Genetic Variants of von Willebrand's Disease

A specific antiserum against an antihaemophilic factor (AHF)-related plasma protein was raised in rabbits. A quantitative immunochemical method was used to determine the amount of this protein present in the plasma of 33 patients with haemophilia A and 70 patients with von Willebrand''s disease. The protein probably consisted of AHF residing in or complexed with the von Willebrand factor. The patients with von Willebrand''s disease were shown to fall into two separate genetic groups, one with decreased and one with normal amounts of the AHF-related protein. The patients with haemophilia A had normal amounts of the protein in their plasma.     

Immunoreactive Corticotrophin Levels in Adrenocortical Insufficiency

Plasma concentrations of immunoreactive corticotrophin (ACTH) have been determined in 14 patients with untreated Addison''s disease and in 42 patients with secondary adrenocortical insufficiency. Basal morning plasma ACTH levels were markedly raised in those with Addison''s disease but were either in the normal range or undetectable in the group with secondary adrenocortical insufficiency. In the group with Addison''s disease circulating ACTH values showed a definite nyctohemeral rhythm, a pronounced rise in response to insulin-induced hypoglycaemia, and an immediate fall following the intravenous injection of corticosteroids, with a half-life of between 13·5 and 44·2 minutes. When assays were performed with antisera directed against the portion of the ACTH molecule responsible for corticosteroidogenesis (the N-terminal portion) the apparent ACTH concentrations were lower than with antisera directed against the non-steroidogenic (C-terminal) portion of the molecule. This emphasizes that different antisera may give different apparent hormone concentrations, and that the ranges of values obtained in normal and abnormal states must be established for each antiserum.     

Serum thyrotrophin concentration: an unreliable test for detection of early hypothyroidism after thyroidectomy.

Three groups of patients who had undergone subtotal thyroidectomy for Graves''s disease, toxic multinodular goitre, or euthyroid multinodular goitre 12 to 15 years before and in whom a normal serum thyroxine (T-4) level was found were each divided into two subgroups on the basis of a normal or a raised serum thyrotrophin concentration. There was no difference in mean serum T-4 concentration between patients with normal and those with raised serum thyrotrophin concentrations, and the values were similar to the mean T-4 values of the normal population. The mean serum triiodothyronine values of all groups were higher than normal, but the mean values of the groups with a normal and a raised serum thyrotrophin were similar. After thyroidectomy a mildly raised serum thyrotrophin does not in itself indicate the presence of hypothyroidism.     

Effect of an oral serotonin antagonist,ketanserin, on plasma ACTH concentrations in Nelson's syndrome.

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson''s syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing''s disease and who had Nelson''s syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson''s syndrome. These results show that it is not indicated in these patients.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

Biochemical predictors for Sars-Cov-2 severity

It is of interest to assess the inflammatory marker profile in SARS-CoV-2 patients and to correlate the levels of systemic inflammatory biomarkers such as neutrophil-to-lymphocyte ratio (NLR), C-Reactive Protein CRP, Ferritin, Creatine kinase (CK), Lactate dehydrogenase (LDH) and liver function analytes total serum proteins, albumin, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with the severity of SARS-CoV-2 infections. A total of 1000 COVID-19 positive patient''s data were collected. Laboratory assessments consisted of NLR (neutrophil-lymphocyte ratio) by cell counter, C Reactive Protein (CRP) by immunoturbidimetry, Ferritin by electrochemiluminescence (ECLIA) and Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Total Bilirubin, Direct Bilirubin, Total Protein and Albumin by spectrophotometry. The mean plasma CRP levels, NLR, ferritin, CK and LDH levels were higher in severe cases than in non-severe cases, and the difference was statistically significant (p<0.05). All liver function tests such as the total and direct bilirubin, AST, ALT, ALP, total protein and albumin were higher in severe patients than non-severe patients and the difference was statistically significant (p<0.05). Data indicate that NLR, CRP, Ferritin, CK, LDH and liver function analytes have a crucial role as prognostic markers for SARS-CoV-2 infections and hence should be routinely recommended for risk assessment and stratification of the patients to reduce the associated morbidity and mortality.     

Increased Oxidative Stress and Altered Levels of Nitric Oxide and Peroxynitrite in Tunisian Patients with Chronic Obstructive Pulmonary Disease: Correlation with Disease Severity and Airflow Obstruction

This study was aimed to evaluate the oxidant–antioxidant imbalance in the pathogenesis of chronic obstructive pulmonary disease (COPD) in Tunisians. We assessed 16 parameters related to the oxidative status that include malondialdehyde (MDA), total protein carbonyls (PCs), and advanced oxidation protein products (AOPP). We also examined the activity of glutathione peroxydase (GSH-Px), catalase, and superoxide dismutase (SOD) in the plasma and erythrocytes. Levels of total thiols, reduced glutathione (GSH), total antioxidant status (TAS), hydrogen peroxide, ascorbic acid, iron, and protein sulfhydryls were determined using spectrophotometry. We also evaluated the level of nitric oxide (NO) and peroxynitrite in plasma from COPD patients and healthy controls. Estimation of DNA damage was determined using the comet assay. Pulmonary functional tests were performed by body plethysmography. Levels of MDA, PC, DNA damage, and AOPP were significantly increased while total thiols, GSH, and TAS were decreased in COPD patients. GSH-Px activity was higher in COPD patients while no difference was found for catalase and SOD. We also observed a lower level of NO and peroxynitrite in COPD patients. Decreased levels of peroxynitrite were found to correlate with disease progression, as well as with forced expiratory volume in 1 s/forced vital capacity among COPD patients. Multivariate analysis revealed that NO is associated with pathological pathways that help to predict patient outcome independently of the degree of airflow obstruction. These results indicate the presence of a systemic oxidative stress and highlight the importance of NO and peroxynitrite as major effectors in COPD development and airflow obstruction.     

Haemorrheological response to plasma exchange in Raynaud's syndrome.

Eight patients with Raynaud''s syndrome were treated by weekly plasma exchange for four weeks using a Haemonetics Model 30 Blood Processor. The mean whole-blood viscosity at a shear rate of 0.77/s was significantly lower after treatment, and the mean index of red-cell deformability was significantly improved. In four patients studied serially the mean percentage fall in whole-blood viscosity after a single plasma exchange was 49% at 0.77/s but only 14% at 91/s. All patients noticed symptomatic improvement including healing of ischaemic digital ulcers. In six patients the number of digital arterial segments containing detectable blood flow was measured by directional Doppler; in all six the number increased. It is concluded that plasma exchange is an effective means of haemorrheological treatment and may be beneficial in patients with digital ischaemia.     

Hypothyroidism after Thyroidectomy for Graves's Disease: A Search for an Explanation

Out of 38 patients who had undergone subtotal thyroidectomy for Graves''s disease seven to 20 years previously 15 developed hypothyroidism. In these 15 patients autoantibodies against thyroid cytoplasm were significantly more frequent than in the 23 euthyroid patients, though there was no difference in the prevalence of autoantibodies against thyroglobulin. Histological examination of the thyroid tissue removed at operation showed that significantly more plasma cells and lymphoid follicles with germinal centres were present in patients who subsequently developed hypothyroidism than in those who remained euthyroid. No differences in the amount of lymphocytic infiltration were seen in hypothyroid and euthyroid patients.The results suggest that B lymphocytes play a part in the development of postoperative hypothyroidism in Graves''s disease. It is proposed that Graves''s disease and Hashimoto''s disease are different aspects of the same basic autoimmune process.     

Decreased tuftsin concentrations in patients who have undergone splenectomy.

Serum tuftsin concentrations were measured, using a radioimmunoassay developed in Israel, in normal subjects and in patients who had undergone splenectomy. Concentrations in those who had undergone traumatic and elective splenectomy were much lower. The tuftsin concentration in 38 patients with Hodgkin''s disease who had undergone splenectomy during staging laparotomy was not significantly different from the mean concentration in other patients who had had elective splenectomy. In four patients who underwent splenectomy for non-malignant haematological disorders measurements made before and after operation showed that tuftsin concentrations fell significantly in the days after operation. The increased susceptibility to overwhelming infections of patients with Hodgkin''s disease and others who have undergone splenectomy may be related to the low tuftsin concentrations. As pre-splenectomy tuftsin concentrations in patients with Hodgkin''s disease were normal, the practice of performing staging laparotomy and splenectomy in patients with Hodgkin''s disease should perhaps be reconsidered.     

Raised titres of anti-klebsiella IgA in ankylosing spondylitis,rheumatoid arthritis,and inflammatory bowel disease

Serum titres of IgA are raised in ankylosing spondylitis and increased titres of antibodies to klebsiella have also been reported. The humoral response was investigated in ankylosing spondylitis and other inflammatory disorders. IgA antibodies to klebsiella pneumoniae K43 were measured in patients with ankylosing spondylitis, Crohn''s disease, ulcerative colitis, and rheumatoid arthritis and in controls. Significantly raised median titres of anti-klebsiella IgA, measured as optical density at 405 nm with an enzyme linked immunosorbent assay (ELISA), were seen among the patients with ankylosing spondylitis (0·7), Crohn''s disease (0·8), rheumatoid arthritis (0·6), and ulcerative colitis (0·8) compared with controls (0·4). Activity of disease in ankylosing spondylitis and titres of anti-klebsiella IgA were not correlated. In contrast, titres of anti-klebsiella IgM were significantly lower in patients with ankylosing spondylitis and ulcerative colitis.The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn''s disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be non-specific, occurring because of possible underlying inflammatory bowel disease in these conditions.     

Patient and general practitioner delays in acute myocardial infarction

The longest component of the total delay in coming under coronary care is patient delay, and it has been suggested that public education might be used to make it shorter. The patterns of patient delay were studied in 450 patients with acute myocardial infarction uncomplicated by cardiac arrest out of hospital, of whom 243 had a previous history of ischaemic heart disease. Patient delays had a skewed distribution with a modal delay of up to one hour, a median delay of two hours, and a mean delay of 10 hours. Two thirds of patients had sought help from their general practitioners within four hours of the onset of symptoms. During the first four hours the longer that patients delayed the lower was the subsequent mortality (27%, 18%, and 9% for delays of one hour or less, up to two hours, and up to four hours, respectively), but patients who delayed four to eight hours had the highest mortality of all (38%). Neither the median value nor the pattern of patient delays was altered by a previous history of ischaemic heart disease.There were pronounced differences in doctor delays, depending on the patient''s age, delay time, and ultimate place of treatment, showing that the doctors'' behaviour was influenced before they had seen their patients. Nevertheless, the median total delay for patients aged up to 70 was one hour 35 minutes, and a higher proportion of patients were seen early after infarction than in recent hospital trials of thrombolytic treatment.These findings suggest that the patients'' call for help and the doctors'' response may be at an instinctive level according to the patients'' distress; these patterns of behaviour may be difficult to modify by public education.     

Plasma and Urinary 11-Hydroxycorticosteroids in Differential Diagnosis of Cushing's Syndrome

Morning plasma 11-hydroxycorticoids, urinary 11-hydroxycorticoids, and urinary 17-oxogenic steroids were measured before and during a dexamethasone suppression test. This consisted in the administration by mouth of 2 mg of dexamethasone daily for 48 hours, followed by 8 mg daily for 48 hours. In addition midnight plasma 11-hydroxycorticoids were measured before the start of the test. The subjects investigated were 21 patients with Cushing''s syndrome, 27 obese female patients, 10 female patients with the Stein-Leventhal syndrome, and 8 female patients with idiopathic hirsutism.The results showed that the clearest distinction between the groups was made by measurement of the basal urinary 11-hydroxycorticoid excretion, where, in the group of patients with Cushing''s syndrome, all the levels were well above the upper limit of normal. In addition raised midnight plasma 11-hydroxycorticoid levels were of great diagnostic value. By using these results together with those of the dexamethasone suppression tests it was possible to make a firm preoperative diagnosis of pituitary-dependent Cushing''s syndrome in 90% of patients in this series.     

Proteomic Analysis of Haptoglobin and Amyloid A Protein Levels in Patients with Vivax Malaria

Advancements in the field of proteomics have provided great opportunities for the development of diagnostic and therapeutic tools against human diseases. In this study, we analyzed haptoglobin and amyloid A protein levels of vivax malaria patients with combinations of depletion of the abundant plasma proteins, 2-dimensional gel electrophoresis (2-DE), image analysis, and mass spectrometry in the plasma between normal healthy donors and vivax malaria patients. The results showed that the expression level of haptoglobin had become significantly lower or undetectable in the plasma of vivax malaria patients due to proteolytic cleavage when compared to healthy donors on 2-DE gels. Meanwhile, serum amyloid A protein was significantly increased in vivax malaria patient''s plasma with high statistical values. These 2 proteins are common acute phase reactants and further large scale evaluation with a larger number of patient''s will be necessary to establish the possible clinical meaning of the existential changes of these proteins in vivax malaria patients. However, our proteomic analysis suggests the feasible values of some plasma proteins, such as haptoglobin and serum amyloid A, as associating factor candidates for vivax malaria.     

Juvenile onset inflammatory bowel disease: height and body mass index in adult life.

OBJECTIVE--To establish the frequency of permanent growth failure in juvenile onset inflammatory bowel disease. DESIGN--Measurement of height and weight in a geographically based cohort at a mean of 14 (range 5.2-29.5) years after diagnosis. Comparison with data from surveys of British adults in 1980 and 1987. SETTING--NHS hospitals throughout Scotland. SUBJECTS--105 Children admitted to hospital during 1968-83 who fulfilled diagnostic criteria for Crohn''s disease or ulcerative colitis and lived in specified regions. 87 were aged over 18 and living in Britain at follow up. MAIN OUTCOME MEASURES--Height, weight, body mass index, and sexual maturity. RESULTS--All patients were sexually mature. 67 of the 70 patients examined were of normal height, and three women with Crohn''s disease were abnormally short. Weight and body mass index were normal in all patients with ulcerative colitis. Patients with Crohn''s disease had significantly lower weight than those with ulcerative colitis (men 66.8 (9.5) kg v 78.4 (13.8) kg, P = 0.04; women 51.5 (8.2) kg v 63.0 (12.1) kg, P < 0.02) irrespective of disease activity. Body mass index was also significantly lower than the normal distribution (P < 0.01). Growth retardation was not mentioned as a problem for any of the 17 patients interviewed only by telephone. CONCLUSIONS--Despite growth retardation in the teenage years most young people with inflammatory bowel disease will eventually achieve normal height. Reasons for lower weight in patients with Crohn''s disease remain to be established.     

Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician''s reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD.     

Outcome of Arthroscopy in Patients with Advanced Osteoarthritis of the Hip

Hip arthroscopy has continued to expand its horizons in treating many conditions other than femoroacetabular impingement (FAI). However, the results of hip arthroscopy are known to be poor if the degree of articular cartilage damage is significant. We wanted to assess, whether the procedure might have a role in the management of young and active patients with advanced osteoarthritis (OA) and whether it should be offered as a treatment modality. 77 consecutive patients with Tönnis grade 2 and 3 osteoarthritis of the hip who had undergone hip arthroscopy were included in the study. Patients'' medical notes, plain radiographs and outcome scores (modified Harris hip score (mHHS), non-arthritic hip score (NAHS)) preoperatively and postoperatively at six weeks, six months, one year and annually thereafter, were analysed. 77 patients consisted of 63 men and 14 women with mean follow-up of 2.8 years (2.2 to 4.2) and mean age at surgery of 43 years (19 to 64). The mean preoperative mHHS and NAHS scores were 58 (28 to 87) and 64 (27 to 93) respectively. The mean improvements in both the mHHS and NAHS scores were significant (p = 0.003 and p = 0.0001 for mHHS at one and two years, p = 0.002 and p = 0.0003 for NAHS at one and two years, respectively). There were 34 patients (44%) who required a total hip replacement at mean of 18 months (6 to 48) after hip arthroscopy. We conclude that hip arthroscopy improves outcome scores in 56% of patients with severe OA of the hip (Tönnis grade 2 and 3) for at least two years after surgery. We thus consider the procedure to be a reasonable option for patients with hip OA, although success of the procedure will be less than if undertaken for certain other conditions.     

Plasma Levels of Immunoreactive Corticotrophin in Patients with Cushing's Syndrome

Plasma levels of immunoreactive corticotrophin (A.C.T.H.) have been determined in 56 patients with Cushing''s syndrome by means of a homologous radioimmunoassay. In untreated Cushing''s disease (bilateral adrenal hyperplasia due to excessive A.C.T.H. secretion from the pituitary) plasma values ranged from 40 to 200 μμg./ml., between 8 and 10 a.m., compared with a range in normal subjects of 12 to 60 μμg./ml. Considerably raised levels, often above 2,000 μμg./ml., were found in patients with Cushing''s disease after bilateral adrenalectomy. A.C.T.H. concentrations were usually higher in patients with bilateral adrenal hyperplasia associated with ectopic A.C.T.H. production than in patients with untreated Cushing''s disease; whereas plasma A.C.T.H. was undetectable in the presence of an adrenocortical tumour. All patients with Cushing''s syndrome failed to show the normal circadian rhythm of circulating A.C.T.H. levels.     

Antiplatelet antibodies in cases of Glanzmann's thrombasthenia with and without a history of multiple platelet transfusion

Antiplatelet antibodies are known to be present in a wide spectrum of patients, which include chronic Idiopathic Thrombocytopenic Purpura (ITP), infections, etc., including Glanzmann''s thrombasthenia (GT) patients who receive multiple platelet transfusions. The presence of natural antibodies to platelet receptors is not studied in cases of GT. We studied the antiplatelet antibodies in 23 patients with GT, 15 of which had received multiple transfusions and eight that had not received transfusions, along with 50 cases of chronic ITP. The prevalence and specificity of platelet-bound antibodies were detected by inhibition assays using O-group platelets on flow cytometry. The mean antiplatelet antibodies in 15 patients of GT who had not received transfusions and eight patients with multiple transfusions was 8427 + 2131.88 and 9038 + 2856 antibodies/platelet, respectively, while in case of the 50 ITP patients studied, it was 22166 + 5616 antibodies/platelet (Normal Range 1500–3200 antibodies/platelet). We conclude that GT patients who have not received transfusions may develop antiplatelet antibodies to the missing/abnormal receptor. Whether this is due to a molecular mimicry or due to some other mechanism needs to be explored.     

Relevance of increased serum thyroxine concentrations associated with normal serum triiodothyronine values in hypothyroid patients receiving thyroxine: a case for "tissue thyrotoxicosis".

Fifteen patients receiving standard thyroxine replacement therapy (100-200 micrograms daily) for primary hypothyroidism and who had persistently raised free thyroxine concentrations in their serum were investigated to see whether the dose being given was too high. In addition to the usual thyroid hormone assays systolic time intervals (which indicate left ventricular contractility) were calculated as accurate reflectors of tissue thyroid activity. All patients showed the expected increased free and total thyroxine concentrations; but mean total and free concentrations of triiodothyronine were normal, while reverse triiodothyronine values were raised. Mean systolic time intervals were significantly reduced as compared with normal and fell within the thyrotoxic range. Seven patients subsequently had their doses of thyroxine reduced by 50 micrograms daily and were reinvestigated one month later. All showed significant falls in circulating thyroxine and triiodothyronine concentrations and an increase in mean systolic time intervals to the normal range. In patients receiving thyroxine replacement therapy for primary hypothyroidism a raised serum thyroxine concentration may indicate tissue thyrotoxicosis and should prompt a reduction of the thyroxine dose.