Female Sex and Alzheimer's Risk: The Menopause Connection.

Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer's disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.

Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

Cutaneous signs of child abuse

Maltreatment of children is a major public health crisis, and it is estimated that each year more than 3 million children are victims of abuse. Safeguarding the welfare of children is a priority, and it is the moral and ethical responsibility of healthcare professionals to detect cases of abuse and intervene appropriately to prevent further harm. Clinicians are often challenged to differentiate signs of child abuse from skin conditions that mimic maltreatment. Because cutaneous injury represents the most recognizable and common form of abuse, dermatologists are often called upon to help distinguish signs of intentional injury from skin conditions that mimic maltreatment. However, few resources specific to dermatologic signs of abuse exist to aid in diagnosis. A review of the literature will provide an educational resource to assist dermatologists and other clinicians in differentiating cutaneous signs of child abuse, including physical and sexual abuse, from mimickers of inflicted injury. LEARNING OBJECTIVE: After completing this learning activity, participants should be able to distinguish signs of intentional injury from skin conditions that mimic maltreatment and understand the clinician's role in the diagnosis and reporting of cases of suspected child abuse.

Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1.

Volatile anesthetics have been shown to activate various two-pore (2P) domain K(+) (K(2P)) channels such as TASK-1 and TREK-1 (TWIK-related acid-sensitive K(+) channel), and mice deficient in these channels are resistant to halothane-induced anesthesia. Here, we investigated whether K(2P) channels were also potentially important targets of intravenous anesthetics. Whole cell patch-clamp techniques were used to determine the effects of the commonly used intravenous anesthetics etomidate and propofol on the acid-sensitive K(+) current in rat ventricular myocytes (which strongly express TASK-1) and selected human K(2P) channels expressed in Xenopus laevis oocytes. In myocytes, etomidate decreased both inward rectifier K(+) (K(ir)) current (I(K1)) and acid-sensitive outward K(+) current at positive potentials, suggesting that this drug may inhibit TASK channels. Indeed, in addition to inhibiting guinea pig Kir2.1 expressed in oocytes, etomidate inhibited human TASK-1 (and TASK-3) in a concentration-dependent fashion. Propofol had no effect on human TASK-1 (or TASK-3) expressed in oocytes. Moreover, we showed that, similar to the known effect of halothane, sevoflurane and the purified R-(-)- and S-(+)-enantiomers of isoflurane, without stereoselectivity, activated human TASK-1. We conclude that intravenous and volatile anesthetics have dissimilar effects on K(2P) channels. Human TASK-1 (and TASK-3) are insensitive to propofol but are inhibited by supraclinical concentrations of etomidate. In contrast, stimulatory effects of sevoflurane and enantiomeric isoflurane on human TASK-1 can be observed at clinically relevant concentrations.

Fatal child neglect.

Child neglect results from either acts of omission or of commission. Fatalities from neglect account for 30% to 40% of deaths caused by child maltreatment. Deaths may occur from failure to provide the basic needs of infancy such as food or medical care. Medical care may also be withheld because of parental religious beliefs. Inadequate supervision may contribute to a child's injury or death through adverse events involving drowning, fires, and firearms. Recognizing the factors contributing to a child's death is facilitated by the action of multidisciplinary child death review teams. As with other forms of child maltreatment, prevention and early intervention strategies are needed to minimize the risk of injury and death to children.

The clinical utility of the rectal-skin temperature difference in the assessment of young infants.

OBJECTIVE: Previous studies have suggested that the degree of difference between rectal temperature and peripheral skin temperature [rectal-skin temperature difference (RSTD)] is predictive of serious illness in young infants. The authors sought to determine the clinical utility of the RSTD in the outpatient evaluation of infants up to 2 months of age for serious infectious illness (SII). METHODS: Simultaneous rectal and skin (anterior mid-lower leg) temperatures were recorded for all infants < or = 2 months of age seen in the ED over a one-year period. The physician's clinical assessment, rectal temperature, skin temperature, laboratory results, and final diagnoses were also recorded. The RSTD (rectal temperature - skin temperature) was calculated for each infant. Final diagnoses were recorded and classified as SII or nonserious illness (NSI). Mean RSTD for each group was calculated and data were analyzed by the Wilcoxon rank sum test and multivariate regression model. RESULTS: A total of 601 infants [mean age of 28 days (range 2-65 days)] were enrolled. Nine percent (57 of 601) of infants had SII. Forty percent (23 of 57) of infants with SII were febrile, and 60% (34 of 57) were afebrile. The mean RSTD of febrile infants with SII was 5.8 +/- 1.7 degrees C (range 3.2-9.7 degrees C) and 5.3 +/- 1.4 degrees C (range 3.0-7.6 degrees C) for febrile infants with NSI. The mean RSTD of afebrile infants with SII was 4.8 +/- 1.8 degrees C (range 2-12.5 degrees C) and 4.4 +/- 1.5 degrees C (range 0.04-10.9 degrees C) for afebrile infants with NSI. The RSTD was not associated with SII in either febrile or afebrile infants (p > 0.05, Wilcoxon rank sum test). A multivariate logistic regression model of age, rectal temperature, and RSTD suggested an independent association of rectal temperature with SII (p < 0.0001), but none between age or RSTD and SII (p > 0.05). CONCLUSION: Once the rectal temperature is known, the RSTD is not a clinically useful test in the evaluation of young infants for serious infectious illness.

Adolescent medicine training in pediatric residency programs: are we doing a good job?

OBJECTIVES: To determine how pediatric residency programs are responding to the new challenges of teaching adolescent medicine (AM) to residents by assessing whether manpower is adequate for training, whether AM curricula and skills are adequately covered by training programs, what types of teaching methodologies are used to train residents in AM, and the needs for new curricular materials to teach AM. DESIGN: A 3-part 92-item survey mailed to all US pediatric residency training programs. SETTING: Pediatric residency programs. PARTICIPANTS: Residency program directors and directors of AM training. MAIN OUTCOME MEASURES: AM divisional structure, clinical sites of training, presence of a block rotation, and faculty of pediatric training programs; training materials used and desired in AM; perceived adequacy of coverage of various AM topics; competency of residents in performing pelvic examinations in sexually active teens; and manpower needs. RESULTS: A total of 155/211 (73.5%) of programs completed the program director and the AM parts of the survey. Ninety-six percent of programs (size range, 5-120 residents) had an AM block rotation and 90% required the AM block; those without a block rotation were more likely to be larger programs. Only 39% of programs felt that the number of AM faculty was adequate for teaching residents. Almost half of the programs reported lack of time, faculty, and curricula to teach content in substance abuse. Besides physicians, AM teachers included nurse practitioners (28%), psychologists (25%), and social workers (19%). Topics most often cited as adequately covered included sexually transmitted diseases (81.9%), confidentiality (79.4%), puberty (77.0%), contraception (76.1%), and menstrual problems (73.5%). Topics least often cited as adequately covered included psychological testing (16.1%), violence in relationships (20.0%), violence and weapon-carrying (29.7%), and sports medicine (29.7%). Fifty-eight percent of 137 respondents thought that all or nearly all of their residents were competent in performing pelvic examinations by the end of training; there was no difference between perceived competence and the residents' use of procedure books. Seventy-four percent used a specific curriculum for teaching AM; materials included chapters/articles (85%), lecture outlines (76.1%), slides (41.9%), videos (35.5%), written case studies (24.5%), computerized cases (6.5%), and CD-ROMs (3.2%). Fifty-two percent used Bright Futures, 48% used the Guidelines for Adolescent Preventive Services, and 14% used the Guide to Clinical Preventive Services for teaching clinical preventive services. Programs that used Bright Futures were more likely to feel that preventive services were adequately covered in their programs than those who did not (78% vs 57%). A majority of programs desired more learner-centered materials. CONCLUSIONS: Although almost all pediatric programs are now providing AM rotations, there is significant variability in adequacy of training across multiple topics important for resident education. Programs desire more learner-centered materials and more faculty to provide comprehensive resident education in AM.

Documentation of child physical abuse: how far have we come?

OBJECTIVES: To determine the effects of increased physician training and a structured clinical form on physician documentation of child physical abuse. DESIGN: Retrospective chart review. PARTICIPANTS: Children evaluated in the pediatric emergency department in 1980 and 1995 who were given the diagnosis of physical abuse. MEASUREMENTS: The unstructured pediatric emergency department form and the structured child abuse reporting form were reviewed for documentation of 20 items including history, physical examination, diagnostic procedures, and disposition. Data documented in 1980 were compared with that in 1995. RESULTS: The only significant differences between 1980 and 1995 concerning documentation on the unstructured pediatric emergency department form were better recording in the latter year of Child Protective Services involvement and case disposition. Half or more of the records omitted documentation of at least one of the following: witnesses to injury, past injuries, description of size and/or color of injuries, illustration, and a genital exam. None of the records contained a developmental history. Significantly fewer skeletal surveys were obtained in 1995, although notation of the results was similar to 1980. For both years, the structured child abuse reporting form improved documentation of only two items: time of arrival to the pediatric emergency department and illustrations of injuries. CONCLUSIONS: Little improvement in physician documentation of child physical abuse was noted between 1980 and 1995 despite increased efforts to educate housestaff in the evaluation of child abuse during this time period. Although a structured form prompted physicians to document dates and times and to illustrate physical injuries on the diagram provided, it did not significantly improve documentation of other items.

Families of borderline patients: a psychoeducational approach.

The development of the psychoeducational form of treatment described in this article has been prompted by changes in our understanding of borderline psychopathology and changes in the health care system in which these patients are treated. After reviewing these background changes, the authors describe the treatment itself, its form, its purpose, and the preliminary suggestions of its effectiveness.

Upper airway obstruction after pharyngeal flap surgery.

Upper airway obstruction after superiorly based pharyngeal flap procedures for the treatment of velopharyngeal insufficiency is described in this series of 32 flaps performed in 29 patients at our institution between 1979 and 1993. A high incidence of upper airway obstruction symptoms (38%) occurred in the early postoperative period but resolved in all but 2 patients within 5 months. None of the patients required flap revision or other procedures for relief of upper airway obstruction. Velopharyngeal insufficiency was improved or completely eliminated in 87% of patients. Significant residual velopharyngeal insufficiency in 13% of patients was treated successfully in all flap revision cases. Race, gender, age at closure, and associated craniofacial anomalies did not correlate with upper airway obstruction or with the efficacy of treatment for velopharyngeal insufficiency. However, patients with transient postoperative upper airway obstruction were only half as likely to suffer residual postoperative velopharyngeal insufficiency. The inverse relationship between velopharyngeal insufficiency and upper airway obstruction (p = .008) suggests that the surgeon may sometimes need to accept some transient upper airway obstruction to achieve correction of velopharyngeal insufficiency.

Microdontia with severe microcephaly and short stature in two brothers: osteodysplastic primordial dwarfism with dental findings.

Two brothers from a black family had microcephaly, short stature, and generalized microdontia. Endocrine and chromosome studies were normal, and mild skeletal manifestations were present. The patients may represent a distinct dental-skeletal dysplasia, possibly osteodysplastic primordial dwarfism type II. Attention to dental manifestations in similar cases may be useful for classification.

Different hepatocytes express the cholesterol 7 alpha-hydroxylase gene during its circadian modulation in vivo.

Cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile salt synthesis from cholesterol is a P450 enzyme (CYP7A). Its expression and activity are regulated by bile salts, cholesterol, hormones and a circadian modulator. Here we define the hepatocytes contributing to the expression of the rat CYP7A gene during its in vivo circadian variation. The diurnal expression of the CYP7A messenger RNA (mRNA) was studied by in situ hybridization and correlated with the diurnal rate of CYP7A gene transcription and mRNA expression. At 10 AM, the time of lowest mRNA expression and gene transcription rate, only four to five hepatocytes, located close to the hepatic venules ("perivenular"), contained the CYP7A mRNA. At 10 PM, the time of highest mRNA expression and fastest in vitro transcription rate, approximately one half of the hepatocytes (still in a "perivenular" location) contained the cholesterol 7 alpha-hydroxylase mRNA. In addition, the measured half-life of the CYP7A mRNA was shorter at 10 AM than at 10 PM suggesting that posttranscriptional mechanisms also contributed to the observed circadian differences. Therefore, the basal transcription rate of the CYP7A gene is maintained by four to five "perivenular" hepatocytes. During the circadian variation, the rate of gene transcription increases in these "perivenular" hepatocytes, but in addition, there is recruitment of other more proximal hepatocytes to transcribe the gene. It is proposed here that the response of specific hepatocytes to the various modulators of CYP7A gene expression is dependent on the relative position of these hepatocytes within the liver cell plate.

Pediatric abuse. New patterns of injury.

The spectrum of abusive symptomatology has continued to expand since the initial report of the battered child syndrome. Many of these abused children present to the ED without a history of trauma. The ED physician must be aware of the range of clinical signs and symptoms to recognize and treat these children.

The effects of bundling on infant temperature.

OBJECTIVE: To determine whether bundling elevates rectal and/or skin temperature of young infants. DESIGN: Randomized, prospective study stratified by age. SETTING: Clinical Studies Center at a teaching hospital in Los Angeles. PATIENTS: Sixty-four well, full-term infants (ages 11 to 95 days). INTERVENTIONS: Control infants (n = 28) were dressed in a disposable diaper and terry coveralls. Bundled infants (n = 36) were dressed as control infants, plus a cap, a receiving blanket, and a thermal blanket. All infants were monitored in an open crib (room temperature 72 degrees to 75 degrees F). Rectal and skin (anterior mid-lower leg) temperatures and infant states were measured at 5-minute intervals from time 0 to 60 minutes and at 62 and 65 minutes. RESULTS: The mean skin temperature of bundled infants increased by 2.67 degrees C/hr; mean rectal temperature increased by 0.06 degrees C/hr. The mean skin temperature of nonbundled infants increased by 1.5 degrees C/hr; mean rectal temperature decreased by less than 0.01 degree C/hr. Comparing bundled infants to nonbundled controls, there was a significant rise in skin temperature (P = .0001) but not in rectal temperature (P > .05, Wilcoxon rank sum test). The study had a power > 98% to detect a rise of .5 degrees C in rectal temperature over 60 minutes. The 95% confidence interval for the change in rectal temperature in bundled infants was -0.03 to +0.15 degrees C. CONCLUSIONS: Bundling a healthy infant in a temperate external environment causes an increase in skin temperature, but not in rectal temperature. Elevated rectal temperatures should therefore, rarely if every be attributed to bundling.