New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review.

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease caused by variants in the SLC34A2 gene encoding the sodium-dependent phosphate transport protein 2B, NaPi-2b. PAM is characterized by deposition of calcium phosphate crystals in the alveoli. Onset and clinical course vary considerably; some patients remain asymptomatic while others develop severe respiratory failure with a significant symptom burden and compromised survival. It is likely that PAM is under-reported due to lack of recognition, misdiagnosis, and mild clinical presentation. Most patients are genetically uncharacterized as the diagnostic confirmation of PAM has traditionally not included a genetic analysis. Genetic testing may in the future be the preferred tool for diagnostics instead of invasive methods. This systematic review aims to provide an overview of the growing knowledge of PAM genetics. Rare variants in SLC34A2 are found in almost all genetically tested patients. So far, 34 allelic variants have been identified in at least 68 patients. A majority of these are present in the homozygous state; however, a few are found in the compound heterozygous form. Most of the allelic variants involve only a single nucleotide. Half of the variants are either nonsense or frameshifts, resulting in premature termination of the protein or decay of the mRNA. There is currently no cure for PAM, and the only effective treatment is lung transplantation. Management is mainly symptomatic, but an improved understanding of the underlying pathophysiology will hopefully result in development of targeted treatment options. More standardized data on PAM patients, including a genetic diagnosis covering larger international populations, would support the design and implementation of clinical studies to the benefit of patients. Further genetic characterization and understanding of how the molecular changes influence disease phenotype will hopefully allow earlier diagnosis and treatment of the disease in the future.

Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis.

BACKGROUND: Variants in SLC34A2 encoding the sodium-dependent phosphate transport protein 2b (NaPi-IIb) cause the rare lung disease pulmonary alveolar microlithiasis (PAM). PAM is characterised by the deposition of calcium-phosphate concretions in the alveoli usually progressing over time. No effective treatment is available. So far, 30 allelic variants in patients have been reported but only a few have been functionally characterised. This study aimed to determine the impact of selected SLC34A2 variants on transporter expression and phosphate uptake in cellular studies. METHODS: Two nonsense variants (c.910A > T and c.1456C > T), one frameshift (c.1328delT), and one in-frame deletion (c.1402_1404delACC) previously reported in patients with PAM were selected for investigation. Wild-type and mutant c-Myc-tagged human NaPi-IIb constructs were expressed in Xenopus laevis oocytes. The transport function was investigated with a 32Pi uptake assay. NaPi-IIb protein expression and localisation were determined with immunoblotting and immunohistochemistry, respectively. RESULTS: Oocytes injected with the wild-type human NaPi-IIb construct had significant 32Pi transport compared to water-injected oocytes. In addition, the protein had a molecular weight as expected for the glycosylated form, and it was readily detectable in the oocyte membrane. Although the protein from the Thr468del construct was synthesised and expressed in the oocyte membrane, phosphate transport was similar to non-injected control oocytes. All other mutants were non-functional and not expressed in the membrane, consistent with the expected impact of the truncations caused by premature stop codons. CONCLUSIONS: Of four analysed SLC34A2 variants, only the Thr468del showed similar protein expression as the wild-type cotransporter in the oocyte membrane. All mutant transporters were non-functional, supporting that dysfunction of NaPi-IIb underlies the pathology of PAM.

Pulmonary Alveolar Microlithiasis - A Review.

Pulmonary Alveolar Microlithiasis (PAM) is a rare genetic disorder causing widespread deposition of calcium-phosphate crystals in the alveolar space. A hallmark of the disease is the discrepancy between perceived symptoms upon diagnosis compared with the extensive, sandstorm-like appearance of the microliths on chest X-ray or HRCT. Caused by a defective sodium-dependent phosphate transport protein due to loss-of-function variants of the SLC34A2 gene, PAM is an autosomal recessive transmitted disorder, and as such has a high correlation to consanguinity. The most common variants of the SLC34A2 gene are single nucleotide biallelic changes, but larger deletions are described. Initial suspicion of PAM on radiological examination should be followed by genetic testing to verify the diagnosis and identify the disease-causing variant. When not available, the diagnosis can be made by means of invasive techniques, such as transbronchial forceps or cryobiopsy, or a surgical lung biopsy. In families with a history of PAM, genetic counseling should be offered, as well as preimplantation/prenatal testing if necessary. As of writing this review, no definitive treatment exists, and PAM may in some cases progress to severe pulmonary disease with respiratory failure and potential death. Patients with PAM should be offered preventative and symptomatic treatments such as vaccinations and oxygen therapy when needed. In some cases, lung transplantation may be required.

Pulmonary alveolar microlithiasis: no longer in the stone age.

Pulmonary alveolar microlithiasis (PAM) is a rare parenchymal lung disease caused by variants in the SCL34A2 gene and characterised by the accumulation of intra-alveolar microliths. PAM has been reported in fewer than 1100 cases throughout the world. It is an autosomal recessive hereditary disease and often associated with consanguinity. Progress with respect to the genetic background and pathophysiology has resulted in an increased understanding of the disease in recent years. Until now, 30 genetic different SLC34A2 variants have been reported, which all are considered significant for disease development. There is no sex difference and the majority of cases are diagnosed at the age of 30-40 years. Many patients are asymptomatic and the diagnosis is made at random. When symptomatic, dyspnoea, cough, chest pain and fatigue are common complaints. The diagnosis of PAM can confidently be based on typical radiographic findings and genetic testing proving rare biallelic SCL34A2 gene variants. Bronchoalveolar lavage and histopathology may show microliths. There is no disease-specific treatment and management is supportive. Lung transplantation should be considered in advanced cases.

Evaluation of the usefulness of EQ-5D as a patient-reported outcome measure using the Paretian classification of health change among patients with chronic heart failure.

PURPOSE: The aim of this study was to evaluate the usefulness of EQ-5D as a patient-reported outcome measure using different analytical methods. Especially we used the Paretian Classification of Health Change, to see if this gave better information compared to measures that are more traditional. For the evaluation we used data from patients with chronic heart failure (HF). METHODS: We compared results of EQ-5D at baseline and at 1 year's follow up for HF patients with preserved or reduced ejection fraction (EF), HFpEF (EF > 50%, n = 930) and HFrEF (EF < 40%, n = 3831) using individual patient data from the Swedish Heart Failure Registry. Statistical analysis included EQ-5D index and proportions for all five dimensions of the EQ-5D. In addition, we also used the Paretian classification of Health Change to judge overall improvements (improved in at least one dimension and not worsened in any other dimension) or worsening (vice versa) in EQ-5D profiles. RESULTS: Mean EQ-5D index showed minor changes at the one-year follow-up, likewise in both groups. The proportions reporting moderate, or severe, problems increased for all five dimensions of the EQ-5D in the HFpEF group. In the HFrEF group this was seen only for three dimensions, with no change for "anxiety/depression" and reduction of problems for "usual activities ". The Paretian classification showed that 24% (n = 200) of the HFpEF group and 34% (n = 1059) of the HFrEF group reported overall improvement while 43% (n = 355) and 39% (n = 1212) respectively reported overall worsening. Multiple logistic regressions showed different patterns of determinants e.g. that treatment in a cardiology clinic only affected overall health outcome in the HFrEF group. CONCLUSION: The usefulness of EQ-5D is dependent on the analytical method used. While the index showed minor differences between groups, analyses of specific dimensions showed different patterns of change in the two groups with better prognosis for the HFrEF group. The Paretian classification of Health Change could further identify subgroups that showed overall improvements or overall worsening. This method can therefore help to identify needs for more tailored interventions in health services.

Prevalence of, associations with, and prognostic role of anemia in heart failure across the ejection fraction spectrum.

BACKGROUND: The role of anemia in heart failure with mid-range and preserved ejection fraction (HFmrEF, EF 40-49% and HFpEF, EF ≥50%) is unknown. We aimed to compare prevalence of, associations with, and prognostic role of anemia in HF across the EF spectrum. METHODS: In patients from the Swedish HF Registry, we assessed the associations between clinical characteristics and anemia (hemoglobin <120 g/L in women and <130 g/L in men) by multivariable logistic regression, and between anemia, composite of all-cause death and HF hospitalization and all-cause death alone by multivariable Cox regression. RESULTS: Of 49,985 patients with HF (anemia = 34%), 23% had HFpEF (anemia = 41%), 21% had HFmrEF (anemia = 35%) and 55% had HFpEF (anemia = 32%). Higher EF was independently associated with higher likelihood of concomitant anemia. Important predictors of anemia across the EF spectrum were male sex, older age, worse New York Heart Association class and renal function, lower systolic blood pressure, higher N-Terminal B-type natriuretic peptides levels, diabetes, valvular disease and in-patient status. Anemia had adjusted hazard ratios (95% CI) for mortality or HF hospitalization 1.24 (1.18-1.30) in HFpEF, 1.26 (1.19-1.34) in HFmrEF and 1.14 (1.10-1.19) in HFrEF; pinteractionEF = 0.003; and for mortality 1.28 (1.20-1.36) in HFpEF, 1.21 (1.13-1.29) in HFmrEF, and 1.30 (1.24-1.35) in HFrEF; pinteractionEF = 0.22. CONCLUSIONS: In this nation-wide registry, prevalence of anemia was higher in HFpEF vs. HFmrEF vs. HFrEF, but was associated with a similarly increased risk of death across the EF spectrum, with greater risk of death or HF hospitalization in HFpEF and HFmrEF vs. HFrEF.

Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis.

BACKGROUND: Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists. METHODS: We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein. RESULTS: We identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity. CONCLUSIONS: Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.

The Swedish Heart Failure Registry: a living, ongoing quality assurance and research in heart failure.

Heart failure (HF) represents a global pandemic. Although in HF with reduced ejection fraction (HFrEF) randomized controlled trials have provided effective treatments, prognosis still remains poor, with signals of undertreatment. HF with mid-range EF (HFmrEF) has no evidence-based therapy, and its characterization is ongoing. Trials in HF with preserved EF (HFpEF) have failed to provide any effective treatment, but there are several concerns about their design. Thus, current challenges in the HF field are: 1) optimizing the use of existing treatments in HFrEF; 2) developing and proving efficacy of new treatments, and of new use of existing treatments in HFpEF and HFmrEF. Here we describe how registry-based research can improve knowledge addressing the unmet needs in HF, and in particular we focus on the contribution of the Swedish Heart Failure Registry to this field.

Association between enrolment in a heart failure quality registry and subsequent mortality-a nationwide cohort study.

AIMS: Heart failure (HF) quality registries report quality of care but it is unknown whether they improve outcomes. The aims were to assess predictors of enrolment in a HF registry, test the hypothesis that enrolment in a HF registry is associated with reduced mortality, and assess potential explanatory factors for this reduction in mortality, if present. METHODS AND RESULTS: We conducted a nationwide prospective cohort study of patients with new-onset HF registered in the Swedish National Patient Registry (NPR, a mandatory registry of ICD-code diagnoses) with or without concurrent registration in the Swedish Heart Failure Registry (SwedeHF, a voluntary quality reporting registry) 2006-2013. The association between demographics, co-morbidities and medications, and enrolment in the SwedeHF, was assessed using multivariable logistic regression. The association between enrolment in the SwedeHF and all-cause mortality was assessed using multivariable Cox regression, with adjustment for demographics, co-morbidities and medications. A total of 231 437 patients were included, of which 21 888 (9.5%) were in the SwedeHF [age (mean ± standard deviation) 74 ± 13 years; 41% women; 68% inpatients] and 209 549 (90.5%) were not (age 78 ± 12 years, 50% women; 79% inpatients). Selected variables independently associated with enrolment in the SwedeHF were male sex, younger age, higher education, absent co-morbidities and co-morbidity-related medications, and use of HF and cardiovascular medications. Over a median (interquartile range) follow-up of 874 (247-1667) days, there were 13.0 vs. 20.8 deaths per 100 patient-years (P < 0.001). The hazard ratio (95% confidence interval) for death for the SwedeHF yes vs. no was 0.65 (0.63-0.66) crude, and increased to 0.80 (0.78-0.81) after adding demographics, to 0.82 (0.80-0.84) after adding co-morbidities and co-morbidity-related medications, to 0.95 (0.93-0.97) after adding cardiovascular medications, and to 1.04 (1.02-1.07) after adding HF-specific medications. CONCLUSION: Heart failure patients of male sex, younger age, and higher education were more likely to be enrolled in a HF quality registry. Enrolment was associated with reduced all-cause mortality that was explained by demographic differences and better utilization of cardiovascular and HF medications.

A comprehensive assessment of the association between anemia, clinical covariates and outcomes in a population-wide heart failure registry.

BACKGROUND: The aim was to investigate the prevalence of, predictors of, and association with mortality and morbidity of anemia in a large unselected cohort of patients with heart failure (HF) and reduced ejection fraction (HFrEF) and to explore if there were specific subgroups of high risk. METHODS: In patients with HFrEF in the Swedish Heart Failure Registry, we assessed hemoglobin levels and associations between baseline characteristics and anemia with logistic regression. Using propensity scores for anemia, we assessed the association between anemia and outcomes with Cox regression, and performed interaction and sub-group analyses. RESULTS: There were 24,511 patients with HFrEF (8303 with anemia). Most important independent predictors of anemia were higher age, male gender and renal dysfunction. One-year survival was 75% with anemia vs. 81% without (p < 0.001). In the matched cohort after propensity score the hazard ratio associated with anemia was for all-cause death 1.34 (1.28-1.40; p < 0.0001), CV mortality 1.28 (1.20-1.36; p < 0.0001), and combined CV mortality or HF hospitalization 1.24 (1.18-1.30; p < 0.0001). In interaction analyses, anemia was associated with greater risk with lower age, male gender, EF 30-39%, and NYHA-class I-II. CONCLUSION: In HFrEF, anemia is associated with higher age, male gender and renal dysfunction and increased risk of mortality and morbidity. The influence of anemia on mortality was significantly greater in younger patients, in men, and in those with more stable HF. The clinical implication of these findings might be in the future to perform targeted treatment studies.

Increased comorbidities in heart failure patients ≥ 85 years but declined from >90 years: data from the Swedish Heart Failure Registry.

OBJECTIVES: Epidemiological studies of elderly heart failure (HF) patients (≥ 85 years) are limited with inconsistent findings. Our objective is to confirm and extend epidemiological study in elderly (≥ 85 years) patients using the Swedish Heart Failure Registry database. METHODS: This retrospective study included 8,347 HF patients aged ≤ 65 years and 15,889 HF patients aged ≥ 85 years. Elderly population was further divided into two subgroups: 11,412 patients were 85-90 years and 4,477 patients were >90 years. RESULTS: The ≥ 85 year group was characterized by more women, higher systolic blood pressure (SBP), lower body-mass index (BMI), more than twice as many HF with normal left ventricular ejection fraction (HFNEF), higher incidence of cardiovascular and non-cardiovascular comorbidities and less use of proven therapeutics compared with the ≤ 65 year group. Compared with the 85-90 year subgroup, the > 90 year subgroup had a decline in cardiovascular and non-cardiovascular comorbidities except renal insufficiency and anaemia which continued to increase with ageing (p<0.01). Tendency was the same regardless of gender but slightly different between systolic HF (SHF) and HFNEF. In the group with HFNEF, there were more women, higher SBP, lower N-terminal pro-B-type natriuretic peptide levels, less ischaemic heart disease, more hypertension and left bundle branch block regardless of age. Atrial fibrillation was more frequent in patients with HFNEF than with SHF in the elderly group (p<0.01). Patients with HFNEF in the > 90 year subgroup had increasing incidence of ischaemic heart disease compared to 85-90 year group (p<0.01). CONCLUSIONS: HF patients ≥ 85 years had increased cardiovascular and non-cardiovascular comorbidities but with a decline from >90 years.

Pulmonary alveolar microlithiasis: two case reports and review of the literature.

Pulmonary alveolar microlithiasis is a rare diffuse lung disease characterised by deposition of calcium phosphate within the alveolar airspaces. The disease is usually discovered from birth up to 40 yrs of age and is often diagnosed incidentally during radiography of the chest for other reasons. Many patients are asymptomatic and the majority of patients either have normal or restrictive pulmonary function. The clinical course of the disease varies. While it remains static in some patients, it progresses into pulmonary fibrosis, respiratory failure and cor pulmonale in others. With the exception of lung transplantation, there is no known effective treatment for the disease. Although the aetiology remains unclear, mutations of the solute carrier family 34 (sodium phosphate), member 2 gene (the SLC34A2 gene), which encodes a sodium/phosphate co-transporter, are considered to be the cause of the disease. We present two cases of pulmonary alveolar microlithiasis with different mutations in the SLC34A2 gene that have not been previously described, and a review of the literature.

Aerosol volatility and enthalpy of sublimation of carboxylic acids.

The enthalpy of sublimation has been determined for nine carboxylic acids, two cyclic (pinonic and pinic acid) and seven straight-chain dicarboxylic acids (C(4) to C(10)). The enthalpy of sublimation was determined from volatility measurements of nano aerosol particles using a volatility tandem differential mobility analyzer (VTDMA) set-up. Compared to the previous use of a VTDMA, this novel method gives enthalpy of sublimation determined over an extended temperature range (DeltaT approximately 40 K). The determined enthalpy of sublimation for the straight-chain dicarboxylic acids ranged from 96 to 161 kJ mol(-1), and the calculated vapor pressures at 298 K are in the range of 10(-6)-10(-3) Pa. These values indicate that dicarboxylic acids can take part in gas-to-particle partitioning at ambient conditions and may contribute to atmospheric nucleation, even though homogeneous nucleation is unlikely. To obtain consistent results, some experimental complications in producing nanosized crystalline aerosol particles were addressed. It was demonstrated that pinonic acid "used as received" needed a further purification step before being suspended as a nanoparticle aerosol. Furthermore, it was noted from distinct differences in thermal properties that aerosols generated from pimelic acid solutions gave two types of particles. These two types were attributed to crystalline and amorphous configurations, and based on measured thermal properties, the enthalpy of vaporization was 127 kJ mol(-1) and that of sublimation was 161 kJ mol(-1). This paper describes a new method that is complementary to other similar methods and provides an extension of existing experimental data on physical properties of atmospherically relevant compounds.

Heart failure registry: a valuable tool for improving the management of patients with heart failure.

AIMS: Guidelines on how to diagnose and treat patients with heart failure (HF) are published regularly. However, many patients do not fulfil the diagnostic criteria and are not treated with recommended drugs. The Swedish Heart Failure Registry (S-HFR) is an instrument which may help to optimize the handling of HF patients. METHODS AND RESULTS: The S-HFR is an Internet-based registry in which participating centres (units) can record details of their HF patients directly online and transfer data from standardized forms or from computerized patient documentation. Up to December 2007, 16,117 patients from 78 units had been included in the S-HFR. Of these, 10,229 patients had been followed for at least 1 year, and 2133 deaths were recorded. Online reports from the registry showed that electrocardiograms were available for 97% of the patients. Sinus rhythm was found in 51% of patients and atrial fibrillation in 38%. Echocardiography was performed in 83% of the patients. Overall, 77% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, 80% were on beta-blockers, 34% on aldosterone antagonists, and 83% on diuretics. CONCLUSION: The S-HFR is a valuable tool for improving the management of patients with HF, since it enables participating centres to focus on their own potential for improving diagnoses and medical treatment, through the online reports provided.

[Can measurement of basal calcitonin replace the pentagastrin test?]. / Kan isoleret måling af kalcitonin erstatte pentagastrintest?

INTRODUCTION: Serum calcitonin is used as a tumour marker in patients with medullary thyroid carcinoma. Traditionally, stimulation of calcitonin secretion with pentagastrin has been used. This may, however, cause significant discomfort for the patient. We studied whether measurements of basal calcitonin could replace the pentagastrin test. MATERIALS AND METHODS: Forty-three patients were consecutively included. Pearson correlation coefficient (r(2)) was used for calculation of calcitonin values. RESULTS: We performed 104 pentagastrin tests in 43 patients. The squared correlation coefficient (r(2)) between calcitonin values before and after stimulation was between 0.662 and 0.919. One patient had very high and rather divergent calcitonin values. Exclusion of this patient increased r(2) to between 0.923 and 0.999. In 9 of 104 pentagastrin tests (8.7% , 95% CI: 3.3-14.1%), serum calcitonin was higher than the cut-off level in normal subjects after pentagastrin stimulation, but lower before (discrepancy). However, this would have no clinical consequences in any of the cases because serum calcitonin remained measurable, i.e. remnant thyroid tissue had to be present. CONCLUSION: In conclusion, good agreement is present between calcitonin values before and after stimulation with pentagastrin. In some cases, the pentagastrin test may be replaced by point measurements of serum calcitonin. However, further studies are necessary.

Influence of OH scavenger on the water effect on secondary organic aerosol formation from ozonolysis of limonene, Delta3-carene, and alpha-pinene.

The effect of OH scavengers on how water vapor influences the formation of secondary organic aerosol (SOA) in ozonolysis of limonene, Delta3-carene, and alpha-pinene at low concentrations has been investigated by using a laminar flow reactor. Cyclohexane and 2-butanol (3-40 x 10(13) molecules cm(-3)) were used as scavengers and compared to experiments without any scavenger. The reactions were conducted at 298 K and at relative humidities between <10 and 80%. The yield of SOA decreased in the order "no scavenger" > 2-butanol > cyclohexane. The effect of water vapor was similar for 2-butanol and without a scavenger, with an increase in particle number and mass concentration with increasing relative humidity. The water effect for cyclohexane was more complex, depending on the terpene, scavenger concentration, and SOA concentration. The water effect seems to be influenced by the HO2/RO2 ratio. The results are discussed in relation to the currently suggested mechanism for alkene ozonolysis and to atmospheric importance. The results imply that the ozone-initiated oxidation of terpenes needs revision in order to fully account for the role of water in the chemical mechanism.

Long-time visual functional results of cataract surgery on low vision patients.

BACKGROUND/AIMS: To assess longitudinal 5-year results of cataract surgery on low vision patients. METHODS: In this prospective, long-time, observational case-series, we report the outcome regarding the subjective visual function (n = 35) assessed by a visual function questionnaire (VF-14) and the visual acuity (n = 30) of surviving low vision patients 5 years after surgery. We compare with data recorded on the same patients before surgery and 4 months postoperatively. RESULTS: Five years after surgery, 57% had unchanged or better VF-14 score compared with preoperatively, and 37% compared with postoperatively. Maculopathy patients had a significantly larger deterioration 5 years after surgery compared with postoperatively (40.2 versus 51.7, p = 0.004), but for the glaucoma patients there was no significant change (52.6 versus 53.1). There were no significant associations between age of the patient and change in VF-14 score or change in visual acuity 5 years after surgery, neither compared with before surgery nor postoperatively. CONCLUSION: Results suggest a favorable functional outcome 5 years after cataract surgery on most low-vision patients. Glaucoma patients have a more stable outcome than patients with macular degeneration. The severity of the disease-process for each individual patient might be the most important factor affecting the long-time results.