Divergence beneath the Brillouin sphere and the phenomenology of prediction error in spherical harmonic series approximations of the gravitational field.

The Brillouin sphere is defined as the smallest sphere, centered at the origin of the geocentric coordinate system, that incorporates all the condensed matter composing the planet. The Brillouin sphere touches the Earth at a single point, and the radial line that begins at the origin and passes through that point is called the singular radial line. For about 60 years there has been a persistent anxiety about whether or not a spherical harmonic (SH) expansion of the external gravitational potential,V, will converge beneath the Brillouin sphere. Recently, it was proven that the probability of such convergence is zero. One of these proofs provided an asymptotic relation, called Costin's formula, for the upper bound,EN, on the absolute value of the prediction error,eN, of a SH series model,VN(θ,λ,r), truncated at some maximum degree,N=nmax. When the SH series is restricted to (or projected onto) a particular radial line, it reduces to a Taylor series (TS) in1/r. Costin's formula isEN≃BN-b(R/r)N, whereRis the radius of the Brillouin sphere. This formula depends on two positive parameters:b, which controls the decay of error amplitude as a function ofNwhenris fixed, and a scale factorB. We show here that Costin's formula derives from a similar asymptotic relation for the upper bound,Anon the absolute value of the TS coefficients,an, for the same radial line. This formula,An≃Kn-k, depends on degree,n, and two positive parameters,kandK, that are analogous tobandB. We use synthetic planets, for which we can compute the potential,V, and also the radial component of gravitational acceleration,gr=∂V/∂r, to hundreds of significant digits, to validate both of these asymptotic formulas. Let superscriptVrefer to asymptotic parameters associated with the coefficients and prediction errors for gravitational potential, and superscriptgto the coefficients and predictions errors associated withgr. For polyhedral planets of uniform density we show thatbV=kV=7/2andbg=kg=5/2almost everywhere. We show that the frequency of oscillation (around zero) of the TS coefficients and the series prediction errors, for a given radial line, is controlled by the geocentric angle,α, between that radial line and the singular radial line. We also derive useful identities connectingKV,BV,Kg, andBg. These identities are expressed in terms of quotients of the various scale factors. The only other quantities involved in these identities areαandR. The phenomenology of 'series divergence' and prediction error (whenr < R) can be described as a function of the truncation degree,N, or the depth,d, beneath the Brillouin sphere. For a fixedr⩽R, asNincreases from very low values, the upper error boundENshrinks until it reaches its minimum (best) value whenNreaches some particular or optimum value,Nopt. WhenN>Nopt, prediction error grows asNcontinues to increase. Eventually, whenN≫Nopt, prediction errors increase exponentially with risingN. If we fix the value ofNand allowR/rto vary, then we find that prediction error in free space beneath the Brillouin sphere increases exponentially with depth,d, beneath the Brillouin sphere. Becausebg=bV-1everywhere, divergence driven prediction error intensifies more rapidly forgrthan forV, both in terms of its dependence onNandd. If we fix bothNandd, and focus on the 'lateral' variations in prediction error, we observe that divergence and prediction error tend to increase (as doesB) as we approach high-amplitude topography.

The effect of noggin interference in a rabbit posterolateral spinal fusion model.

STUDY DESIGN: Noggin protein levels and spinal fusion rates were compared in a rabbit model after application of siRNA against BMP antagonist noggin in paraspinal muscle. OBJECTIVE: To test whether endogenous BMPs are sufficient to form bone in the absence of their antagonists, using noggin siRNA to interrupt the negative feedback loop on endogenous BMP within the paraspinal muscles in rabbits. Unused Posterolateral lumbar fusion is a standard surgical treatment for many spinal disorders, yet even under ideal conditions the rate of non-fusion approaches 25 %. BMPs are effective in promoting bone formation, and are inhibited by antagonists such as noggin. We have previously shown that in this model, endogenous BMPs are present and endogenous BMP antagonist noggin is strongly increased during spinal fusion. Previous studies have found that noggin siRNA enhanced spinal fusion in combination with supra-physiological amounts of exogenous BMP; however, the effect of the siRNA alone remains unknown. METHODS: A posterolateral intertransverse rabbit lumbar fusion was utilized, as established by Boden et al. SiRNA against noggin was electroporated into paraspinal muscle to determine its effect on fusion. Outcome measures included noggin protein expression, and assessment of spinal fusion at 6 weeks. RESULTS: SiRNAs were effective in reducing overexpressed noggin in vitro. Noggin protein was successfully knocked down in vivo for the initial 7 days in our rabbit model and returned to detectable levels by 4 weeks and to normal levels by 6 weeks. The overall fusion rate was not significantly enhanced compared to established controls from our earlier work (Tang et al.). CONCLUSIONS: Early noggin suppression does not appear to enhance the BMP activity sufficiently to significantly affect final fusion rates in our model.

Length of uninterrupted CGG repeats determines instability in the FMR1 gene.

Analysis of 84 human X chromosomes for the presence of interrupting AGG trinucleotides within the CGG repeat tract of the FMR1 gene revealed that most alleles possess two interspersed AGGs and that the longest tract of uninterrupted CGG repeats is usually found at the 3' end. Variation in the length of the repeat appears polar. Alleles containing between 34 and 55 repeats, with documented unstable transmissions, were shown to have lost one or both AGG interruptions. These comparisons define an instability threshold of 34-38 uninterrupted CGG repeats. Analysis of premutation alleles in Fragile X syndrome carriers reveals that 70% of these alleles contain a single AGG interruption. These data suggest that the loss of an AGG is an important mutational event in the generation of unstable alleles predisposed to the Fragile X syndrome.

A new species of Isospora (Apicomplexa: Eimeriidae) from the greenfinch Carduelis chloris (Passeriformes: Fringillidae).

A new species of isosporan (Apicomplexa: Eimeriidae) is reported from the greenfinch, Carduelis chloris (Passeriformes: Fringillidae), in England. Oocysts of Isospora daszaki n.sp. are spherical to subspherical, 18.8 × 20.3 (16.8-22.4 × 16.8-25.2) µm, with a shape index (length/width) of 1.08 (1.07-1.1). Micropyle, polar granules and oocyst residuum are absent. Sporocysts are 9.4 × 14.8 (8.4-11.2 × 12.6-18.2) µm, a shape index of 1.6, with Stieda and substieda bodies. Gamogony was seen in the ileum, and merozoites were present in blood lymphocytes.

Impact of dual diagnosis on healthcare and criminal justice costs after release from Queensland prisons: a prospective cohort study.

BACKGROUND: People released from prison have poorer health than the general public, with a particularly high prevalence of mental illness and harmful substance use. High-frequency use of hospital-based services is costly, and greater investment in transitional support and primary care services to improve the health of people leaving prison may therefore be cost-effective. METHODS: A prospective cohort study of 1303 men and women released from prisons in Queensland, Australia, between 2008 and 2010, using linked data was performed. We calculated healthcare costs and the cost of re-incarceration. We compared healthcare costs to the general public, and assessed the impact of past mental illness, substance use disorder, and dual diagnosis on both healthcare and criminal justice costs. RESULTS: Healthcare costs among the cohort were 2.1-fold higher than expected based on costs among the public. Dual diagnosis was associated with 3.5-fold higher healthcare costs (95% CI 2.6-4.6) and 2.8-fold higher re-incarceration costs (95% CI 1.6-5.0), compared with no past diagnosis of either mental illness or substance use disorder. CONCLUSIONS: People released from prison incur high healthcare costs, primarily due to high rates of engagement with emergency health services and hospital admissions. Comorbid mental illness and substance use disorders are associated with high health and criminal justice costs among people recently released from prison.

Depression, stigma and quality of life in people with drug-susceptible TB and drug-resistant TB in Vietnam.

BACKGROUND: Drug resistance poses a major barrier to global control of TB - a leading infectious cause of death. Depression and stigma occur commonly among people with TB. However, the relationship between drug-resistant forms of TB, depression and stigma are not well understood.OBJECTIVE: To compare depression, stigma and health-related quality of life (HRQoL), among people with drug-susceptible TB (DS-TB) and multidrug-resistant TB (MDR-TB).METHODS: A cross-sectional study of people treated for DS-TB and MDR-TB in four provinces of Vietnam. The survey included a stigma scale (Vietnamese Tuberculosis Stigma Scale), depression scale (9-item Patient Health Questionnaire) and HRQoL scale (Functional Assessment of Chronic Illness Therapy - Tuberculosis). Differences between the two populations were compared using linear regression.RESULTS: Eighty-one people with DS-TB and 315 people with MDR-TB participated in the study. People with MDR-TB had a higher prevalence of depression than those with DS-TB (difference 17.8%, χ² 8.64). The mean depression and stigma scores were higher for people with MDR-TB than those with DS-TB (adjusted difference [AD] 8.6 and 7.6 respectively). People with MDR-TB reported lower HRQoL than those with DS-TB (AD -23.8).CONCLUSION: Depression and stigma are common among people with TB in Vietnam. Strategies to prevent and treat depressive symptoms and stigma in people with TB are critical to a holistic, patient-centred approach to care.

Evolution of hepatitis C virus NS5A region in breakthrough patients during pegylated interferon and ribavirin therapy*.

Investigating the evolution of the hepatitis C viral (HCV) genome in the small number of patients that experience viral breakthrough might shed light on the problem of resistance to interferon therapy. Within the HCV genome, sequence diversity of the viral nonstructural 5A protein-coding region (NS5A) has been linked to interferon responsiveness. We analysed the temporal sequence changes within NS5A in genotype 1a patients: 6 breakthrough (BT), 12 sustained virologic responders (SVR) and 12 non-responders (NR), all of whom had received full dose peg-interferon and ribavirin therapy. The entire NS5A region was amplified by reverse transcription (RT)-PCR followed by direct sequencing of serum samples from baseline and three on-treatment time points for each group. Comparing baseline sequences with week 12 and later time points, BT patients resembled SVR patients in having a higher number of amino acid substitutions at week 12 than NR patients; however, the number of amino acid substitutions in this group decreased at and after BT. Substitutions were focused in the V3 and flanking regions in BT patients but not in SVR patients. The high number of substitutions in NS5A in both BT and SVR groups suggests that selective pressure is associated with viral response to therapy. Our results provide evidence that amino acid substitutions within the NS5A coding region may reflect a host response that drives selective pressure for viral adaptation.

Tuberculosis among children, adolescents and young adults in the Philippines: a surveillance report.

The Philippines, a country with a young population, is currently experiencing an intense and persistent tuberculosis epidemic. We analysed patient-based national surveillance data to investigate the epidemiology of reported tuberculosis among children (aged 0-9 years), adolescents (aged 10-19 years) and young adults (aged 20-24 years) to better understand the burden of disease and treatment outcomes in these age groups. Descriptive analyses were performed to assess age-related patterns in notifications and treatment outcomes. Data quality was assessed against international benchmarks at the national and regional levels. Overall, 27.3% of tuberculosis notifications for the Philippines in 2015 pertained to children, adolescents and young adults aged 0-24 years. Treatment outcomes were generally favourable, with 81% of patients being cured or completing treatment. The data quality assessment revealed substantial regional variation in some indicators and suggested potential underdetection of tuberculosis in children aged 0-4 years. Children, adolescents and young adults in the Philippines constitute a substantial proportion of patients in the national tuberculosis surveillance data set. Long-term progress against tuberculosis in the Philippines relies on improving the control of tuberculosis in these key age groups.

Effects of maternal diabetes on fetal rat lung ion transport. Contribution of alveolar and bronchiolar epithelial cells to Na+,K(+)-ATPase expression.

Fetuses of streptozotocin-induced diabetic rats exhibited delayed lung maturation and a 40% reduction in the steady-state level of lung Na+,K(+)-ATPase alpha 1 subunit mRNA and Na+,K(+)-ATPase activity at 21 d of gestation. In in situ hybridization experiments the signal specific for Na(+)-pump alpha 1 subunit message was strongest above columnar epithelial cells of air-conducting structures. Strong labeling was also present above cuboidal cells lining the forming alveoli, but not above mesenchymal cells. Immunocytochemical localization of the protein paralleled the distribution of the mRNA. Mesenchymal cells were more abundant in fetal lungs of diabetic mothers, and thus the decreased overall levels of Na+,K(+)-ATPase may result from the observed morphological pulmonary immaturity. One day after birth there was no apparent difference in lung morphology at the light microscopic level, in the localization or the steady-state level of Na+,K(+)-ATPase alpha 1 isoform mRNA, or in enzyme activity. Na+,K(+)-ATPase has a likely role in the active phase of fluid absorption in the airways of newborns before the onset of breathing. Decreased fluid clearance and lack of thinning of the lung's connective tissue may contribute to the increased risk for respiratory distress in infants of diabetic mothers.

ETCare: a randomized, controlled, masked trial comparing two solutions for upper airway care in the NICU.

BACKGROUND: Small quantities of normal saline are sometimes instilled into the endotracheal tube of intubated neonates, to assist with the removal of thick secretions and maintain patency of the endotracheal tube. However, saline is detrimental to the innate immune system of the upper airway mucosa, rapidly unfolding and inactivating antimicrobial peptides such as LL-37. We previously reported the preparation and feasibility testing of 'ETCare', a low-sodium, physiologically based solution for airway care, and we now report results of a randomized, masked, controlled, two-centered study testing ETCare vs sterile saline among 60 intubated NICU patients. STUDY DESIGN: Sixty intubated NICU patients were randomized to having their airway care with ETCare vs saline. Three hypotheses were tested: (1) tolerance - patients will tolerate ETCare for airway care as well as they tolerate saline, (2) nosocomial infections - ETCare will result in fewer tracheal aspirates where organisms grow and fewer cases of nosocomial sepsis, and (3) chronic lung disuse - ETCare will result in fewer patients discharged home on supplemental O2. RESULTS: Thirty NICU patients with an endotracheal tube in place were randomized to receive their airway care with ETCare, and 30 to receive their care with saline. Only the pharmacist was aware of the randomization; the two solutions were visually indistinguishable and were dispensed in identical syringes. Tolerance of the solutions was similar. The ETCare recipients had trends toward fewer positive blood cultures (odds ratios (OR), 0.48; 95% confidence interval (CI), 0.13 to 1.68), and fewer discharges home on supplemental O2 (OR, 0.43; 95% CI, 0.14 to 1.32; P=0.075). CONCLUSIONS: On the basis of this study and our previous 10-patient feasibility trial, we maintain that, for airway care, intubated NICU patients tolerate ETCare as well as saline. Data from this study can be used in estimating the sample sizes needed for a phase III trial. We speculate that such a trial will demonstrate that, compared with saline, ETCare will result in fewer nosocomial infections and less chronic lung disease.

Tuberculosis in adolescents and young adults: epidemiology and treatment outcomes in the Western Cape.

SETTING: Western Cape Province, South Africa. OBJECTIVES: To characterise tuberculosis (TB) epidemiology, disease presentation and treatment outcomes among adolescents (age 10-19 years) and young adults (age 20-24 years) in the Western Cape. DESIGN: A retrospective, cross-sectional review of routine patient-level data from the Electronic TB Register (ETR.Net) for 2013. Site of TB disease, human immunodeficiency virus (HIV) status and TB treatment outcomes were analysed by 5-year age groups (<5, 5-9, 10-14, 15-19, 20-24 and 25 years of age). TB notification rates were calculated using census data. RESULTS: Adolescents and young adults comprised 18.0% of all new TB notifications in 2013. The notification rate was 141 TB cases/100 000 person-years (py) among 10-14 year olds, 418/100 000 py among 15-19 year olds and 627/100 000 py among 20-24 year olds. HIV prevalence among TB patients was 10.9% in 10-14 year olds, 8.8% in 15-19 year olds and 27.2% in 20-24 year olds. Older adolescents (age 15-19 years) and young adults (age 20-24 years) with HIV co-infection had poor treatment outcomes: 15.6% discontinued treatment prematurely and 4.0% died. CONCLUSIONS: Young people in the Western Cape suffer a substantial burden of TB, and those with TB-HIV co-infection are at high risk of treatment discontinuation.

Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues.

The antileukemia drug amsacrine and seven analogues were tested for in vitro activity against five multidrug-resistant human leukemia cell sublines (two derived from each of two Jurkat parent lines and one from the K562 line) and the corresponding parent lines (Jurkat, K562, and P388 leukemia). Resistant cell lines were derived by exposure to either amsacrine or doxorubicin. The resistance factor was calculated as the ratio of the mean IC50 value for the resistant cell line to that for the parent line. IC50 was defined as the concentration of drug inhibiting cell growth to 50% of that in control (drug-free) cultures. Patterns of cross-resistance were visualized by plotting the deviations of resistance factors from the mean resistance factor, on a logarithmic scale. Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered. Four main patterns were evident: a transport-related multidrug-resistance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously. Since some of the sublines tested showed evidence of altered topoisomerase II activity, it appears that changes in the resistance pattern in these lines may reflect changes in the stability of the ternary complexes formed by the drug, the altered enzyme, and the DNA. The resistance factor was reduced from more than 100-fold to about 13-fold in three of the sublines tested and from eightfold to twofold in two others. This finding suggests that appropriate drug design may overcome several forms of multidrug resistance in human leukemia and other types of cancer.

Intrinsic pituitary interleukin-1 beta is induced by bacterial lipopolysaccharide.

Using a specific antiserum recognizing recombinant rat interleukin-1 beta (IL-1 beta), immunoreactive material was localized to cytoplasmic granules in anterior pituitary endocrine cells and colocalized with TSH in thyrotropes. Authenticity was established by Northern blot hybridization using a specific rat IL-1 beta cRNA probe, revealing a 1.8-kilobase mRNA identical to that in the spleen. The marked increase in anterior pituitary IL-1 beta message after the administration of bacterial lipopolysaccharide, raises the possibility that IL-1 beta may be involved in paracrine or autocrine regulation of pituitary function during infectious challenge.

Diurnal pattern of plasma growth hormone-binding protein in man.

The identification of specific GH-binding proteins (GH-BP) in human plasma, one of which is a fragment of the GH receptor, has added new complexity to the state of GH in the circulation. A major proportion of GH circulates in complexed form, which differs in kinetics and possibly bioactivity from free GH. Little is known about the regulation of the GH-BP, their constancy or variation in plasma, or plasma factors affecting GH binding. Consequently, the temporal pattern of bound and free GH in plasma is also unknown. Knowledge about possible spontaneous variability in GH-BP levels/activity is required for physiological investigations and comparative studies among different populations. To address these issues, we measured GH-binding activity in plasma every hour over a 24-h period in six normal adults (three men and three women). A standardized GH binding assay, employing incubation of plasma with [125I]GH and separation of bound from free GH by gel filtration, was used. GH-BP activity showed no significant diurnal variation in any subject. The average GH-BP activity was similar in all subjects, although statistically significant differences were found between some subjects. No age- or sex-related differences were identified. We conclude that in normal man plasma GH-BP activity is constant throughout the day, thereby implying 1) constancy of binding protein (and possibly GH receptor) concentration, and 2) absence of significant fluctuations in potential binding inhibitors/enhancers in plasma.

The APC E1317Q variant in adenomatous polyps and colorectal cancers.

Genetic susceptibility may play a role in many colorectal cancers (CRCs). Known syndromes such as familial adenomatous polyposis and hereditary nonpolyposis CRC account for <5% of CRCs. The germ-line missense variant of the APC gene, E1317Q, has been proposed to confer a risk for colonic adenomatous polyps (adenomas), but not for CRCs in the general population. These findings are contradictory and controversial. In the present study, 608 cases (377 patients with CRC, 145 patients with 4-100 lifetime adenomas, and 86 with < or =3 lifetime adenomas), and 679 controls (362 spouses and 317 patients with normal colonoscopy) were screened for the APC E1317Q variant. The frequency of heterozygotes for E1317Q among patients with CRC (2.4%), patients with 4-100 adenomas (1.4%), and < or =3 adenomas (3.5%) did not differ from spouse controls (2.8%). When CRC patients were examined by DNA mismatch repair status, age at onset (< or =age 50 versus >50), or family history of CRC, no differences in the frequency of E1317Q were found. The APC variant E1317Q does not appear to be associated with increased risk for colorectal neoplasia in the general population. However, when we used normal colonoscopy controls (E1317Q carrier frequency = 0.3%), the prevalence of E1317Q was significantly increased in CRC patients, in patients with < or =3 adenomas, and in CRC patients with intact mismatch repair status, suggesting a possible role for E1317Q in colorectal tumorigenesis. These results underscore the importance of carefully defining the controls to be used in comparisons of allele frequencies.

Late-onset SCA2: 33 CAG repeats are sufficient to cause disease.

SCA-2 is an autosomal dominant inherited disorder characterized by ataxia, slow saccades, and hyporeflexia. The authors evaluated a patient with a mild balance problem with a SCA-2 allele sized at 33 CAG repeats. The authors then ascertained her 91 year-old mother, who showed disease onset at age 86 with an SCA-2 allele of identical size. Their study indicates that 33 CAG repeats can be pathogenic at the SCA-2 locus, though such an allele may produce an extremely late onset and gradual rate of disease progression.

Management of individual tumor syndromes. Medullary thyroid carcinoma and hyperparathyroidism.

Significant advances have been made in the understanding of the pathophysiology and the ability to effectively screen for and treat medullary thyroid carcinoma. The parafollicular cells, or C-cells, are the cell of origin for medullary thyroid carcinoma. C-cell hyperplasia is a premalignant disease that progresses rapidly to medullary thyroid carcinoma. C-cells produce calcitonin, which serves as a marker to prospectively screen patients for C-cell disease. One major concern in screening for this disease has been the incidence of false positive results. This problem is addressed in light of new, more stringent criteria for the diagnosis of C-cell hyperplasia. The association of hyperparathyroidism with MEN 2 is discussed with evidence that thyroidectomy of C-cell disease may affect the incidence of parathyroid disease.

Biochemical evaluation of adrenal dysfunction: the laboratory perspective.

In this study, we reviewed the diagnostic efficiency of laboratory tests that are performed for assessment of patients with Cushing's syndrome or adrenal insufficiency. Baseline laboratory data from patients subsequently diagnosed with adrenal dysfunction were analyzed for tests performed between 1987 and 1989 at our institution. Results were analyzed for 36 patients diagnosed with pituitary-dependent Cushing's syndrome, 15 with ectopic Cushing's syndrome, 12 with adrenal-dependent Cushing's syndrome, 20 with primary adrenal insufficiency, and 7 with secondary adrenal insufficiency. Tests reviewed were plasma cortisol, plasma corticotropin, urinary free cortisol, urinary 17-ketosteroids, urinary ketogenic steroids, low-dose and high-dose dexamethasone suppression, and metyrapone stimulation. Our findings suggest that a substantial proportion of diagnoses could be based on the results of three tests--plasma corticotropin, plasma cortisol, and urinary free cortisol. We present a nomogram that combines the results of plasma corticotropin and plasma cortisol testing to enhance the diagnostic efficiency of these tests.

Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion.

Autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders that generally present in adulthood. Spinocerebellar ataxia type 2 typically presents with progressive cerebellar symptoms, slow ocular saccades, and peripheral neuropathy. The onset of symptoms is usually between 20 and 40 years. We describe an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa were noted at 10 months. Her father had mild spinocerebellar ataxia first noted at age 22 years. Molecular studies of the SCA2 gene showed a CAG expansion of 43 repeats in the father and an extreme CAG repeat expansion of more than 200 in the baby. Our report expands the known phenotype and genotype of SCA2. Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.

Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study.

More than 900 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported to the cystic fibrosis (CF) consortium. A missense mutation, S1235R, was originally reported in a CF patient with a second mutation (G628R) on the same chromosome. The clinical significance of S1235R was not clear. S1235R is not among the commonly reported mutations, and it is not routinely screened for in most laboratories. However, we have detected the S1235R allele at a frequency that is significantly higher than that of many other CF mutations. Among more than 3,000 patients tested for either a possible diagnosis of CF or to determine CF carrier status, we identified 51 patients heterozygous for S1235R. No patients were homozygous for S1235R. Five patients were compound heterozygotes for a second CFTR mutation: two cases (one family) were N1303K/S1235R and three unrelated cases were deltaF508/S1235R. Our data suggest that S1235R, when combined with a second CF mutation, may be pathogenic, although phenotypic manifestations appear to be variable. The possibility that this represents a rare polymorphism cannot be discounted completely. Genetic counseling is difficult when S1235R is identified, even in the presence of a second known mutation, especially in prenatal cases.