Cavity-Enhanced 2D Material Quantum Emitters Deterministically Integrated with Silicon Nitride Microresonators.

Optically active defects in 2D materials, such as hexagonal boron nitride (hBN) and transition-metal dichalcogenides (TMDs), are an attractive class of single-photon emitters with high brightness, operation up to room temperature, site-specific engineering of emitter arrays with strain and irradiation techniques, and tunability with external electric fields. In this work, we demonstrate a novel approach to precisely align and embed hBN and TMDs within background-free silicon nitride microring resonators. Through the Purcell effect, high-purity hBN emitters exhibit a cavity-enhanced spectral coupling efficiency of up to 46% at room temperature, exceeding the theoretical limit (up to 40%) for cavity-free waveguide-emitter coupling and demonstrating nearly a 1 order of magnitude improvement over previous work. The devices are fabricated with a CMOS-compatible process and exhibit no degradation of the 2D material optical properties, robustness to thermal annealing, and 100 nm positioning accuracy of quantum emitters within single-mode waveguides, opening a path for scalable quantum photonic chips with on-demand single-photon sources.

Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland.

Pulmonary alveolar proteinosis and glomerulonephritis in lysinuric protein intolerance: case reports and autopsy findings of four pediatric patients.

Lysinuric protein intolerance is an autosomal recessive disease caused by defective transport of cationic amino acids. Of the 38 lysinuric protein intolerance patients diagnosed in Finland since 1965, four pediatric patients have died. We describe the clinical courses and autopsy findings for these patients. All patients developed acute respiratory insufficiency. In addition to pulmonary hemorrhages, three of the patients had pulmonary alveolar proteinosis and one had cholesterol granulomas. Three patients had a clinically obvious renal insufficiency, but all four showed histologic signs of immune complex-mediated glomerulonephritis. The patients also developed hepatic insufficiency with fatty degeneration or cirrhosis. All patients showed anemia, thrombocytopenia, and a severe bleeding tendency. The bone marrow of three patients was hypercellular, but the amount of megakaryocytes was decreased in two cases. Amyloid was present in the lymph nodes and the spleen. Bone specimens showed osteoporosis. We conclude that pediatric patients with lysinuric protein intolerance are predisposed to develop pulmonary alveolar proteinosis and glomerulonephritis. They are also at risk of protein malnutrition in the active growth phase, probably due to higher requirements for total nitrogen and amino acids.

Pulmonary manifestations in lysinuric protein intolerance.

STUDY OBJECTIVES: To evaluate the pulmonary manifestations and the course of acute respiratory insufficiency associated with lysinuric protein intolerance (LPI). DESIGN: Retrospective review of clinical data and chest radiographs (total 225) obtained during the lifetime follow-up of 31 LPI patients. About half of the 25 patients without respiratory symptoms underwent high-resolution computed tomography (HRCT) of the lungs, radionuclide perfusion imaging, whole body plethysmography, and diffusing capacity measurements. PATIENTS: Thirty-one Finnish patients with LPI. RESULTS: During the follow-up period, four children with LPI died in respiratory insufficiency, 1 adult had an episode of respiratory insufficiency, and another had chronic symptoms, whereas 25 patients remained symptom-free. The radiologic findings in acute progressive respiratory insufficiency were uniform: at first, reticulonodular interstitial densities and, later on, progressive airspace disease. At autopsy, three patients showed pulmonary alveolar proteinosis and one had pulmonary hemorrhage and cholesterol granulomas. One adult had reversible respiratory insufficiency with signs of bronchiolitis obliterans, another adult had recurrent episodes of chest pain, dyspnea, and hypoxia. Of the symptom-free patients, one third (8 of 25) had signs suggestive of pulmonary fibrosis evidenced on chest radiographs and two thirds (8 of 14) had signs evidenced by HRCT films. Most symptom-free patients showed mild abnormalities either in perfusion imaging (9 of 12) or in function tests (8 of 12). CONCLUSION: In childhood, patients with LPI are highly predisposed to develop pulmonary hemorrhages and alveolar proteinosis. Interstitial lung densities may precede the acute phase. Most adult LPI patients show radiologic signs of interstitial lung disease but only a few show clinical impairment.

Very low-dose methotrexate in the treatment of GVHD in children.

Acute GVHD is an important clinical problem frequently encountered in relation to stem cell transplantation. In its initial treatment glucocorticoids remain the established drug of choice. In the face of the side-effects related to therapy with glucocorticoids other, possibly less toxic, options for the initial treatment of acute GVHD might be of use. We report the successful treatment of progressive cutaneous acute GVHD up to grade II in five pediatric recipients of unrelated marrow grafts.

Abnormal pulmonary macrophages in lysinuric protein intolerance. Ultrastructural, morphometric, and x-ray microanalytic study.

Pediatric patients with lysinuric protein intolerance are predisposed to develop alveolar hemorrhage and pulmonary alveolar proteinosis. We evaluated the ultrastructural features of pulmonary alveolar proteinosis and the potential abnormality of pulmonary macrophages in lysinuric protein intolerance. Lung tissue specimens obtained at autopsy were examined by transmission electron microscopy. Pulmonary macrophages from bronchoalveolar lavages were studied by electron microscopy, morphometry, and x-ray microanalysis and compared with control cells. The macrophages of patients with lysinuric protein intolerance contained significantly more multilamellar structures than did control cells and showed electron-dense material identified to contain excess iron. The predisposition to develop alveolar proteinosis and the abnormal ultrastructure of pulmonary macrophages suggest altered phospholipid metabolism in patients with lysinuric protein intolerance. The marked intramacrophageal accumulations of iron might indicate altered iron metabolism or subclinical hemorrhages in lung tissue.

Osteoporosis in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids. Patients have an increased incidence of fractures and their skeletal radiographs show osteoporosis. The aim of the study was to characterize the osteopenia in LPI. Twenty-nine Finnish LPI patients (age range 3.7-44.4 years) were screened for parameters of bone metabolism. Morphometric analysis of bone was carried out in specimens of 9 patients. Collagen synthesis was studied with cultured skin fibroblasts (4 patients) and collagen fibril sizes (3 patients) were measured using electron microscopy. Most histological bone specimens (8/9) showed osteoporosis. Osteomalacia was excluded. Routine clinical laboratory tests were unrevealing. The concentrations of free hydroxyproline and type III procollagen N-propeptide in serum and the urinary excretion of hydroxyproline were increased in almost all patients during their growth and in about half of adult patients. Collagen synthesis in LPI fibroblast cultures was significantly decreased compared with that in age-matched controls at 5 (p < 0.01), 14 (p < 0.01) and still at 30 years (p < 0.01), whereas no difference was observed at the age of 44 years (p = N.S.). Osteoporosis in LPI might reflect defective matrix protein synthesis caused by protein deprivation and deficiency of cationic amino acids. Increased collagen turnover can also contribute to the osteoporosis.

Skeletal manifestations of lysinuric protein intolerance. A follow-up study of 29 patients.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease caused by defective transport of the cationic amino acids lysine, arginine, and ornithine at the cell membrane. About 80 patients with LPI have been described worldwide, almost half of them in Finland. The symptoms appear in early childhood as a failure to thrive, growth retardation, muscular hypotonia, and episodes of stupor after protein-rich meals. Twenty-nine Finnish patients (current median age 24.8 years, range 3.7-47.9 years) over a mean follow-up time of 18.1 years (range 1.2-27.2 years) had 57 fractures after minor trauma, mostly in childhood. Their 440 skeletal radiographs showed severe osteoporosis (13/29), controversially abnormal thickening of cortex of the metacarpals (7/29), or thin cortices of the long bones (5/29), endplate impression of vertebrae (8/29), rickets-like metaphyses (2/29), or early destruction of cartilage (3/29). Skeletal maturation was delayed by 1-5 years in 23 of 24 patients. There was no correlation between fracture incidence, radiological bone structure, and delayed skeletal maturation.

B and T cell immunity in patients with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is characterized by defective cellular transport of the dibasic amino acids, secondary dysfunction of the urea cycle, aversion to dietary protein, failure to thrive, hepatosplenomegaly and osteoporosis. Because several patients have suffered from recurrent respiratory infections and/or severe generalized varicella, and a few have developed systemic lupus, vasculitis or other autoimmune diseases, we have now evaluated the function of patients' immune systems. Serum concentrations of one to three IgG subclasses were decreased in 10 of the 12 patients studied. Antibody titres against diphtheria, tetanus and Haemophilus influenzae (Hib) were below the detection limit of the assay in four, three and eight of the 11 patients examined, respectively. (Re)vaccination of these 11 patients led to satisfactory responses against tetanus, but two patients still failed to develop measurable antibodies against diphtheria, two against Hib and six against one or more of the three serotypes of 23-valent pneumococcus vaccine. The proportions of T cells of all lymphocytes and the proliferative responses of the peripheral blood mononuclear cells were normal. In conclusion, humoral immune responses in some patients with LPI are defective and these patients may benefit from intravenous immunoglobulin therapy.