Observation of Anomalous Orbital Angular Momentum Transfer in Parametric Nonlinearity.

Orbital angular momentum (OAM) conservation plays an important role in shaping and controlling structured light with nonlinear optics. The OAM of a beam originating from three-wave mixing should be the sum or difference of the other two inputs because no light-matter OAM exchange occurs in parametric nonlinear interactions. Here, we report anomalous OAM transfer in parametric upconversion, in which a Hermite-Gauss mode signal interacts with a specially engineered pump capable of astigmatic transformation, resulting in Laguerre-Gaussian mode sum-frequency generation (SFG). The anomaly here refers to the fact that the pump and signal both carry no net OAM, while their SFG does. We reveal experimentally that there is also an OAM inflow to the residual pump, having the same amount of that to the SFG but with the opposite sign, and thus holds system OAM conservation. This unexpected OAM selection rule improves our understanding of OAM transfer among interacting waves and may inspire new ideas for controlling OAM states via nonlinear optics.

Correction: In situ synthesis of chiral AuNCs with aggregation-induced emission using glutathione and ceria precursor nanosheets for glutathione biosensing.

Correction for 'In situ synthesis of chiral AuNCs with aggregation-induced emission using glutathione and ceria precursor nanosheets for glutathione biosensing' by Mohamed Ibrahim Halawa et al., Analyst, 2022, https://doi.org/10.1039/d2an00939k.

In situ synthesis of chiral AuNCs with aggregation-induced emission using glutathione and ceria precursor nanosheets for glutathione biosensing.

In the present study, a mediator release test (MRT) strategy has been designed for the photoluminescent sensing of glutathione (GSH). On the basis of the redox reaction of GSH and cerium-based nanosheets (Ce(CO3)2 NSs), Ce3+ ions were released to act as a mediator for the photoluminescence emission of the Au-thiolate complexes through an aggregation-induced emission (AIE) process. Remarkably, AIE was also accompanied by high chirality for the in situ synthesis of AuNCs using Ce(CO3)2 NSs as a template and GSH as a releaser for oligomeric Au-thiolate complexes. Multiple characterization techniques, including high-resolution transmission electron microscopy (HRTEM), atomic force microscopy (AFM), selected-area electron diffraction (SAED), X-ray powder diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), were employed to check the structure and morphology of the Ce(CO3)2 NSs as well as the successful in situ fabrication of the AuNCs. Using this new MRT strategy, an eco-friendly, selective, biocompatible and label-free AIE probe was established for the sensitive sensing of GSH with a limit of detection (LOD) of 1.02 µM. Moreover, this switch-on luminescent nanoplatform of the conjugate probe of Au-thiolate/Ce-based NSs was successfully applied for the selective and reliable GSH detection in human serum samples.

Development of luminol-based chemiluminescence approach for ultrasensitive sensing of Hg(II) using povidone-I2 protected gold nanoparticles as an efficient coreactant.

In this work, we fabricated gold nanoparticles (AuNPs) capped with both polyvinyl pyrrolidone (PVP) and iodine (I2) to act as efficient chemiluminescent coreactants for luminol. AuNPs synthesis was based on the direct chemical reduction of Au3+ with NaBH4 in the presence of PVP-I2 complex. The successful synthesis of PVP-I2@AuNPs was confirmed with scanning electron microscopy (SEM) and UV-vis spectrophotometry. Chemiluminescence (CL) intensity of luminol was greatly enhanced, upon its chemical reaction with chemisorbed I2 on AuNPs surfaces owing to the excellent catalytic activity of AuNPs. The PVP-I2@AuNPs/luminol CL sensing system was successfully applied for determination of Hg2+ ions and the results displayed linearity in a wide range from 0.5 to 2000 nM and an ultrasensitive response to 1.0 nM Hg2+. The detection limit of Hg2+ ions was 0.1 nM, which was 100 times lower than the limit value (10 nM) defined by the U.S. Environmental Protection Agency in drinkable water. This ultrasensitive luminogenic system for Hg2+ detection also exhibited excellent selectivity among 13 types of metals, suggesting that the luminol/PVP-I2@AuNPs system is a promising sensor for real-time detection of Hg2+. Graphical abstract.

Solvent and Surface/Interface Effect on the Hierarchical Assemblies of Chiral Aggregation-Induced Emitting Molecules.

The core of aggregation-induced emitting (AIE) molecules was their aggregation behavior. It was, in essence, a self-assembly process driven by noncovalent interactions, which were governed not only by the chemical structures of the molecules but also by the conditions where the self-assemblies were formed. The self-assemblies of two AIE molecules, tetraphenylethene (TPE) derivatives carrying one valine attachment (TPE-Val) and two valine attachments (TPE-2Val), were studied. Both kinds of molecules self-assembled into supramolecular helical fibers with different handedness upon the addition of poor solvent to their solution. However, when deposited on air/water interface, both kinds of molecules formed aligned elementary helical fibers instead of supramolecular fibers. The lateral solvophobic effect exerted by water molecules caused a shift of the original noncovalent balance between molecules and solvent; thus, the supramolecular helical assemblies were unraveled into aligned helical elementary fibers. Similar elementary assemblies were formed on the surface of 3-aminopropyl triethoxysilane-modified mica, confirming the lateral solvophobic effect on the self-assemblies of the molecules.

Multiple Anti-Counterfeiting Guarantees from a Simple Tetraphenylethylene Derivative - High-Contrasted and Multi-State Mechanochromism and Photochromism.

Herein the novel tetraphenylethylene (TPE) derivative 1 was designed with an integration of aggregation-induced emission (AIE), multi-state mechanochromism and self-recovery photochromism. The molecule was susceptible to grinding, heating and vapor fuming and showed corresponding transition of its emission colors. The heated powder or single crystal of 1 exhibited reversible photochromism. After a short period of UV irradiation, it showed a bright red color, but recovered to its original white appearance within 1 min. The photochromism is due to the formation of photocyclization intermediates upon UV irradiation, while the eversible mechanochromism is attributed to the weak molecular interactions derived from head-to-tail stacking of the molecules. This reversible multi-state, high-contrasted and rapid responsive mechanochromic and photochromic property cooperatively provide double enhancement of a multimode guarantee in advanced anti-counterfeiting.

Combined proximal tubulopathy, crystal-storing histiocytosis, and cast nephropathy in a patient with light chain multiple myeloma.

BACKGROUND: The diagnosis of myeloma, a plasma dyscrasia, often results from the workup of unexplained renal disease. Persistent renal failure in myeloma is commonly caused by tubular nephropathy due to circulating immunoglobulins and free light chains. Myeloma cast nephropathy is characterized by crystalline precipitates of monoclonal light chains within distal tubules. Immunoglobulin crystallization rarely occurs intracellularly, within proximal tubular cells (light chain proximal tubulopathy) and interstitial histiocytes (crystal-storing histiocytosis). We present a case report of a rare simultaneous occurrence of light chain proximal tubulopathy, crystal-storing histiocytosis, and myeloma cast nephropathy in a patient with κ light chain multiple myeloma. CASE PRESENTATION: A 48-years-old man presented with uremia and anemia. Laboratory examination revealed low levels of serum IgG, IgA, and IgM. Serum and urine immunofixation electrophoresis showed a free κ monoclonal band. Bone marrow aspiration and biopsy revealed hypercellularity with marked plasmacytosis. Light microscopy revealed eosinophilic cuboid- and rhomboid-shaped crystals in the cytoplasm of proximal tubular epithelial cells, diffuse large mononuclear and multinuclear cells in the interstitium, and obstructed distal tubules with cast and giant cell reaction. Immunohistochemical examination indicated intense staining for κ light chains within casts, histiocytes, and tubular epithelial cells. Electron microscopy revealed electro-dense cuboid-, rhomboid-, or needle-shaped crystalline inclusions in proximal tubular epithelial cells and interstitial histiocytes. According to these results, we confirmed that this patient with myeloma exhibited simultaneous light chain proximal tubulopathy, crystal-storing histiocytosis, and myeloma cast nephropathy, which were attributed to monoclonal κ light chains. In addition to dialysis, the patient received induction chemotherapy with a combination of bortezomib, cyclophosphamide, and dexamethasone, followed by maintenance therapy with thalidomide. However, the patient did not regain renal function even when less than 5% plasma cells were detected in the bone marrow. CONCLUSION: To the best of our knowledge, this is the first report of simultaneous light chain proximal tubulopathy, crystal-storing histiocytosis, and myeloma cast nephropathy in κ light chain multiple myeloma.

Palatal fistula risk after primary palatoplasty: a retrospective comparison of humanitarian operations and tertiary hospitals.

BACKGROUND: Humanitarian surgical organisations provide cleft palate repair for patients without access to surgical care. Despite decades of experience, very little research has assessed the outcomes of these trips. This study investigates the fistula rate in patients from two cohorts in rural China and one in the USA. METHODS: This retrospective study compared the odds of fistula presentation among three cohorts whose palates were repaired between April, 2005, and November, 2009. The primary cohort included 97 Chinese patients operated on in China by surgeons from ReSurge International. A second Chinese cohort of 250 patients was operated on at Huaxi University Hospital by Chinese surgeons. The third cohort of 120 patients from the University of California San Francisco (UCSF) was included for comparison over the same time period; data was taken from medical records. Age, fistula presentation, and Veau Class were compared between the three cohorts with χ(2) tests. Logistic regression was used to analyse predictors of fistula presentation among the three cohorts. This study received institutional review board approval from the UCSF, the Harvard School of Public Health, and physicians at Huaxi University Hospital, and written consent was obtained from study participants in China. FINDINGS: The fistula risk was 35·4% in ReSurge patients, 12·8% for patients at Huaxi University Hospital, and 2·5% for patients at UCSF (p<0·001). At the time of surgery 15·5% of the ReSurge patients were younger than 2 years old, whereas 90·8% of the UCSF children and 41·6% of the Huaxi children were (p<0·001). In the ReSurge cohort, 20·6% of patients had a Veau class of I or II, wheras 40·8% and 58·9% of UCSF and Huaxi patients, respectively, were in class I or II (p<0·001). Age and Veau Class were associated with fistula formation in a univariate analysis. (Veau Class III or IV vs I or II, odds ratio [OR] 6·399 [95% CI 3·182-12·871]; age, OR 1·071 [95% CI 1·024-1·122]). A multivariate model controlling for the surgical group, age at palatoplasty, and sex showed an association between Veau Class and the odds of fistula presentation (Class III or IV vs I or II, OR 5·630 [95% CI 2·677-11·837). In this model, UCSF patients and Huaxi patients had 0·064 and 0·451 times the odds of developing a fistula, respectively, compared with ReSurge patients (p<0·001 both). INTERPRETATION: Chinese children undergoing palatoplasty on surgical missions have higher post-operative odds of palatal fistula than do children treated by local physicians. Children in low-resource settings have higher complication rates than do children in high-resource settings. Older age at palatoplasty and a Veau class III and IV are associated with post-palatoplasty fistula. Furthermore demographic, socioeconomic, and cultural differences could play a part in palatoplasty fistula outcomes between these three populations. More research is needed to determine the effects of post-operative care, the skill of the providers, and the technique used in the surgery that play a role on fistula outcomes after primary palatoplasty, particularly in low-resource environments. FUNDING: None.

Click Synthesis, Aggregation-Induced Emission and Chirality, Circularly Polarized Luminescence, and Helical Self-Assembly of a Leucine-Containing Silole.

By introducing chiral leucine pendants to silole scaffold, leucine-containing silole (Silole-Leu) is synthesized and it is endowed with not only aggregation-induced emission and circular dichroism, but excellent chiral polarized luminescence as well. Silole-Leu also has the capacity to self-assemble into nano/micro helical luminescent fibers and the dimension of the fibers can be tuned by adjusting the ratio and volume of mixed solvents for evaporation as revealed by atomic force microscope, scanning electron microscope, and fluorescence microscope. The characteristic helicity of microfibers is directly visualized for the first time by using fluorescence microscope.

Anti-Kasha triplet energy transfer and excitation wavelength dependent persistent luminescence from host-guest doping systems.

Anti-Kasha's process in organic luminogens has attracted many attentions since its discovery. However, only limited examples of anti-Kasha's rule have been reported and anti-Kasha triplet energy transfer (ET) is even less-touched. Benefiting from anti-Kasha's rule, this work provided an efficient strategy to realize excitation wavelength dependent (Ex-De) afterglow in a host-guest system. The host has almost imperceptible RTP upon 365 nm excitation and guest is totally RTP inactive, while the doping host-guest system exhibits Ex-De afterglow with improved quantum yields. Anti-Kasha triplet ET process is realized from the higher excited triplet state T2 of host to the lowest excited singlet state S1 of the aggregated/unimolecular guest. ET efficiency in the doping system could be tuned by simply changing its processing methods to guide host and guest to adopt denser or looser intermolecular packing. The strategy of anti-Kasha triplet ET endows the host-guest doping system with multiple stimuli-responsive properties, including Ex-De afterglow, mechano-, and thermal-triggered afterglow behaviors. The corresponding applications of these properties are also realized in multiple information anti-counterfeiting and display.

Tunable helical assemblies of L-alanine methyl ester-containing polyphenylacetylene.

The self-assemblying behaviors of L-alanine methyl ester-containing polyphenylacetylene (PPA-Ala, in Chart 1 ) were investigated upon the evaporation of its solvent on mica and on air/water interfaces. The introduction of chiral amino acid attachments to the polyphenylacetylene backbone induced a helical conformation of the backbone, which was stabilized by various noncovalent interactions, especially hydrophobic effect and hydrogen bonds. The helicity of the polymer was further amplified in its higher-order self-assemblies as the formation of helical fibers on the surface of mica upon natural evaporation of its THF solution. By LB technique, the polymer chains were guided to form ordered parallel ridges and highly aligned, with their helical conformation still remaining. The reorganization of the chiral polymer chains on air/water interface was associated with the additional hydrophobic effect of PPA-Ala on an air/water interface. The polymer backbones had to adopt different arrangements to minimize their contact with water, and this adjustment led to the formation of aligned polymer ridges under proper surface pressure.

Cola-colored dialysate as a gastrointestinal sequelae of cardiac surgery in a patient who underwent peritoneal dialysis.

The discoloration of effluent peritoneal dialysate, which is transparent in origin, is seen in some particular conditions including chyloperitoneum, calcium channel blocker usage, hemoperitoneum, perforated cholecystitis, iron administration, and hemorrhagic pancreatitis. We report a case of a 60-year-old woman who underwent peritoneal dialysis for 3 years and presented with conspicuous cola-colored (brownish-black) dialysate after a cardiac surgery. The findings of the dialysate analysis and the abdominal computed tomography showed that this discoloration could be due to the presence of methemalbumin caused by pancreatitis (not hemorrhagic) combined with intra-abdominal bleeding-both of which are rare gastrointestinal complications of cardiac surgery. She eventually died of pulseless electrical activity due to severe sepsis with profound shock. Therefore, the rare event of cola-colored peritoneal dialysate could present as severe gastrointestinal sequelae of cardiac surgery and may indicate a poor prognosis.

Insight into Isomeric Effect on the Photoluminescence and Mechanoluminescence of Cyanostilbene Derivatives.

Molecular structures, packings, and intermolecular interactions significantly affect the photophysical properties of organic luminogens. In this work, the photoluminescence (PL) and mechanoluminescence (ML) of two pairs of isomers, 1/2 and 3/4, were systematically explored. The fluorescence of crystals 1c and 4c is much brighter than that of their isomers 2c and 3c, respectively. Only 1c is ML-active among all four molecules. Single-crystal structural analysis revealed that isomerization of a substituent group affected their molecular packing and intermolecular interactions. Stronger intermolecular interaction and intact three-dimensional hydrogen-bonded networks were formed only in crystal 1c, which were essential for preventing slippage of molecular layers and generating ML; the other molecules were either lacking π-π interactions or C-H···π interactions. Theoretical calculation suggested that the energy barrier between the Franck-Condon (FC) structure and minimum energy crossing point (MECP) structure of 2/3 was much lower than that of 1/4. Nonradiative decay channels of molecules 2 and 3 were thus more easily activated, which led to their lower quantum yield.

Two Cholesterol-Containing Pyrene Derivatives: Subtle Spacer Difference, Diverse Stimuli-Responsive Luminescence, Chirality, and Self-Assembly Behaviors.

Two chiral molecules 1 and 2 were designed and synthesized with a pyrene moiety directly linked to a chiral cholesterol moiety and connected through a methylene spacer, respectively. Influence of the spacer on their stimuli-responsive luminescence, chirality, and self-assembly behaviors was systematically investigated. Molecules 1 and 2 had similar aggregation-induced emission enhancement (AIEE) in solution, because of carrying the same fluorescence moiety. Both molecules displayed mechanochromism (MC) property but with different color contrast, whereas only 2 showed mechanoluminescence (ML) activity. When doping in liquid crystal molecule 5CB, both molecules induced the formation of chiral nematic liquid crystals (N*-LCs) with strong circularly polarized luminescence (CPL). Molecule 2 induced single handedness signal, irrespective of doping ratios, while 1-doped N*-LCs showed an inversion of CPL signal from negative to positive upon the increase of doping ratios. Molecules 1 and 2 also self-assembled into different coassemblies with 5CB. Their distinct behaviors were attributed to the influence of the methylene spacer, which caused different molecular conformation and steric bulkiness; accordingly, it changed intermolecular interactions and molecular packing of the two molecules and led to diverse chirality and luminescence. This work provided important model molecules to better understand the molecular structure-property relationship and guide the design of novel functional molecules.

An ultrasensitive chemiluminescent biosensor for tracing glutathione in human serum using BSA@AuNCs as a peroxidase-mimetic nanozyme on a luminol/artesunate system.

In this work, a nanosensor chemiluminescent (CL) probe for sensing glutathione (GSH) was developed, for the first time, based on its inhibition of the intrinsic peroxidase-mimetic effect of BSA@AuNCs. The endoperoxide linkage of artesunate could be hydrolyzed by BSA@AuNCs resulting in the release of reactive oxygen species (ROS), and the consequent generation of strong CL emission. By virtue of the strong covalent interactions of -S⋯Au-, GSH could greatly suppress the peroxidase-mimetic effect of BSA@AuNCs, leading to a drastic CL quenching. The CL quenching efficiency increased proportionally to the logarithm of GSH concentration through the linearity range of 50.0-5000.0 nM with a limit of detection of 5.2 nM. This CL-based strategy for GSH tracing demonstrated the advantages of ultrasensitivity, high selectivity and simplicity. This strategy was successfully utilized to measure GSH levels in human serum with reasonable recovery results of 98.71%, 103.18%, and 101.68%, suggesting that this turn-off CL sensor is a promising candidate for GSH in biological and clinical samples.

Direct Visualization of Chiral Amplification of Chiral Aggregation Induced Emission Molecules in Nematic Liquid Crystals.

Chiral amplification in liquid crystals (LCs) is a well-known strategy. However, current knowledge about the underlying mechanism was still lacking; in particular, how it was realized at the nano scale still remained to be revealed. Here, we provide systematical exploration of chiral amplification of chiral aggregation induced emission (AIE) molecules in LCs from direct visualization of their co-assemblies at the nano scale to theoretical calculation of the molecular packing modes on a single molecular level. Using AFM imaging,we directly visualized the co-assembly formed by chiral AIE molecules/LCs at the nano scale: the chiral AIE molecules self-assembled into helical fibers to serve as the helical template for LCs to bind, while the LCs helically bound to the helical fibers to form the co-assembly, giving the morphology of pearled necklaces or thick rods. Theoretical calculation suggested that chiral AIE molecules were packed into left-handed helical fibers with a large volume of empty space between neighboring molecules, which provided the binding cites for LCs. Structural analysis showed that the π-π stacking between aromatic groups from LCs and TPE groups and the σ-π hyperconjugation between LC aromatic groups and cholesterol aliphatic groups play an important role in stabilizing the binding of LCs in the confined space on the surface of the helical assemblies.

Controllable room temperature phosphorescence, mechanoluminescence and polymorphism of a carbazole derivative.

Room temperature phosphorescence (RTP) and mechanoluminescence (ML) materials are in high demand because of their promising applications in optoelectronic devices. However, most materials bear only one of these properties and molecules bearing both of them are rarely reported. Here, we report a carbazole derivative 1, which displays both RTP activity and near-ultraviolet ML properties. These properties are highly related to the packing modes and molecular configuration as revealed by the analysis of their crystal structures and theoretical calculations. The near-ultraviolet ML of 1 can further serve as the exciting light source to transfer its energy to luminescent dyes to realize colorful ML. The thermal-responsive RTP of 1 can be utilized to prepare anti-counterfeiting tags for simple security protection. This work has put forward a simple but efficient strategy to prepare multifunctional molecular systems bearing both RTP and ML properties.

Direct evidence of the role of ATPγS in the binding of single-stranded binding protein (Escherichia coli) and RecA to single-stranded DNA.

To gain insight into the influence of ATPγS on the competitive binding of RecA and single-stranded binding protein (SSB) on single-stranded DNA (ssDNA), AFM imaging was used to examine the three-dimensional structures of the different complexes formed by the binding of the two proteins on ssDNA in the presence and absence of ATPγS. In the presence of ATPγS, RecA attaches to ssDNA, displacing SSB, to form continuous binding regions that caused considerable elongation of the strand. When ATPγS is absent, RecA could not compete with SSB and only binds at a few sites that correspond to the vacancy in ssDNA left when SSB unbinds. These results provide direct evidence that, while SSB binding affinity to DNA is substantially higher than that of RecA, the presence of ATPγS is sufficient to alter the events and enable RecA coating of DNA.

Novel Synthesis of Thiolated Gold Nanoclusters Induced by Lanthanides for Ultrasensitive and Luminescent Detection of the Potential Anthrax Spores' Biomarker.

In this study, we reported a facile, one-pot, and "green" synthesis of glutathione-protected gold nanoclusters (GSH@AuNCs) initiated by samarium (Sm3+) lanthanides for the first time. Sm3+ lanthanides more efficiently induced the formation of GSH@AuNCs with significantly enhanced luminescence than other lanthanides or heavy metal ions (Cd2+, Pb2+) did. Using this strategy, a detection for Sm3+ was made with a linearity range of (10.0-100.0 µM) and a limit of detection (LOD) of 0.5 µM. The Sm3+-based GSH@AuNCs were characterized by eco-friendliness, photostability, and low-cost synthesis with low biological toxicity and had great potential in the application for biosensing and bioimaging. They were successfully employed in the detection of dipicolinic acid (DPA), a well-reported biomarker for sensing potential infection by strongly hazardous anthrax spores. A good linear response was obtained for DPA detection ranging from 1.0 to 120.0 µM with a low LOD of 0.1 µM, which was much lower (600 times) than the infectious dosage of anthrax spores (6 × 10-5 M). The detection was due to the strong binding affinity and strong chelation capability of DPA to Sm3+ lanthanides, which caused the dissociation of the aggregates with an obvious decrease or even a turning-off effect of their luminescence.

The clinicopathological implications of endothelial tubuloreticular inclusions found in glomeruli having histopathology of idiopathic membranous nephropathy.

BACKGROUND: The pathological recognition of secondary membranous nephropathy (MN) is sometimes difficult, especially in those showing primary idiopathic MN-like histomorphology. The ultrastructural finding of tubuloreticular inclusions (TRIs) in MN always evokes suspicion of their association with underlying diseases such as viral infections and autoimmune diseases. However, it is not clear whether some other underlying diseases are associated with TRI expression in MN. Since treatment of the underlying diseases is the primary consideration for the management of secondary MN, it is important to make out the clinical significance of TRI expression in MN. METHODS: Excluding the patients fully qualified for systemic lupus erythematosus (SLE) diagnostic criteria, we recruited 36 cases having a renal biopsy featured with histopathology of primary idiopathic MN but ultrastructural appearance of TRIs in glomerular endothelial cells (GECs). We investigated their clinical and pathological profiles and focused on the potential connections with the underlying diseases and treatment outcomes. RESULTS: One-third of our cases showed no identifiable underlying aetiology. Other underlying disease groups included autoimmune disease (25%), hepatitis (14.7%), potential Helicobacter pylori infection (13%), diabetes (5.6%) and lymphoma (5.6%). Pathologically, patients in the autoimmune group tended to have more heterogeneous membranous deposits with frequent mesangial and subendothelial deposits. While all patients of the autoimmune group presented complement C1q in glomeruli, more than two-thirds of the patients in others groups were negative for C1q. Clinically, the patients in autoimmune and hepatitis groups were younger in age and had less remission of proteinuria following treatment, while the other groups of patients achieved partial or complete remission more frequently. CONCLUSION: The underlying diseases of our patients were consistent with the major disease categories that have been frequently linked to secondary MN. The HP group was more akin to undefined groups regarding their pathological and clinical profiles. Since the MN in the undefined group might be the only renal manifestation antedating other clinical presentations of the corresponding underlying disease, a long-term follow-up and meticulous search for aetiological factors are required to validate this assumption.