aims. The study’s first aim is to determine the share of total variance in HIV infection that is apportioned to zip codes, counties, and MSAs among people who inject drugs (PWID). In the United States, PWID account for 22% of people living with HIV,36 and a growing body of literature demonstrates that features of neighborhoods such as census-tract racial composition and block-level social or physical disorder are associated with HIV-related outcomes among PWID,37,38 as are features of MSAs, including drug-related law enforcement, income inequality, residential segregation, and health service access.39–41 Revealing the geographical scale to which variance in HIV infection is apportioned among PWID can stimulate hypotheses about inequities in exposure to place-based determinants of HIV and inform the development and tailoring of place-based interventions. For example, finding high MSA-level variance in HIV infection may support analyses of whether MSA-level variations in health care service access predict variance in HIV serostatus and, if they do, support interventions to increase health care access in low-access MSAs. In contrast, if little to no variance in HIV infection among PWID is apportioned to MSAs, PWID may encounter a relatively uniform exposure to health care service access.Previous studies have found that variance in some health outcomes vary across racial/ethnic groups.42,43 The second aim of this study therefore tests the hypothesis that variance in HIV infection will differ within each of 3 racial/ethnic groups of PWID: non-Hispanic/Latino Whites, non-Hispanic/Latino Blacks, and Hispanics/Latinos.     

Long-Term Weight Loss and Metabolic Health in Adults Concerned With Maintaining or Losing Weight: Findings From NHANES

More than two-thirds of American adults are overweight or obese, with many attempting to lose weight to avoid adverse health outcomes and improve well-being. Achieving long-term weight loss (LTWL) success, defined as reaching at least a 5% to 10% weight loss goal, is challenging, yet important for overall metabolic health. It is currently unclear whether achieving higher thresholds of LTWL is associated with improved health. Therefore, the purpose of this study was to examine the association between LTWL thresholds (5%-9.9%, 10%-14.9%, 15%-19.9%, ≥20%) and metabolic health (metabolic syndrome and metabolic risk z score) among 7670 US adult respondents to the National Health and Nutrition Examination Survey (2007-2014) who were overweight or obese (past or present), were not underweight in the past year, not pregnant, and attempting to lose or maintain weight. A subsample of 3362 participants was used in the analysis of the metabolic risk z score. Multivariable regression models were constructed adjusting for covariates. Results indicate that the lowest and the 2 highest LTWL thresholds were related to lower odds for metabolic syndrome; for example, greater than or equal to 20% LTWL (odds ratio=0.52; 95% CI, 0.23-0.44; P<.001). All LTWL thresholds were significantly associated with the metabolic risk z score, with the largest effect among the 2 highest LTWL thresholds, that is, 15% to 19.9% LTWL (β=?0.45; 95% CI, ?0.54 to ?0.36; P<.001) and greater than or equal to 20% LTWL (β=?0.35; 95% CI, ?0.53 to ?0.17; P<.001). In conclusion, although achieving the currently recommended LTWL target was related to improved metabolic health, the 15% LTWL threshold was associated with more favorable outcomes.