Surviving winter on the Qinghai-Tibetan Plateau: Pikas suppress energy demands and exploit yak feces to survive winter.

The Qinghai-Tibetan Plateau, with low precipitation, low oxygen partial pressure, and temperatures routinely dropping below -30 °C in winter, presents several physiological challenges to its fauna. Yet it is home to many endemic mammalian species, including the plateau pika (Ochotona curzoniae). How these small animals that are incapable of hibernation survive the winter is an enigma. Measurements of daily energy expenditure (DEE) using the doubly labeled water method show that pikas suppress their DEE during winter. At the same body weight, pikas in winter expend 29.7% less than in summer, despite ambient temperatures being approximately 25 °C lower. Combined with resting metabolic rates (RMRs), this gives them an exceptionally low metabolic scope in winter (DEE/RMRt = 1.60 ± 0.30; RMRt is resting metabolic rate at thermoneutrality). Using implanted body temperature loggers and filming in the wild, we show that this is achieved by reducing body temperature and physical activity. Thyroid hormone (T3 and T4) measurements indicate this metabolic suppression is probably mediated via the thyroid axis. Winter activity was lower at sites where domestic yak (Bos grunniens) densities were higher. Pikas supplement their food intake at these sites by eating yak feces, demonstrated by direct observation, identification of yak DNA in pika stomach contents, and greater convergence in the yak/pika microbiotas in winter. This interspecific coprophagy allows pikas to thrive where yak are abundant and partially explains why pika densities are higher where domestic yak, their supposed direct competitors for food, are more abundant.

Clinical utility of nailfold capillaroscopy.

Nailfold capillaroscopy (NFC) is a simple noninvasive microscopic technique used to identify characteristic morphological abnormalities in the nailfold capillaries. The presence of this microvasculopathy appears to be of fundamental importance in the pathological processes that underlie the scleroderma spectrum disorders (including dermatomyositis and antisynthetase myositis). This review discusses the different methodologies and techniques in performing NFC and stresses the diagnostic utility achieved with simple 'bedside' techniques utilising the ophthalmoscope, dermatoscope or smart phone. Recent advances in reporting abnormal microvascular patterns and vascular metrics (e.g. capillary density and dropout) are discussed. The aetiopathogenesis of the microvasculopathy is currently unknown but its close association with Raynaud Phenomena and specific autoantibodies together with recent observations from sequential NFC allows speculations on its possible mechanism. Finally, future developments in the use of NFC as a possible biomarker in the management of the scleroderma spectrum disorders are discussed, with a recommendation that NFC becomes more widely available, particularly in rheumatological, immunological and dermatological practice. NFC provides a clinically accessible window on the pathologic process fundamental to scleroderma-related disease.

The clinical utility of contemporary oral epithelial dysplasia grading systems.

INTRODUCTION: Clinical management of oral potentially malignant disorders relies on accurate histopathological assessment of the presence and grade of oral epithelial dysplasia. While adjunctive laboratory tests have provided useful prognostic information, none are in widespread clinical use. This study was performed to assess the clinical utility of two contemporary oral epithelial dysplasia grading systems. METHODS: Patients were identified from a clinical database. Oral epithelial dysplasia grading was performed by three oral and maxillofacial pathologists blinded to clinical outcome using the WHO 2017 system and a binary classification. The primary outcome measure was the development of oral squamous cell carcinoma, termed 'malignant transformation'. RESULTS: One hundred thirty-one cases satisfied the inclusion criteria, of which 23 underwent malignant transformation. There was substantial inter-rater agreement between the study pathologists for both grading systems, measured using kappa statistics (κ = 0.753 - 0.784). However, there was only moderate agreement between the consensus WHO 2017 dysplasia grade for the study against the original grade assigned by a pool of six pathologists in the context of the clinical service (κ = 0.491). Higher grade categories correlated with an increased risk of developing cancer using both grading systems. CONCLUSION: This study demonstrates that the WHO 2017 and binary grading systems are reproducible between calibrated pathologists and that consensus reporting is likely to improve the consistency of grading. The WHO and binary systems were prognostically comparable. We recommend that institutions implement consensus oral epithelial dysplasia grading and prospectively audit the effectiveness of risk stratifying their patients with oral potentially malignant disorders. (249 words).

Dysplasia and DNA ploidy to prognosticate clinical outcome in oral potentially malignant disorders.

BACKGROUND: Oral potentially malignant disorders are a clinical conundrum as there are no reliable methods to predict their behaviour. We combine conventional oral epithelial dysplasia grading with DNA ploidy analysis to examine the validity of this approach to risk assessment in a cohort of patients with known clinical outcomes. METHODS: Sections from diagnostic biopsies were assessed for oral epithelial dysplasia using the WHO grading system, and DNA ploidy analysis was performed using established methods. Patients reviewed for a minimum of 5 years who did not develop oral squamous cell carcinoma were classified as "non-transforming" cases. Patients that developed oral squamous cell carcinoma ≥ 6 months after the initial diagnostic biopsy were classified as having "malignant transformation." RESULTS: Ninety cases were included in the study. Seventy cases yielded informative DNA ploidy results. Of these 70 cases, 31 progressed to cancer. Oral epithelial dysplasia grading and DNA ploidy status were both significantly associated with clinical outcome (P < 0.05). Severe dysplasia had a hazard ratio of 3.50 (CI: 1.46, 8.45; P = 0.005) compared to cases with mild dysplasia. Aneuploidy had a hazard ratio of 2.09 (CI: 1.01, 4.32; P = 0.046) compared to cases with a diploid/tetraploid status. Receiver operating characteristic analysis gave an area under the curve of 0.617 for DNA ploidy status and 0.688 when DNA ploidy status was combined with dysplasia grading. CONCLUSION: Our findings suggest that combining dysplasia grading with DNA ploidy status has clinical utility which could be used to develop novel management algorithms.

Scleroderma renal crisis: observations from the South Australian Scleroderma Register.

BACKGROUND: Scleroderma renal crisis (SRC) is a rare but feared complication with high morbidity and mortality. Its aetiopathogenesis is unclear. AIM: To investigate epidemiological, serologic and clinical features of all patients with SRC listed on the population-based South Australian Scleroderma Register and to examine possible factors in aetiopathogenesis. METHOD: A case note review was performed on all SRC patients with relevant data extracted to determine incidence, clinical phenotype, presence of autoantibodies and survival. Possible precipitating and aetiopathogenic factors were also examined. Data from the South Australian Scleroderma Register and Australia Bureau of Statistics was sourced for comparative purposes. RESULTS: Over the 34-year period (1985-2018), 30 patients (21 females, 9 males) presented with SRC giving a South Australian mean annual incidence of 0.58/million/year (95% CI 0.39-0.89). Twenty-eight of these patients had diffuse cutaneous scleroderma and two with limited cutaneous scleroderma. The mean age at first symptom of scleroderma was 51.2 ± 15.9 (mean ± SD) years with SRC occurring 4.6 years later (median = 3.0 years, range 0.1-20 years). Possible precipitating factors for SRC included high dose steroids in five patients. Twelve patients were anti- RNA polymerase3 (RNAPol3) positive and two were anti-topoisomerase 1 (Topo1) positive. Renal outcome was poor with 13 patients requiring renal replacement therapy and two proceeding to renal transplantation. The mean age at death was 61.2 ± 11.6 years with SRC patient survival being significantly shorter than patients with diffuse scleroderma without renal involvement (P = 0.002). There was no significant difference in survival between the 1985-2002 and the 2003-2018 SRC cohorts (P = 0.2). Nailfold capillaroscopy performed in 10 patients revealed extensive microvascular damage with prominent capillary drop out. CONCLUSION: SRC is a rare occurrence with an incidence of 0.58/million/year in South Australia. This frequency has not changed over time. It continues to have a severe adverse outcome with frequent requirement for renal replacement therapy and poor survival. Nailfold capillaroscopy revealed evidence of extensive capillary damage. No improvement in survival was observed over the 34-year study period.

The"Newcastle Nomogram"-Statistical modelling predicts malignant transformation in potentially malignant disorders.

BACKGROUND: Nomograms are graphical calculating devices used to predict risk of malignant transformation (MT) or response to treatment during cancer management. To date, a nomogram has not been used to predict clinical outcome during oral potentially malignant disorder (PMD) treatment. The aim of this study was to create a nomogram for use by clinicians to predict the probability of MT, thereby facilitating accurate assessment of risk and objective decision-making during individual patient management. METHODS: Clinico-pathological data from a previously treated cohort of 590 newly presenting PMD patients were reviewed and clinical outcomes categorized as disease free, persistent PMD or MT. Multiple logistic regression was used to predict the probability of MT in the cohort using age, gender, lesion type, site and incision biopsy histopathological diagnoses. Internal validation and calibration of the model was performed using the bootstrap method (n = 1000), and bias-corrected indices of model performance were computed. RESULTS: Potentially malignant disorders were predominantly leukoplakias (79%), presenting most frequently at floor of mouth and lateral tongue sites (51%); 99 patients (17%) developed oral squamous cell carcinoma during the study period. The nomogram performed well when MT predictions were compared with patient outcome data, demonstrating good bias-corrected discrimination and calibration (Dxy  = 0.58; C = 0.790), with a sensitivity of 87% and specificity 63%, and a positive predictive value of 32% and negative predictive value 96%. CONCLUSION: The "Newcastle Nomogram" has been developed to predict the probability of MT in PMD, based on an internally validated statistical model. Based upon readily available and patient-specific clinico-pathological data, it provides clinicians with a pragmatic diagrammatic aid for clinical decision-making during diagnosis and management of PMD.

Potentially malignant disorders revisited-The lichenoid lesion/proliferative verrucous leukoplakia conundrum.

BACKGROUND: Clinically identifiable potentially malignant disorders (PMD) precede oral squamous cell carcinoma development. Oral lichenoid lesions (OLL) and proliferative verrucous leukoplakia (PVL) are specific precursor lesions believed to exhibit both treatment resistance and a high risk of malignant transformation (MT). METHODS: A retrospective review of 590 PMD patients treated in Northern England by CO2 laser surgery between 1996 and 2014 was carried out. Lesions exhibiting lichenoid or proliferative verrucous features were identified from the patient database and their clinicopathological features and outcome post-treatment determined at the study census date of 31 December 2014. RESULTS: One hundred and 98 patients were identified as follows: 118 OLL and 80 PVL, most frequently leukoplakia at ventrolateral tongue and floor of mouth sites, equally distributed between males and females. Most exhibited dysplasia on incision biopsy (72% OLL; 85% PVL) and were treated by laser excision rather than ablation (88.1% OLL; 86.25% PVL). OLL were more common in younger patients (OLL 57.1 year; PVL 62.25 years; P = .008) and more likely than PVL to present as erythroleukoplakia (OLL 15.3%; PVL 2.5%; P = .003). Whilst no significant difference was seen between OLL and PVL achieving disease-free status (69.5% and 65%, respectively; P = .55), this was less than the overall PMD cohort (74.2%). MT was identified in 2 OLL (1.7%) and 2 PVL (2.5%) during follow-up. CONCLUSION: One-third of PMD cases showed features of OLL or PVL, probably representing a disease presentation continuum. Post-treatment disease-free status was less common in OLL and PVL, although MT was infrequent.

Direct analysis of δ2H and δ18O in natural and enriched human urine using laser-based, off-axis integrated cavity output spectroscopy.

The stable isotopes of hydrogen (δ(2)H) and oxygen (δ(18)O) in human urine are measured during studies of total energy expenditure by the doubly labeled water method, measurement of total body water, and measurement of insulin resistance by glucose disposal among other applications. An ultrasensitive laser absorption spectrometer based on off-axis integrated cavity output spectroscopy was demonstrated for simple and inexpensive measurement of stable isotopes in natural isotopic abundance and isotopically enriched human urine. Preparation of urine for analysis was simple and rapid (approximately 25 samples per hour), requiring no decolorizing or distillation steps. Analysis schemes were demonstrated to address sample-to-sample memory while still allowing analysis of 45 natural or 30 enriched urine samples per day. The instrument was linear over a wide range of water isotopes (δ(2)H = -454 to +1702 ‰ and δ(18)O = -58.3 to +265 ‰). Measurements of human urine were precise to better than 0.65 ‰ 1σ for δ(2)H and 0.09 ‰ 1σ for δ(18)O for natural urines, 1.1 ‰ 1σ for δ(2)H and 0.13 ‰ 1σ for δ(18)O for low enriched urines, and 1.0 ‰ 1σ for δ(2)H and 0.08 ‰ 1σ for δ(18)O for high enriched urines. Furthermore, the accuracy of the isotope measurements of human urines was verified to better than ±0.81 ‰ in δ(2)H and ±0.13 ‰ in δ(18)O (average deviation) against three independent isotope-ratio mass spectrometry laboratories. The ability to immediately and inexpensively measure the stable isotopes of water in human urine is expected to increase the number and variety of experiments which can be undertaken.

A seminal monograph: Mackay and Burnet's Autoimmune diseases.

Mackay and Burnet's Autoimmune diseases, published in 1962, marked the beginning of autoimmunity as a clinical science and led to the future acceptance of the existence of autoimmunity. While there is still controversy regarding the mechanisms of autoimmunity, the authors' insightful hypothesis based on clonal selection theory and the emergence of "forbidden clones", due to somatic mutations, is still current, with recent evidence giving further credence to this hypothesis. We salute Mackay and Burnet on the 50th anniversary of this seminal publication. It is particularly pleasing that it has an iconic Australian origin.

Deep Learning for Clinical Image Analyses in Oral Squamous Cell Carcinoma: A Review.

Importance: Oral squamous cell carcinoma (SCC) is a lethal malignant neoplasm with a high rate of tumor metastasis and recurrence. Accurate diagnosis, prognosis prediction, and metastasis detection can improve patient outcomes. Deep learning for clinical image analysis can be used for diagnosis and prognosis in cancers, including oral SCC; its use in these areas can improve patient care and outcome. Observations: This review is a summary of the use of deep learning models for diagnosis, prognosis, and metastasis detection for oral SCC by analyzing information from pathological and radiographic images. Specifically, deep learning has been used to classify different cell types, to differentiate cancer cells from nonmalignant cells, and to identify oral SCC from other cancer types. It can also be used to predict survival, to differentiate between tumor grades, and to detect lymph node metastasis. In general, the performance of these deep learning models has an accuracy ranging from 77.89% to 97.51% and 76% to 94.2% with the use of pathological and radiographic images, respectively. The review also discusses the importance of using good-quality clinical images in sufficient quantity on model performance. Conclusions and Relevance: Applying pathological and radiographic images in deep learning models for diagnosis and prognosis of oral SCC has been explored, and most studies report results showing good classification accuracy. The successful use of deep learning in these areas has a high clinical translatability in the improvement of patient care.

Apoptosis in the rheumatoid arthritis synovial membrane: modulation by disease-modifying anti-rheumatic drug treatment.

OBJECTIVES: RA is characterized at the synovial tissue level by synovial lining hyperplasia, angiogenesis and mononuclear cell infiltrates. A failure of apoptotic pathways may explain these pathological changes in RA synovial tissue. This study aims to demonstrate the presence of initiators and inhibitors of apoptosis in RA synovial tissue and the effect of treatment with DMARDs on apoptotic pathways in RA. METHODS: Synovial biopsy specimens were obtained at arthroscopy from 16 RA patients before and at 3- or 6-month intervals after commencing treatment with a DMARD. Apoptosis (by the terminal deoxynucleotidyl transferase mediated dUTP nick end labelling method and polyADP-ribose polymerase staining), proteins regulating apoptosis [Fas, FADD-like IL1b converting enzyme inhibitory protein (FLIP), Bcl-2, Survivin and X-linked inhibitor of apoptosis protein (XIAP)] and the presence of activated caspases (caspases 3 and 8) were detected by immunohistochemistry and quantified using image analysis and semiquantitative techniques. RESULTS: Fifteen patients responded to treatment, with an ACR response of > or =20%, 13 achieving an ACR response of > or =50% and 3 achieving an ACR remission. There was a significant reduction in SM macrophages and memory T cells, with an increase in fibroblast-like synovial lining cells following DMARD treatment. Apoptosis was not detected in the inflamed synovial tissue of RA patients before starting treatment, despite evidence of caspase activation, but was detectable after successful treatment with DMARDs. Inhibitors of activated caspases (FLIP, Survivin and XIAP) were detected in RA synovial tissue and were down-modulated with successful DMARD treatment. CONCLUSIONS: Apoptotic pathways are defective in RA synovial tissue from patients with active disease, despite the presence of activated caspases, possibly due to the abundant expression of inhibitors of the caspase pathway in RA synovial tissue. DMARD treatment can modulate apoptosis in the RA SM, which may lead to restoration of the SM architecture towards that of normal synovial tissue.

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples.

OBJECTIVES: To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. MATERIALS AND METHODS: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. RESULTS: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. CONCLUSIONS: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.

Anti-Ro52 antibodies, antisynthetase antibodies, and antisynthetase syndrome.

We present a case of antisynthetase syndrome manifesting with interstitial lung disease, mechanic's hands, nailfold abnormalities, and subclinical myositis, in the presence of antibodies to the aminoacyl tRNA synthetase PL-12 and also to Ro52. Antibodies to Ro52 have been recently associated with idiopathic inflammatory myositis, but there have only been occasional reports of this antibody occurring in association with aminoacyl tRNA synthetases, including PL-12. Our case adds to the descriptions of the concurrence of antibodies to PL-12 and Ro52. The mechanism for the coupling of antibody response remains elusive but is likely to play a fundamental role in disease pathogenesis.

The prognostic role of PD-L1 expression for survival in head and neck squamous cell carcinoma: A systematic review and meta-analysis.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is primarily located on the surface of tumor cells. PD-L1 expression detected by immunohistochemistry (IHC) assays has been widely studied to predict survival outcomes in head and neck squamous cell carcinoma (HNSCC) recently. We aimed to review comprehensively the prognostic role of PD-L1 expression for survival in HNSCC. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane Library and Scopus to identify studies investigating the prognostic role of PD-L1 expression in HNSCC. All studies published before March 31, 2018 were screened. Included studies were assessed using the Quality in Prognosis Studies (QUIPS) tool. Data were extracted and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), disease-specific survival (DSS) were combined and presented as hazard ratios (HR) with 95% confidence interval (CI) using the generic inverse-variance method. RESULTS: Twenty-three studies with 3105 patients were analysed. The overall positive rate of PD-L1 in HNSCC was 0.42 (95% CI: 0.36-0.48). There was no significant difference between PD-L1-positive and -negative HNSCC patients in OS (HR: 0.98; 95% CI: 0.71-1.37; p = 0.93), DFS (HR: 1.07; 95% CI: 0.68-1.70; p = 0.76), and DSS (HR: 0.90; 95% CI: 0.63-1.29; p = 0.56). An improved PFS was observed in patients with positive PD-L1 expression (HR: 0.71; 95% CI: 0.55-0.93; p = 0.01). In patients with low CD8+ tumor-infiltrating T cells, a poorer OS was detected in patients with positive PD-L1 expression (HR: 1.90; 95% CI: 1.07-3.36; p = 0.03). Patients with HPV-positive HNSCC were associated with increased PD-L1 expression (OR: 1.99; 95% CI: 1.50-2.64; p < 0.001). However, PD-L1 expression showed no significant benefit on OS in HPV-positive HNSCC (HR: 1.04; 95% CI: 0.65-1.65; p = 0.88). CONCLUSIONS: PD-L1 expression detected by IHC was not recommended to predict survival in HNSCC patients. However, the positive PD-L1 expression might predict better PFS in patients with advanced HNSCC. The combined effects of PD-L1 expression and CD8+ tumor-infiltrating T cells should be further elucidated.

The Clinical Presentation of Oral Potentially Malignant Disorders.

Early detection of oral cancer improves survival rates significantly, however, the incidence of oral cancer has continued to rise in the UK - between 2002-2012, it increased by more than 30%. There is currently no national screening programme for oral cancer, so undertaking a full examination of the oral mucosa during routine dental appointments is vital. Although strong evidence is still lacking, oral cancer is thought to be preceded by oral potential malignant disorders (OPMDs) or oral precancerous diseases. These mainly present as white/red lesions within the mouth and their clinical appearance can be challenging to diagnose accurately, which can lead to them being misdiagnosed as negligible problems. Dentists must keep up to date with OPMDs detection and ensure they are capable of correctly recognising lesions that carry a potential risk. This paper aims to provide a brief overview on OPMDs, highlighting potentially malignant disorders as they may present to the practitioner, showing their typical clinical appearance, and suggesting differential diagnosis and clinical management in dental practice.

Histopathological and ultrastructural features of dermal telangiectasias in systemic sclerosis.

AIMS: To investigate the histological, ultrastructural and immunohistochemical features of the vascular lining of dermal telangiectasia, a characteristic clinical finding in scleroderma. METHODS: Standard histological, electron microscopic and immunohistological techniques were used to examine dermal telangiectasias in five patients with limited scleroderma, the most common scleroderma variant in Caucasian populations. RESULTS: The telangiectasias were dilated postcapillary venules located in the papillary and superficial reticular dermis. The vessel walls consisted of non-fenestrated endothelial cells surrounded by a variable number of pericytes and smooth muscle cells. There were no unique ultrastructural features. Thickened collagen fibres in the reticular or deep dermis were seen in all but one patient, although in variable and generally minimal quantities. Surrounding infiltrating inflammatory cells were scarce. No enhanced endothelial staining was obtained with antibodies directed against endoglin, endothelin, E-selectin and ICAM-1 suggesting a resting or inactivated state. CONCLUSION: The immunohistological and ultrastructural features of the lining endothelium of established telangiectasias in long-standing, limited scleroderma appear benign. It would be of interest to examine telangiectasias in the early phase of their formation. Alternatively, other explanations need to be explored in understanding the aetiopathogenesis of telangiectasia in scleroderma.

IgM paraproteinaemia: disease associations and laboratory features.

AIMS: To review the disease associations and laboratory features occurring in IgM paraproteinaemia. METHODS: Systematic review of all new serum IgM paraproteins detected over a 6-year period in an immunodiagnostic laboratory serving a population of 400,000 people. Clinical diagnoses were ascertained from a computerised laboratory database or clinical notes, whilst associated laboratory features were obtained from the same sources. RESULTS: The 125 IgM paraproteins detected constitute 19.7% of all new paraproteins observed over the period of study. IgM paraproteinaemia occurred more commonly in males and its frequency increased with age. Approximately 30% were associated with B cell lymphoproliferative disorders (Waldenstrom's macroglobulinaemia, non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, amyloid, etc.) with the remainder being labelled as monoclonal IgM gammopathies of uncertain significance (four having a peripheral neuropathy). At clinical presentation, patients with lymphoproliferative disorders tended to have higher levels of IgM, beta2-microglobulin, the presence of free urinary light chains and demonstrated molecular size heterogenicity of the paraprotein (presence of decamers, oligomers and monomers in addition to the pentamer) but there was considerable overlap. A good correlation was noted between paraprotein concentration and viscosity in most patients. CONCLUSION: IgM paraproteinaemia was most frequently encountered in the context of a gammopathy of uncertain significance. Features which suggested lymphoproliferative disorders included higher levels of paraprotein (>15 g/l) elevated levels of beta2-microglobulin and the presence of urinary free high chain. However, as much overlap was seen, regular monitoring of paraprotein levels is considered mandatory in the management of these patients.

Paraproteins: a regional South Australian experience.

We have performed a systematic review of all new serum and urinary paraproteins detected over a six year period in an immunodiagnostic laboratory serving a population of 400,000 people. Clinical diagnoses and associated laboratory features were ascertained from a computerized laboratory database or from clinical notes. Over the period of study, serum or urine paraproteins were detected in 613 new patients. These consisted of 568 patients with serum paraproteins and 45 patients with urinary monoclonal free light chain (in the absence of a serum paraprotein). These paraproteins occurred more commonly in males and the frequency increased with age. Approximately 30% of the serum paraproteins and 60% of urinary monoclonal free light chain were associated with B cell lymphoproliferative disorders (multiple myeloma, plasmacytoma, Waldenstrom's macroglobulinemia, non-Hodgkins lymphoma, chronic lymphocytic leukemia, etc) with the remainder being labeled as monoclonal gammopathies of uncertain significance (MGUS). At clinical presentation, patients with lymphoproliferative disorders tended to have higher levels of paraprotein, B2 microglobulin, the presence of free urinary light chain and demonstrated molecular size heterogeneity of the paraprotein but there was considerable overlap. A good correlation was noted between paraprotein concentration and viscosity in most patients. In conclusion paraproteins were most frequently encountered in the context of a gammopathy of uncertain significance. Features which suggested lymphoproliferative disorders included higher levels of serum paraprotein (> 15 g/l), elevated levels of B2-microglobulin and the presence of urinary free high chain. However, as much overlap was seen with patients with MGUS, regular monitoring of paraprotein level is considered mandatory in the management of these patients.

Clinical utility of telangiectasia of hands in scleroderma and other rheumatic disorders.

Telangiectasia of the hands were observed in 76% of patients with scleroderma (n = 53) as compared with 12% of patients with other rheumatic disorders (n = 100) and in 13% of healthy subjects (n = 30). In scleroderma, telangiectasia of the hands were commonly multiple (mean number +/- SD = 22.9+/-30.1) with 7.3% being >1 mm in size. They were found in greater numbers in those patients with the limited subtype. The distribution of telangiectasia was observed on all but 4 of 158 sectors of the hand with significant higher numbers on the ventral surface of the digits. Significant associations of telangiectasia of the hands were also observed with numbers of telangiectasia on face and lips (p = 0.001), disease duration (p = 0.002), surface area of digital calcinosis (p = 0.03) and with the presence of the centromere antibody (p = 0.005). Possible associations were observed with prior gastrointestinal bleeds (particularly with telangiectasia >1 mm) and with isolated pulmonary hypertension. No significant correlation was found between number of telangiectasia and with nailfold capillary size or density. In conclusion, multiple telangiectasia of the hands were most commonly observed in patients with the centromere positive, limited subtype of scleroderma of long duration. Their pathogenesis is unknown.