Heterogeneity of CFTR modulator-induced sweat chloride concentrations in people with cystic fibrosis.

BACKGROUND: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator. METHODS: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies. RESULTS: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %). CONCLUSIONS: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population.

Characterizing CFTR modulated sweat chloride response across the cf population: Initial results from the CHEC-SC study.

BACKGROUND: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy. METHODS: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses. RESULTS: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response. CONCLUSIONS: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Progress in understanding mood disorders: optogenetic dissection of neural circuits.

Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression-like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit-targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression-related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders.

Stressful life events and physical abuse among pregnant women in North Carolina.

OBJECTIVES: This study estimates the prevalence of stressful life events and physical abuse among North Carolina women prior to infant delivery, and examines potential associations between abuse and the other stressors. METHODS: Data were from the North Carolina Pregnancy Risk Assessment Monitoring System, a statewide representative survey of over 2,600 postpartum women. The survey assessed women's sociodemographic characteristics and their experiences of physical abuse and 13 other stressful life events before delivery. The prevalences of each life event and abuse were estimated. Logistic regression modeled the probability of women having high levels of stressful life events in relation to physical abuse and sociodemographics. RESULTS: Most women were married, white, high school graduates, aged 20 or older. The most common stressful life events were residential moves, increased arguing with husbands/partners, family member hospitalizations, financial hardship, and deaths of loved ones. Fourteen percent of women had high levels of stressful events (5 or more), and almost 9% were physically abused. Abuse was positively associated with increased arguing with husbands/partners, physical fighting, having someone close with an alcohol/drug problem, becoming separated/divorced, and financial hardship. Logistic regression analysis showed that a high level of stressful life events was significantly more likely among women abused both before and during pregnancy (OR = 11.94) and among women abused before but not during pregnancy (OR = 14.19). CONCLUSIONS: The high frequency of multiple stressful events and abuse in women's lives suggests that women's care providers should ask their patients about these issues, and offer appropriate referral/interventions to those in need.

Who gets screened during pregnancy for partner violence?

CONTEXT: Despite recommendations to screen prenatal care patients for partner violence, the prevalence of such screening is unknown. OBJECTIVES: To estimate the statewide prevalence of partner violence screening during prenatal care among a representative sample of North Carolina women with newborns and to compare women screened for partner violence with women not screened. DESIGN, SETTING, AND PARTICIPANTS: This investigation examines data gathered through the North Carolina Pregnancy Risk Assessment Monitoring System, a random sample of more than 2600 recently postpartum women who were delivered of newborns between July 1997 and December 1998. MAIN OUTCOME MEASURES: Self-reports of violence, health service factors, and sociodemographic characteristics. ANALYSIS: The prevalence of screening was computed, and odds ratios and 95% confidence intervals were used to examine bivariate and multivariable associations between being screened for partner violence and other factors. RESULTS: Thirty-seven percent of women reported being screened for partner violence during prenatal care. Logistic regression analysis found that women were more likely to be screened if they received prenatal care from (1) a public provider paid by a public source; (2) a private provider paid by a public source; or (3) a public provider paid by a private source. CONCLUSIONS: These findings suggest that the majority of prenatal care patients in North Carolina are not screened for partner violence. Screening appears to be most highly associated with whether a woman is a patient in the public sector or the private sector, and with the source of payment for prenatal care. Arch Fam Med. 2000;9:1093-1099

Estimating the market for nursing personnel in North Carolina.

PURPOSE: To facilitate nurse workforce planning in the United States at the state level, the North Carolina Center for Nursing conducted a statewide survey of nurse employers to describe the current market for nurses; identify the types of nursing personnel in short supply; estimate the effect of organizational changes on nursing demand; examine preferences for RNs with varying levels of education; and identify the specific skills or competencies desired by employers. DESIGN: Descriptive. METHODS: A geographically stratified random sample of 909 nurse-employing organizations in North Carolina was surveyed in 1996 by telephone. A total of 667 interviews were completed for a response rate of 78%. Descriptive statistics and correlation analyses are reported. RESULTS: A nursing labor market was found characterized by uncertainty in hospitals, particularly those undergoing reorganization, but of definite growth outside of hospitals. Demand is increasing for unlicensed assistive personnel, RNs with baccalaureate degrees, some advanced practice RNs, and in hospitals, for RNs with master's degrees in management. Recruitment continues to be a major challenge to hospitals in specialty areas, particularly critical care and surgery. In the community sector, demand is strong for all types of nursing personnel. Tests for substitution of specific types of nursing personnel revealed no systematic substitution by employers. Critical thinking and management skills were competencies most valued by hospital employers while specific clinical competencies, including assessment skills and technical skills, received priority emphasis by community-based employers. CONCLUSIONS: Although change is occurring in the health system of North Carolina, there remains a strong demand for nursing personnel. The findings pose a challenge to produce a nursing workforce sufficient in numbers and education.

Delayed repair of congenital diaphragmatic hernia with early high-frequency oscillatory ventilation during preoperative stabilization.

PURPOSE: The authors reviewed their experience in the management of CDH after the introduction of early high-frequency oscillatory ventilation (HFOV) during the preoperative stabilization period and delayed CDH repair. METHODS: This is a retrospective analysis of 24 consecutive infants with CDH treated at University of California, Irvine Medical Center (UCIMC) during a 36-month period from January 1993 to December 1996. RESULTS: Two patients were excluded from the study: one fetus with a prenatal diagnosis was referred for fetal surgery; one infant received CDH repair at another institution 2 weeks before transfer to UCIMC. Eight (36%) infants were inborn, and nine (41%) had a prenatal diagnosis of CDH. Median gestational age was 40 weeks (range, 29 to 42 weeks). Median birth weight was 3,019 g (range, 1,205 to 4,337 g). The defect was left sided in 18 infants (86%). Twenty-one infants were intubated within 5 hours of life, 15 had an AaDO2 greater than 610, 11 had an oxygenation index greater than 40, and 11 had a pH of less than 7.2. The median ratio of pulmonary artery pressure to systemic blood pressure was 0.93 (range, 0.51 to 1.15) in 12 infants. Eighteen infants were placed on HFOV within a median of 1 hour of life. Nitric oxide was given to six infants and surfactant to eight. Four infants were referred for extracorporeal membrane oxygenation (ECMO). Repair of CDH was performed on infants at a median age of 33.5 hours (range, 5.5 to 322). Six (30%) received a prosthetic patch. Overall 18 of 22 infants survived (81%); three survivors received ECMO. Two infants of the survivor group had congenital heart anomalies: one ventricular septal defect (VSD) and one double-outlet right ventricle with a VSD. Of the four nonsurvivors, one had lethal cardiac anomalies and bilateral CDH, two had severe bilateral pulmonary hypoplasia (one received ECMO), and one infant was a 29-week premature baby who did not qualify for ECMO. CONCLUSION: We report a survival rate of 81% (18 of 22) with the management of CDH by delayed surgical repair, early postnatal HFOV, and selective referral for ECMO.

The importance of family functioning to caregiver adaptation in mothers of child cancer patients: testing a social ecological model.

This study was designed to investigate associations between family relationships, personal-psychological caregiver adaptation (ie, depressive symptomatology, sense of burden), and ability to function within the health care system (perceived doctor-parent relationship) in mothers of child cancer patients. Data were collected through a survey of a sample of 29 mothers whose children were diagnosed with some form of childhood cancer, mainly leukemia. Family functioning was positively related to both caregiver adaptation and doctor-parent relationship. Mothers who reported decreased maternal depression and burden were significantly more likely to report respectively improved spousal relationships and improved spousal communication. Mothers reporting more positive doctor-parent relationships also described themselves as having improved relationships with spouse and child, and improved spousal communication. Maternal well-being and doctor-parent relationship were not directly related. By suggesting that both intrapsychic and instrumental maternal adaptation are influenced by positive relationships in the family, this study provides support for the social ecological model of stress. The possibility that family factors exert a direct influence on both caregiver intrapsychic well-being and instrumental skills argues for the importance of their being carefully considered in any models evaluating caregiver adaptation.

Cytomegalovirus enteritis in a premature infant.

BACKGROUND/PURPOSE: Up to 2.5% of newborn infants are cytomegalovirus (CMV) positive at birth. Five percent will be symptomatic at birth, including cytomegalic inclusion disease. Symptoms such as hearing loss and mental retardation will ultimately develop in 15%. METHODS: The authors describe a case of CMV enteritis in a 2.2-kg newborn that presented as necrotizing enterocolitis (NEC) and subsequently developed a colonic stricture. RESULTS: There are four reports of neonatal CMV enteritis in the nonEnglish-language literature. Cytomegalovirus enteritis has become prevalent among the immunosuppressed pediatric and adult patient population. CONCLUSIONS: We propose the addition of CMV to the list of pathogens responsible for NEC. A review of neonatal CMV infection is provided.

Inducible gene expression of the human immunodeficiency virus LTR in a replication-incompetent herpes simplex virus vector.

Although replication-incompetent herpes simplex virus (HSV) vectors have the capability to express foreign genes, successful development of these vectors for gene delivery would require that expression of the foreign gene be regulated. To investigate the feasibility of obtaining inducible expression of a foreign gene in such a vector, a replication-incompetent HSV vector, vd120/LTR beta, was developed that used the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) to express the Escherichia coli lacZ gene. Examination of lacZ expression from the HIV-1 LTR in vd120/LTR beta-infected cells indicated that the LTR was active as a promoter under both replicating and nonreplicating conditions, although expression of lacZ under nonreplicating conditions was approximately 4-fold lower. In addition, the LTR expressed lacZ in a manner distinct from that of well-characterized HSV-1 promoters of each temporal class. The effect of the HIV-1 regulatory protein Tat on expression from the LTR in vd120/LTR beta was examined by infection of two different HeLa-derived cell lines that constitutively expressed Tat, HL2/3, and HLtat. Compared to infection of HeLa cells, lacZ expression from vd120/LTR beta-infected HL2/3 and HLtat cells increased from 4- to 24-fold, depending on the multiplicity of vector infection. Sustained expression of lacZ from the LTR in vd120/LTR beta-infected cells was not observed even in the continuous presence of Tat, although vector could be recovered for up to 5 days after infection. However, the amount of recoverable vector decreased during this time, suggesting that cellular cytotoxicity may account for some of the decrease in Tat-mediated expression from the LTR.

Effects of brefeldin A on galactosphingolipid synthesis in an immortalized Schwann cell line: evidence for different intracellular locations of galactosylceramide sulfotransferase and ceramide galactosyltransferase activities.

Brefeldin A (BFA) has been used extensively to study the intracellular transport and processing of proteins and sphingolipids because of its dramatic alteration of the structural and functional organization of the Golgi. We have examined the effect of BFA on the synthesis of galactosylceramide sulfate (SGalCer) and its immediate precursor galactosylceramide (GalCer) in an immortalized Schwann cell line (S16) to determine the intracellular sites of synthesis of these two related glycolipids. During a 6-h labeling period, a dose-dependent inhibition of [35S]sulfate incorporation into SGalCer was observed with 95% inhibition occurring at 0.5 microgram/ml BFA. Labeling of newly synthesized galactosphingolipids with [3H]-palmitic acid for 6 h in the presence of BFA resulted in increased incorporation of label into GalCer containing nonhydroxy fatty acids (NFA-GalCer) to 162% of control values, whereas labeling of GalCer containing 2-hydroxy fatty acids (HFA-GalCer) was reduced to 63% of control. After 24 h, these values were at 366 and 91%, respectively. These results indicate that at least some of the HFA-GalCer was initially synthesized at a location distal to the BFA block and separate from the site of NFA-GalCer synthesis. Examination of [3H]palmitic acid incorporation into free ceramides showed an increase of 133 and 161% for hydroxy and nonhydroxy fatty acid ceramides, respectively, in cells treated for 6 h with BFA in comparison with levels found in untreated control cells, indicating that BFA did not block fatty acid 2-hydroxylation or the formation of HFA ceramide.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin and heparin.

Antithrombin, the main inhibitor of thrombosis in blood, is bound and activated by the heparin-like side-chains that line the small vasculature. We now have good depictions of the heparin-binding site on antithrombin, and of the way in which mutations at this site cause thrombotic disease. The interaction of heparin with antithrombin is, however, a kinetic one, with binding being followed by formation of a complex with thrombin and then release from the heparin. Our understanding of the processes involved is currently based on crystallographic models but, for a mobile mechanism, these merely provide snapshots - what is needed is a movie.

Using students' salient beliefs to design an instructional intervention to promote AIDS compassion and understanding in the middle school.

This article documents the construction and validation of a videotaped message to persuade middle school students to volunteer as the laboratory partner of a classmate who has AIDS. Based on well-established social-psychological models of persuasion, message arguments are designed either to reinforce or to downplay the modal salient beliefs held by message recipients about the intended behavior. The end-product of this precisely tailored, six-step process is instruction which not only promotes the adoption of tolerant and compassionate attitudes, but also provides an opportunity for the practice of essential life skills such as decision making and problem solving. The process itself is offered as a model for designing any instructional material which addresses today's growing list of AIDS-related issues having both moral and ethical implications.

Focal intestinal perforation in the extremely-low-birth-weight infant.

The purposes of this report were to (1) document the clinical and laboratory features of 11 extremely-low-birth-weight (ELBW) infants with focal intestinal perforation and (2) investigate the clinical events possibly associated with these perforations by examining matched pairs of infants with and without focal intestinal perforation. During the study period 173 infants with birth weights between 600 and 1000 gm were admitted to the neonatal intensive care nursery. Eleven of these ELBW infants had focal intestinal perforations and formed the study group. These infants were matched with 11 ELBW infants who did not have intestinal perforations or signs of inflammatory bowel disease. The matched pairs were similar in all respects except for a significantly higher percent increase in blood urea nitrogen level after treatment with indomethacin (Wilcoxon signed-rank test, p < 0.02) in infants with intestinal perforation. At laparotomy the perforations were noted to be focal, often multiple, and on the antimesenteric border of the distal ileum. None of the infants showed clinical, radiographic, or intraoperative findings that were consistent with classifications for necrotizing enterocolitis (NEC). The incidence of focal intestinal perforation in ELBW infants was 6% versus 2% for typical NEC. In addition, four of the 11 infants with intestinal perforation had positive cultures for either Staphylococcus epidermidis or Candida albicans, whereas none of the infants without perforation had positive cultures during the study period (Fisher's exact test, p < 0.09). We conclude that the clinical presentation and the characteristic intestinal lesions in this group of ELBW infants are distinct from those in typical cases of NEC.(ABSTRACT TRUNCATED AT 250 WORDS)