Anorexia in Medicare Fee-for-Service Beneficiaries: A Claims-Based Analysis of Epidemiology and Mortality.

OBJECTIVES: Loss of appetite in older adults can lead to malnutrition, weight loss, frailty, and death, but little is known about its epidemiology in the United States (US). The objective of this study was to estimate the annual prevalence and incidence of anorexia in older adults with Medicare fee-for-service (FFS) health insurance. DESIGN: Retrospective and observational analysis of administrative health insurance claims data. SETTING: This study included Medicare FFS claims from all settings (eg, hospital inpatient/outpatient, office, assisted living facility, skilled nursing facility, hospice, rehabilitation facility, home). PARTICIPANTS: This study included all individuals aged 65 to 115 years old with continuous Medicare FFS medical coverage (Parts A and/or B) for at least one 12-month period from October 1, 2015, to September 30, 2021 (ie, approximately 30 million individuals each year). INTERVENTION: Not applicable. MEASUREMENTS: Anorexia was identified using medical claims with the ICD-10 diagnosis code "R63.0: Anorexia". This study compared individuals with anorexia to a control group without anorexia with respect to demographics, comorbidities using the Charlson Comorbidity Index (CCI), Claims-based Frailty Index (CFI), and annual mortality. The annual prevalence and incidence of anorexia were estimated for each 12-month period from October 1, 2015, to September 30, 2021. RESULTS: The number of individuals with anorexia ranged from 317,964 to 328,977 per year, a mean annual prevalence rate of 1.1%. The number of individuals newly diagnosed with anorexia ranged from 243,391 to 281,071 per year, a mean annual incidence rate of 0.9%. Individuals with anorexia had a mean (±standard deviation) age of 80.5±8.7 years (vs 74.9±7.5 years without anorexia; p<.001), 64.4% were female (vs 53.8%; p<.001), and 78.4% were White (vs 83.2%; p<.001). The most common CCI comorbidities for those with anorexia were chronic pulmonary disease (39.4%), dementia (38.3%), and peripheral vascular disease (38.0%). Median (interquartile range [IQR]) CCI with anorexia was 4 [5] (vs 1 [3] without anorexia; p<.001). The annual mortality rate among those with anorexia was 22.3% (vs 4.1% without anorexia; relative risk 5.49 [95% confidence interval, 5.45-5.53]). CONCLUSION: Approximately 1% of all adults aged 65-115 years old with Medicare FFS insurance are diagnosed with anorexia each year based on ICD-10 codes reported in claims. These individuals have a higher comorbidity burden and an increased risk of annual mortality compared to those without a diagnosis of anorexia. Further analyses are needed to better understand the relationship between anorexia, comorbidities, frailty, mortality, and other health outcomes.

Systematic review: occupational physical activity and low back pain.

BACKGROUND: Although various occupational physical activities are suspected of contributing to low back pain (LBP), causal relationships have not been confirmed, complicating adjudication of work injuries, return to work instructions and preventive efforts. AIMS: To summarize eight systematic review (SR) reports that examined evidence supporting causal relationships between bending/twisting, awkward postures, sitting, standing/walking, carrying, pushing/pulling, lifting and manual handling/assisting patients and LBP. METHODS: A literature search was conducted to identify eligible studies. Methodological quality was assessed using a modified Newcastle-Ottawa Scale (NOS). Levels of evidence supporting factors for causation were examined using a Bradford Hill framework. Results were presented in eight SR reports, each focused on one or more related physical activities. This study summarizes findings from those reports and offers clinicians an overview. RESULTS: Collectively, the eight SR reports included 99 studies. None found strong evidence supporting a causal relationship between any occupational physical activity considered and LBP. Conflicting evidence was found between LBP and bending, twisting, lifting or pushing/pulling, but only for statistical association, not causation. Strong evidence against a causal relationship was found between LBP and manual handling/assisting patients, awkward postures, carrying, sitting, standing or walking. CONCLUSIONS: Although occupational physical activities are suspected of causing LBP, findings from the eight SR reports did not support this hypothesis. This may be related to insufficient or poor quality scientific literature, as well as the difficulty of establishing causation of LBP. These population-level findings do not preclude the possibility that individuals may attribute their LBP to specific occupational physical activities.

Prolotherapy injections for chronic low-back pain.

BACKGROUND: Prolotherapy involves repeated injections of irritant solutions to strengthen lumbosacral ligaments and reduce some types of chronic low-back pain; spinal manipulation and exercises are often used to enhance its effectiveness. OBJECTIVES: To determine the efficacy of prolotherapy in adults with chronic low-back pain. SEARCH STRATEGY: We searched CENTRAL 2006, Issue 3 and MEDLINE, EMBASE, CINAHL, and AMED from their respective beginnings to October 2006, with no restrictions on language, and consulted content experts. SELECTION CRITERIA: We included randomised (RCT) and quasi-randomised controlled trials (QRCT) that compared prolotherapy injections to control injections, alone or in combination with other treatments, which measured pain or disability before and after the intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials and assessed methodological quality. Intervention protocols varied from study to study, making meta-analysis impossible. MAIN RESULTS: We identified five high quality studies with a total of 366 participants. All measured pain or disability levels at six months, and four measured the proportion of participants reporting a greater than 50% reduction in pain or disability scores. Three randomized controlled trials (206 participants) found that prolotherapy injections alone are no more effective than control injection for chronic low-back pain and disability. At six months, there was no difference between groups in mean pain or disability scores (2 RCTs; 184 participants) and no difference in proportions who reported over 50% improvement in pain or disability (3 RCTs; 206 participants). These trials could not be pooled due to clinical heterogeneity. Two RCTs (160 participants) found that prolotherapy injections, given with spinal manipulation, exercise, and other therapies, are more effective than control injections for chronic low-back pain and disability. At six months, one study reported a significant difference between groups in mean pain and disability scores, whereas the other study did not. Both studies reported a significant difference in the proportion of individuals who reported over 50% reduction in disability or pain. Co-interventions confounded interpretation of results and clinical heterogeneity in the trials prevented pooling. AUTHORS' CONCLUSIONS: There is conflicting evidence regarding the efficacy of prolotherapy injections for patients with chronic low-back pain. When used alone, prolotherapy is not an effective treatment for chronic low-back pain. When combined with spinal manipulation, exercise, and other co-interventions, prolotherapy may improve chronic low-back pain and disability. Conclusions are confounded by clinical heterogeneity amongst studies and by the presence of co-interventions.

The murine Fhit gene is highly similar to its human orthologue and maps to a common fragile site region.

The human FHIT gene is a putative tumor suppressor gene that maps to human chromosome band 3p14.2 in a region that is frequently deleted in cancers. It exhibits both genomic deletions and aberrant transcripts in a variety of tumors and spans the common fragile site FRA3B. This fragile site extends over a broad region of several hundred kb within the FHIT gene and may account for its instability in tumors. As one test of this hypothesis, we isolated the murine Fhit gene and asked whether it also contains a common fragile site and if it is unstable in mouse tumors or tumor cell lines. The Fhit gene was isolated, and the sequence was found to be 87.5% identical to that of the human FHIT gene in the open reading frame. Using fluorescence in situ hybridization, Fhit was assigned to mouse chromosome band 14A2, in a region that was previously shown to contain an aphidicolin-inducible mouse fragile site. Fluorescence in situ hybridization with genomic clones containing Fhit and flanking sequences demonstrated that gaps and breaks in the fragile site occur over a broad region within and proximal to the Fhit locus. Thus, the physical relationship of Fhit to a common fragile site is similar to that observed with the orthologous human FHIT gene and FRA3B.

Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations.

BACKGROUND: Hereditary lymphoedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphoedema of the limbs, with variable age of onset, and extra aberrant growth of eyelashes from the Meibomian gland (distichiasis). Other major reported complications include cardiac defects, cleft palate, and extradural cysts. Photophobia, exotropia, ptosis, congenital ectropion, and congenital cataracts are additional eye findings. Recently, we reported that truncating mutations in the forkhead transcription family member FOXC2 resulted in LD in two families. METHODS: The clinical findings in seven additional families with LD, including the original family described by Falls and Kertesz, were determined and mutational analyses were performed. RESULTS: Distichiasis was the most common clinical feature followed by age dependent lymphoedema. There is a wide variation of associated secondary features including tetralogy of Fallot and cleft palate. The mutational analyses identified truncating mutations in all of the families studied (two nonsense, one deletion, three insertion, and one insertion-deletion), which most likely result in haploinsufficiency of FOXC2. CONCLUSIONS: FOXC2 mutations are highly penetrant with variable expressivity which is not explicable by the pattern of mutations.

Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant.

A polymerase chain reaction (PCR)-based strategy was used to isolate a mouse cDNA (mCtr1) encoding a Cu transport protein. The deduced mCtr1 protein sequence exhibits 92% identity to human Ctr1, and has structural features in common with known high affinity Cu transporters from yeast. The expression of mouse Ctr1 functionally complements baker's yeast cells defective in high affinity Cu transport. Characterization of the mCtr1 genomic clone showed that the mCtr1 coding sequence is encompassed within four exons and that the mCtr1 locus maps to chromosome band 4C1-2. RNA blotting analysis demonstrated that mCtr1 is ubiquitously expressed, with high levels in liver and kidney, and early in embryonic development. Steady state mammalian Ctr1 mRNA levels were not changed in response to cellular Cu availability, which is distinct from the highly Cu-regulated transcription of genes encoding yeast high affinity Cu transporters. These studies provide fundamental information for further investigations on the function and regulation of Ctr1 in Cu acquisition in mammals.

Maternal anthropometry and idiopathic preterm labor.

OBJECTIVE: To assess the etiologic role of maternal short stature, low pre-pregnancy body mass index (BMI), and low rate of gestational weight gain in idiopathic preterm labor. METHODS: We carried out a three-center case-control study of 555 women with idiopathic onset of preterm labor (before 37 completed weeks), including two overlapping (ie, nonmutually exclusive) subsamples: cases with early preterm labor (before 34 completed weeks) and cases with recurrent preterm labor (before 37 completed weeks plus a history of prior preterm delivery or second-trimester miscarriage). Controls were matched to cases by race and smoking history. All subjects responded in person to questions about height, pre-pregnancy weight, gestational weight gain, and obstetric and sociodemographic histories. RESULTS: Maternal height, pre-pregnancy weight, and gestational weight gain demonstrated excellent test-retest reliability, with intra-class correlation coefficients of 0.97, 0.99, and 0.91, respectively. Based on matched analyses, women with a height of 157.5 cm or less had an increased risk of idiopathic preterm labor (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.25-2.74), as did those with a pre-pregnancy BMI less than 19.8 kg/m2 (OR 1.63, 95% CI 1.09-2.44) or a gestational weight gain rate less than 0.27 kg/week (OR 1.74, 95% CI 1.16-2.62). Conditional logistic regression models containing all three anthropometric variables and controlling for parity, marital status, language, age, and education yielded virtually identical point estimates and CIs. CONCLUSION: Maternal short stature, low pre-pregnancy BMI, and low rate of gestational weight gain may lead to shortened gestation by increasing the risk of idiopathic preterm labor.

Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review.

OBJECTIVE: The objective of this paper is to review the literature regarding Withania somnifera (ashwagandha, WS) a commonly used herb in Ayurvedic medicine. Specifically, the literature was reviewed for articles pertaining to chemical properties, therapeutic benefits, and toxicity. DESIGN: This review is in a narrative format and consists of all publications relevant to ashwagandha that were identified by the authors through a systematic search of major computerized medical databases; no statistical pooling of results or evaluation of the quality of the studies was performed due to the widely different methods employed by each study. RESULTS: Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound. CONCLUSION: Preliminary studies have found various constituents of ashwagandha exhibit a variety of therapeutic effects with little or no associated toxicity. These results are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety of conditions should also be conducted.

Cervicogenic headaches: a critical review.

BACKGROUND CONTEXT: The notion that headaches may originate from disorders of the cervical spine and can be relieved by treatments directed at the neck is gaining recognition among headache clinicians but is often neglected in the spine literature. PURPOSE: To review and summarize the literature on cervicogenic headaches in the following areas: historical perspective, diagnostic criteria, epidemiology, pathogenesis, differential diagnosis, and treatment. STUDY DESIGN/SETTING: A systematic literature review of cervicogenic headache was performed. METHODS: Three computerized medical databases (Medline, Cumulative Index to Nursing and Allied Health Literature [CINAHL], Mantis) were searched for the terms "cervicogenic" and "headache." After cross-referencing, we retrieved 164 unique citations; 48 citations were added from other sources, for a total of 212 citations, although all were not used. RESULTS: Hilton described the concept of headaches originating from the cervical spine in 1860. In 1983 Sjaastad introduced the term "cervicogenic headache" (CGH). Diagnostic criteria have been established by several expert groups, with agreement that these headaches start in the neck or occipital region and are associated with tenderness of cervical paraspinal tissues. Prevalence estimates range from 0.4% to 2.5% of the general population to 15% to 20% of patients with chronic headaches. CGH affects patients with a mean age of 42.9 years, has a 4:1 female disposition, and tends to be chronic. Almost any pathology affecting the cervical spine has been implicated in the genesis of CGH as a result of convergence of sensory input from the cervical structures within the spinal nucleus of the trigeminal nerve. The main differential diagnoses are tension type headache and migraine headache, with considerable overlap in symptoms and findings between these conditions. No specific pathology has been noted on imaging or diagnostic studies which correlates with CGH. CGH seems unresponsive to common headache medication. Small, noncontrolled case series have reported moderate success with surgery and injections. A few randomized controlled trials and a number of case series support the use of cervical manipulation, transcutaneous electrical nerve stimulation, and botulinum toxin injection. CONCLUSIONS: There remains considerable controversy and confusion on all matters pertaining to the topic of CGH. However, the amount of interest in the topic is growing, and it is anticipated that further research will help to clarify the theory, diagnosis, and treatment options for patients with CGH. Until then, it is essential that clinicians maintain an open, cautious, and critical approach to the literature on cervicogenic headaches.

Ayurveda: a historical perspective and principles of the traditional healthcare system in India.

Ayurveda, the science of life, is a comprehensive medical system that has been the traditional system of healthcare in India for more than 5000 years. This medical system was well established around 2500 to 600 BC, when it evolved into 2 schools: the School of Physicians and the School of Surgeons, similar to allopathy. Charak Samhita, Susrut Samhita, and Ashtang Hridaya Samhita are the Senior Triad texts, and Madhav Nidan Samhita, Sarangdhar Samhita, and Bhavprakash Samhita are the Junior Triad texts. Around 600 BC. Ayurveda was branched into internal medicine; pediatrics; psychiatry; surgery; eye, ear, nose, and throat; toxicology; geriatrics; and eugenics/aphrodisiacs. The body is composed of 3 body doshas, 3 mental doshas, 7 dhatus, and malas. The harmony among the body doshas of vata (nervous system), pitta (enzymes), and kapha (mucus) and the gunas, or mental doshas (which are human attributes: satogun [godly], rajas [kingly], and tamas [evil]), constitutes health, and their disharmony constitutes disease. The management of illness requires balancing the doshas back into a harmonious state through lifestyle interventions, spiritual nurturing, and treatment with herbo-mineral formulas based on one's mental and bodily constitution.

Healthcare and disease management in Ayurveda.

Because the disharmony of mental doshas (satogun, rajogun, and tamogun) and body doshas (vata, pitta, and kapha) are the major cause of illness, the goal of illness management in Ayurveda is to bring back harmony among the doshas. The management includes clinical examination, diagnosis, and dietary and lifestyle interventions and treatment. The clinical examination consists of Astha Sthana Pariksha (8-point diagnosis: pulse-diagnosis, urine, stool, tongue, voice and body sound, eye, skin, and total body appearance examinations) and examination of the digestive system and the patient's physical strength. The treatment consists of cleansing (Panchkarma), palliation (improve digestion, remove toxic waste, fasting, observe thirst, exercise, sunbathing, and meditation), mental nurturing, and spiritual healing depending on the disturbed doshas and the patient's constitution. The preferred use of bhasms and herbal formulas over the respective metallic salts or the single herbs is discussed. This review suggests a great potential for integration of Ayurvedic therapies into the healthcare system in the United States.

Intra-articular hyaluronic acid (viscosupplementation) for hip osteoarthritis.

In viscosupplementation, a glycosaminoglycan called hyaluronic acid (HA) is administered via intra-articular injection to patients with osteoarthritis (OA). Two systematic reviews found that HA for hip OA may relieve pain and improve function. Randomized controlled trials had differing results. Uncontrolled studies suggest that there are moderate improvements regarding pain and function for three to six months after HA injection. There is no evidence regarding the cost-effectiveness of this therapy. No serious adverse events have been reported after intra-articular injection of HA for hip OA. The best available evidence suggests that HA may offer symptomatic relief in patients with mild to moderate hip OA for whom other conservative therapies are contraindicated or have failed. Currently, there is insufficient good quality evidence to determine this conclusively.

Intra-articular hyaluronic acid (viscosupplementation) for knee osteoarthritis.

(1) In viscosupplementation, a glycosaminoglycan (GAG) called hyaluronic acid (HA) is administered via intra-articular (IA) injection for patients with knee osteoarthritis (OA). (2) Evidence suggests modest short-term reductions in pain and improvements in function, and no superiority among HA products. (3) Adverse events are rare, benign, temporary, and likely associated with the IA injection. (4) Economic analyses of mixed quality suggest that HA may be cost effective compared with usual care. (5) Clinical practice guidelines and evidence suggest that this approach is most suitable for patients with mild to moderate knee OA, and in those for whom other approaches are contraindicated, or have failed.

A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease.

Menkes disease and occipital horn syndrome (OHS) are allelic, X-linked recessive copper-deficiency disorders resulting from mutations in ATP7A, or MNK. Classic Menkes disease has a severe phenotype, with death in early childhood, whereas OHS has a milder phenotype, with, mainly, connective-tissue abnormalities. Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity. Recently, it was reported that ATP7A-transcript levels as low as 2%-5% of normal are sufficient to result in the milder phenotype, OHS, rather than the phenotype of Menkes disease. In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced. Although abundant levels of mutant transcript are present, there are substantially reduced levels of the truncated protein, which lacks the key dileucine motif L1487L1488. It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane. The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease. The data from the present report support the concepts that (1) OHS results from lower levels of functional ATP7A and (2) ATP7A does not require the dileucine motif to function in copper efflux.

Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma.

Common fragile sites have been proposed to play a mechanistic role in chromosome translocations and other rearrangements in cancer cells in vivo based on their behavior in vitro and their co-localization with cancer translocation breakpoints. This hypothesis has been the subject of controversy, because associations have been made at the chromosomal level and because of the large number of both fragile sites and cancer chromosome breakpoints. Tests of this hypothesis at the molecular level are now possible with the cloning of common fragile site loci and the use of fragile site clones in the analysis of rearranged chromosomes. FRA3B, the most frequently seen common fragile site, lies within the large FHIT gene. It is now well established that this region is the site of frequent, large intragenic deletions and aberrant transcripts in a number of tumors and tumor cell lines. In contrast, only one tumor-associated translocation involving the FHIT gene has been reported. We have found translocations in both homologs of chromosome 3 in an early-passage esophageal adenocarcinoma cell line. This cell line showed no normal FHIT transcripts by reverse transcription polymerase chain reaction. Subsequent chromosome analysis showed translocations of the short arms of both homologs of chromosome 3: t(3;16) and t(3;4). The breakpoints of both translocations were shown by fluorescence in situ hybridization and polymerase chain reaction to be in the FHIT gene, at or near the center of the fragile site region. Using rapid amplification of cDNA ends with FHIT primers, a noncoding chimeric transcript resulting from t(3;16) was identified. These data provide direct support for the hypothesis that FRA3B, and likely other common fragile sites, may be "hot spots" for translocations in certain cancers, as they are for deletions, and that such translocations have the potential to form abnormal chimeric transcripts. In addition, the results suggest selection for loss of a functional FHIT gene by the translocation events.

Pacifier use, early weaning, and cry/fuss behavior: a randomized controlled trial.

CONTEXT: The World Health Organization and the United Nations Children's Fund strongly discourage use of pacifiers because of their perceived interference with breastfeeding. Observational studies have reported a strong association between pacifier use and early weaning, but such studies are unable to determine whether the association is causal. OBJECTIVES: To test whether regular pacifier use is causally related to weaning by 3 months postpartum and to examine differences in results according to randomized intervention allocation vs observational use or nonuse of pacifiers. DESIGN: Double-blind, randomized controlled trial conducted from January 1998 to August 1999. SETTING: Postpartum unit of a university teaching hospital in Montreal, Quebec. PARTICIPANTS: A total of 281 healthy, breastfeeding women and their healthy, term singleton infants. INTERVENTIONS: Participants were randomly allocated to 1 of 2 counseling interventions provided by a research nurse trained in location counseling. The experimental intervention (n = 140) differed from the control (n = 141) by recommending avoidance of pacifier use and suggesting alternative ways to comfort a crying or fussing infant. MAIN OUTCOME MEASURES: Early weaning, defined as weaning within the first 3 months, compared between groups; 24-hour infant behavior logs detailing frequency and duration of crying, fussing, and pacifier use at 4, 6, and 9 weeks. RESULTS: A total of 258 mother-infant pairs (91.8%) completed follow-up. The experimental intervention increased total avoidance of pacifier use (38.6% vs 16.0% in the control group), reduced daily use (40.8% vs 55.7%), and decreased the mean number of pacifier insertions per day (0.8 vs 2.4 at 4 weeks [P<.001]; 0.8 vs 3.0 at 6 weeks [P<.001]; and 1.3 vs 3.0 at 9 weeks [P =.004]). In the analysis based on randomized intervention allocation, the experimental intervention had no discernible effect on weaning at 3 months (18.9% vs 18.3% in the experimental vs control group; relative risk [RR], 1.0; 95% confidence interval [CI], 0.6-1.7), and no effect was observed on cry/fuss behavior (in the experimental vs control groups, respectively, total daily duration, 143 vs 151 minutes at 4 weeks [P =.49]; 128 vs 131 minutes at 6 weeks [P =.81]; and 110 vs 104 minutes at 9 weeks [P =.58]). When randomized allocation was ignored, however, we observed a strong observational association between exposure to daily pacifier use and weaning by 3 months (25.0% vs 12.9% of the exposed vs unexposed groups; RR, 1.9; 95% CI, 1.1-3.3). CONCLUSIONS: We found a strong observational association between pacifier use and early weaning. No such association was observed, however, when our data were analyzed by randomized allocation, strongly suggesting that pacifier use is a marker of breastfeeding difficulties or reduced motivation to breastfeed, rather than a true cause of early weaning.

Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome.

Lymphedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphedema of the limbs, with variable age at onset, and double rows of eyelashes (distichiasis). Other complications may include cardiac defects, cleft palate, extradural cysts, and photophobia, suggesting a defect in a gene with pleiotrophic effects acting during development. We previously reported neonatal lymphedema, similar to that in Turner syndrome, associated with a t(Y;16)(q12;q24.3) translocation. A candidate gene was not found on the Y chromosome, and we directed our efforts toward the chromosome 16 breakpoint. Subsequently, a gene for LD was mapped, by linkage studies, to a 16-cM region at 16q24.3. By FISH, we determined that the translocation breakpoint was within this critical region and further narrowed the breakpoint to a 20-kb interval. Because the translocation did not appear to interrupt a gene, we considered candidate genes in the immediate region that might be inactivated by position effect. In two additional unrelated families with LD, we identified inactivating mutations-a nonsense mutation and a frameshift mutation-in the FOXC2 (MFH-1) gene. FOXC2 is a member of the forkhead/winged-helix family of transcription factors, whose members are involved in diverse developmental pathways. FOXC2 knockout mice display cardiovascular, craniofacial, and vertebral abnormalities similar to those seen in LD syndrome. Our findings show that FOXC2 haploinsufficiency results in LD. FOXC2 represents the second known gene to result in hereditary lymphedema, and LD is only the second hereditary disorder known to be caused by a mutation in a forkhead-family gene.

Maternal asthma and idiopathic preterm labor.

Previous studies suggest that women with asthma are at increased risk of preterm birth. Moreover, drugs (especially beta-agonists) used to treat asthma are also used to treat preterm labor. The authors carried out a case-control study of 555 women from three hospital centers with idiopathic preterm labor (< 37 weeks), including two overlapping (i.e., non-mutually exclusive) subsamples: cases with early idiopathic preterm labor (< 34 weeks) and cases with idiopathic recurrent preterm labor (< 37 weeks plus a previous history of preterm delivery or second-trimester miscarriage). Controls were matched to cases according to race and smoking history prior to and during pregnancy. All subjects responded in person to questions about atopic, respiratory, obstetric, and sociodemographic histories. Subjects in the early and recurrent preterm labor subsamples were also asked to undergo spirometric testing with methacholine challenge 6-12 weeks after delivery. Cases were significantly more likely to report histories of asthma symptoms and physician-diagnosed asthma (matched odds ratios of 2-3) than controls, particularly those cases with recurrent preterm labor. No significant associations were observed, however, with methacholine responsiveness. These results could not be explained by residual confounding by smoking or other variables, nor by selective recall of asthma symptoms and histories by cases. Women with asthma are at increased risk of idiopathic preterm labor. The fact that no such association was seen with methacholine responsiveness suggests that nonatopic, noncholinergic mechanisms may link bronchial and uterine smooth muscle lability.