Spectrum Of Clinical Severity Research Articles

Diagnosis and management of thalassaemia

Thalassaemia is the commonest inherited anaemia world wide. There is wide spectrum of clinical severity spanning from insignificant to transfusion dependence. It is caused by abnormalities in the structure, manufacture or function of the globins that form the tetramers of normal adult haemoglobin A. The primary changes in erythropoiesis lead to the secondary changes of anaemia, splenomegaly, bone marrow expansion, extra medullary haemopoiesis, bone deformities and iron accumulation which in turn lead to long term organ damage. The anaemia itself results from a combination of ineffective erythropoiesis, peripheral haemolysis and an overall reduction in haemoglobin synthesis. Optimum management with early detection, appropriate transfusion, iron chelation and monitoring for complications can offer a good quality of life and a near normal lifespan. The major threats to this outcome in developed countries are serious infections and organ damage from iron overload.

Catheter-directed Therapies for Acute Pulmonary Embolism: It is Time to Establish a Role

Acute pulmonary embolism (PE) is associated with a broad spectrum of clinical severity. However, despite the varying presentations, therapy is primarily limited to anticoagulation. The only widely accepted exception to the use of anticoagulation alone is in those patients with massive acute PE, in whom systemic fibrinolysis is generally considered the most appropriate option. Unfortunately, there is a large group of patients without massive PE who do worse with heparin alone, and systemic fibrinolysis has not been consistently shown to be beneficial in these patients. The role of catheter directed therapies (CDT) needs to be further investigated for this all too common patient subset.

Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa: A Consensus‐Generated Clinical Research Tool

Epidermolysis bullosa (EB) is a genetic condition characterized by skin fragility and blistering. There is no instrument available for clinical outcome research measurements. Our aim was to develop a comprehensive instrument that is easy to use in the context of interventional studies. Item collection was accomplished using a two-step Delphi Internet survey process for practitioners and qualitative content analysis of patient and family interviews. Items were reduced based on frequency and importance using a 4-point Likert scale and were subject to consensus (>80% agreement) using the nominal group technique. Pilot data testing was performed in 21 consecutive patients attending an EB clinic. The final score, Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa (iscorEB), is a combined score that contains clinician items grouped in five domains (skin, mucosa, organ involvement, laboratory abnormalities, and complications and procedures; maximum score 114) and patient-derived items (pain, itch, functional limitations, sleep, mood, and effect on daily and leisurely activities; maximum score 120). Pilot testing revealed that combined (see below) and subscores were able to differentiate between EB subtypes and degrees of clinical severity (EB simplex 21.7 ± 16.5, junctional EB 28.0 ± 20.7, dystrophic EB 57.3 ± 24.6, p = 0.007; mild 17.3 ± 9.6, moderate 41.0 ± 19.4, and severe 64.5 ± 22.6, p < 0.001). There was high correlation between clinician and patient subscores (correlation coefficient = 0.79, p < 0.001). iscorEB seems to be a sensitive tool in differentiating between EB types and across the clinical spectrum of severity. Further validation studies are needed.

Studies in primary and iPSC-derived human Gaucher macrophages demonstrate impaired macrophage function and defective autophagy

computerized tomography (HRCT) mainly in type I GD adults. So, this study will determine the clinical spectrum of severity of lung involvement in Egyptian children mainly type 3 GD, the radiological changes,assess clinical significance of these findings and their response to ERT. The study included 34 GD children diagnosed by enzyme assay and genotype and are on ERT, imiglucerase 30-60 IU/kg/2 weeks. 31 GD type 3 children (29L444P/L444P, 2 D409H/D409H) and 3 GD type I (1 R359Q/R359Q and 2 with unknown genotype) were followed over 7 years. Their pulmonary status was clinically and radiologically assessed by chest x-ray and HRCT and its response to ERT determined. Clinical variables and radiological findings were statistically correlated. Patients’ median age is 8.6 years and mean duration of ERT is 6.5 years. Twenty (59%) type 3 L4444P/L444P GD children, 13 males and 7 females had chest symptoms with 14 having recurrent chest infections, dyspnea and wheezing, 4 requiring intensive care admission and 1 died of severe pulmonary involvement. Children showed statistically significant higher prevalence of chest symptoms at younger age (p= 0.04). The chest xray and HRCT findings included coarse interstitial pulmonary thickening of variable severity in 26/34(76.5%) and in 90% of the symptomatic group. Other changes included bronchiectasis, gound glass veiling, hyperinflation, mediastinal lymphadenopathy, military infiltration, consolidation, atelectasis and air trapping. In 12/14 asymptomatic GD children findings varied from interstitial thickening to ground glass veiling and bronchiectactic changes. 3 children were splenectomised without worsening of their chest condition. In 13 symptomatic children there was dramatic clinical response to ERT but radiological findings were stationary. All L444P/L444P children showed moderate to severe neurological involvement, 4 had epilepsy, 8 mesenteric lymphadenopathy, 3 severe bone involvement, 2 severe skeletal deformities, aortic and mitral calcifications in D409H/D409H patients. Nearly all children with recurrent infections and significant chest findings have at least one other severe system involvement. Our study showed heterogeneity in clinical presentation and response of lung involvement to ERT in type 3 GD children. 76.5% had variable degrees of interstitial lung disease and nearly all children without clinical lung involvement had abnormal radiological findings. Chest symptoms showed improvement in 65%. Lung involvement can be among the determinants of severity of type 3 GD in children.

Regional consensus opinion for the management of Beta thalassemia major in the Arabian Gulf area

Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.

Spatial patterns of clinically significant G6PD deficiency: variants, prevalence and an overall national risk index

Background Threat of haemolytic anaemia in individuals with a deficiency in glucose-6-phosphate dehydrogenase (G6PD) enzyme activity prevents widespread use of primaquine, a vital drug for malaria elimination. Significant genetic variation underpins this human enzyme disorder, reflected as a spectrum of clinical severity following exposure to oxidative agents such as primaquine. Across malaria endemic countries (MECs), the prevalence and genetic basis of this predisposing condition vary greatly. An understanding of the relative risks presented by G6PD deficiency, in terms of prevalence and severity, is necessary to rationally determine primaquine drug policy.

Coinfection with hepatitis a and leptospira in jaundice children

Mixed infection is a challenge to the treating clinician. Infection like Hepatitis A and Leptospirosis are prevalent in developing countries. The spectrum of clinical severity of both Leptospira and Hepatitis A ranges from mild infection to jaundice. Awareness and appropriate use of investigations can overcome the diagnostic dilemmas.

Nail Involvement in Epidermolysis Bullosa

Nail abnormalities are a common feature in most subtypes of epidermolysis bullosa (EB), and they recently have been included among the criteria for scoring EB severity. Trauma undoubtedly contributes to the development of nail dystrophy, and for this reason the great toenails often are affected more severely. The nail abnormalities may be the first or the only symptom of EB. Nail abnormalities observed in EB are not specific or pathognomonic, as they result from nail bed and matrix scarring. The spectrum of clinical severity is large, and nail abnormalities may cause severe disability or just be a mild cosmetic problem. This article reviews the nail abnormalities observed in EB.

Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity

The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.

Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration

Spinocerebellar ataxia type 7 (SCA7) is unique among CAG/polyglutamine (polyQ) repeat diseases due to dramatic intergenerational instability in repeat length and an associated cone-rod dystrophy retinal degeneration phenotype. SCA7 is caused by a polyQ expansion in the protein ataxin-7. Like other neurodegenerative diseases caused by polyQ expansion mutations, the spectrum of clinical severity and disease progression worsens with increasing polyQ length. Several potential mechanisms for the molecular pathogenesis of polyQ-expanded ataxin-7 have been suggested. These include, but are not limited to, alteration of endogenous ataxin-7 function, abnormal processing and stability of polyQ ataxin-7, and alteration of transcriptional regulation via interaction of polyQ-expanded ataxin-7 with other transcriptional regulators. Ataxin-7's normal function as a transcription factor may contribute to the selective vulnerability of specific cellular populations in SCA7, and the resolution of the mechanistic basis of this pathogenic cascade is a major focus of SCA7 disease research. PolyQ-expanded ataxin-7 can cause non-cell autonomous neurodegeneration in cerebellar Purkinje cells. Advances in understanding SCA7's molecular basis have led to important insights into cell-type specific neurodegeneration. We expect that further study of ataxin-7 normal function, insights into the molecular basis of SCA7 neurodegeneration, and the development of therapeutic interventions for SCA7 will greatly influence related endeavors directed at other CAG/polyQ repeat diseases.

Characteristics and Outcomes of Older Adults with Community‐Acquired Pneumococcal Bacteremia

To describe baseline characteristics and clinical outcomes of older adults with pneumococcal bacteremia, compare the frequency of serious outcomes according to pneumococcal vaccination status, and assess factors associated with mortality. Population-based case-series. Group Health Cooperative, a health maintenance organization in Washington State. Community-dwelling adults aged 65 and older with a first episode of pneumococcal bacteremia between 1988 and 2002. Demographic characteristics, underlying medical conditions, vaccination status, and clinical outcomes, including death, hospitalization, length of hospital stay, and postdischarge care, were assessed using chart review. The mean age of the 200 elderly patients with pneumococcal bacteremia was 78; 61% were female. Forty percent had had chart-documented pneumococcal vaccination before the onset of bacteremia. The spectrum of clinical severity and consequences was broad. Ten percent were treated as outpatients. Of the 90% who were hospitalized, 16% were admitted to the intensive care unit. All-cause mortality at 30 days was 11%. Of survivors, 23% were discharged with home services, and another 20% were discharged to a nursing home. After controlling for age, sex, and pneumococcal vaccination status, predictors of death included coronary artery disease (odds ratio (OR)=4.6, 95% confidence interval (CI)=1.4-14.5) and immunocompromising conditions (OR=5.0, 95% CI=1.6-15.7). Outcomes were similar in patients who did and did not receive pneumococcal vaccination. In this elderly group, pneumococcal bacteremia was associated with substantial morbidity, mortality, and loss of independence. Coronary artery disease and immunocompromising conditions were independent predictors of death.

Infectious causes of pityriasis lichenoides: a case of fulminant infectious mononucleosis

Pityriasis lichenoides is a rare cutaneous eruption of unknown cause that spans a spectrum of clinical severity. Infectious agents have long been suspected as etiologic factors. The present case is the first to demonstrate a known EBV-mediated process evolving and resolving in concert with pityriasis lichenoides. Epstein-Barr virus, Toxoplasma gondii, and HIV are the most frequently reported infectious triggers of pityriasis lichenoides. Pityriasis lichenoides may arise secondary to EBV-mediated acute infectious mononucleosis.

Epidemiology of venous disorders in the general and occupational populations.

Chronic venous disorders of the lower limbs rank among the most common conditions affecting mankind (1). These disorders comprise a wide spectrum of clinical severity, varying from minor symptoms to disabling disease, and include asymptomatic venous incompetence, telangiectasis, reticular varices, trunk varices, and, in its gravest form, stasis skin changes and ulceration. In contrast to many other chronic conditions, patients and physicians alike often trivialize the presence and severity of venous disorders. There seems to be a high level of acceptance among affected persons of complaints of the legs stemming from venous disorders (2). This might be due to the fact that varicose veins are slowly progressing conditions and are common in the population.

Epidemiology of asthma

Asthma is the commonest chronic condition of childhood atllicting the developed world. Most modern definitions of asthma include the three concepts of an airway disorder which is associated with inflammation, variable but reversible airflow obstruction and an increased responsiveness of the airways to a variety of stimuli. This clinical diagnosis is of limited use when attempts have been made to determine the prevalence of asthma around the world because not all doctors would agree on the same diagnostic criteria. There are other difficulties for the epidemiologist. There is no single diagnostic test for asthma so the diagnosis remains clinical. Although wheeze is characteristic, it is not invariable and can occur in other conditions. Cough may be the only symptom of asthma in young children but cough, itself, is a very non-specific symptom. Airway hyper-responsiveness is demonstrable in most older asthmatic children but this physiological abnormality has an unreliable association with symptoms. Childhood asthma is a collection of respiratory syndromes with a wide spectrum of clinical severity. By it’s nature, symptoms come and go and the natural history of the condition changes over time. These features of childhood asthma are only some of the reasons why studies and assessment of asthma morbidity have been so difficult to conduct and interpret.

Type III posterior urethral valves: Presentation and management

The clinical and radiographic presentation of infants with type III posterior urethral valves help to distinguish them from patients with the more common type I valves. The diaphragmatic valvular obstruction may make catheterization impossible. Percutaneous cystography can confirm the diagnosis and allow for short-term decompression. The presence of smooth-walled bladders with narrow posterior urethras is unique to type III valves but is not always present. Type III valves present within a spectrum of clinical severity; however, the majority involve significant renal impairment. The prognosis for survival and renal function appears poorer for patients with type III valves than for those with type I valves.

Occurrence of respiratory syncytial virus subtypes in hospitalized children in Cleveland, Ohio from 1985 to 1988

In order to determine the frequency of occurrence of the two respiratory syncytial virus (RSV) subtypes in hospitalized children in Cleveland, Ohio, we analyzed clinical isolates obtained during three consecutive winter epidemic seasons between 1985 and 1988. RSV was recovered from the frozen clinical specimens of 197 patients: 176 subtype A, and 21 subtype B. Subtype A predominated during all three epidemic seasons, ranging from 83 to 94% of isolates. We surveyed the clinical records of 16 children with subtype B, and 101 children with subtype A infections, hospitalized at the University Hospitals of Cleveland during these winter epidemics and found no differences in age, sex, race, or clinical spectrum of severity of disease caused by the two subtypes. In contrast to previously reported data, subtype A predominated in each of the winter seasons studied within this community. We conclude that both subtypes circulate concurrently within the community during the winter. In hospitalized children both subtypes appear to cause a similar spectrum of disease. Both the concurrent circulation of RSV subtypes and the similar spectrum of illness pose for important considerations in the development of effective vaccines against this common respiratory agent in children.

Pancreatic exocrine secretion in acute experimental pancreatitis

Little is known about exocrine pancreatic secretory function in patients with acute pancreatitis, in particular during the early phase of the disease. Therefore, this study evaluates basal and stimulated pancreatic secretion in vivo and in vitro in four different models of acute pancreatitis which reflect its clinical spectrum of severity: (a) edematous pancreatitis induced in the rat by seven IP injections of 50 μg/kg cerulein at hourly intervals; (b) edematous pancreatitis with cellular necrosis induced in the mouse by seven IP injections of 50 μg/kg cerulein at hourly intervals; (c) hemorrhagic pancreatitis induced in the mouse by feeding an ethionine-supplemented, choline-deficient diet for 66 hours; and (d) hemorrhagic pancreatitis induced in the rat by retrograde infusion of 0.6 mL 5% sodium taurocholate into the pancreatic duct. Secretory studies were performed in vivo and in vitro at various times after onset of pancreatitis. The results show that the exocrine pancreas gradually became resistant to cholecystokinin stimulation after the onset of acute pancreatitis in all four animal models. Cholecystokinin-stimulated secretion was almost abolished in vivo and in vitro at the time of maximal histological damage. In vivo basal secretion was also reduced. In vitro there was an increase in basal release of amylase from isolated acini that was not caused by an increase in luminal secretion but by enzyme release from damaged cells. The time course of improvement of secretory function after acute experimental pancreatitis depended on the severity of the pancreatitis. Recovery of secretory capacity took longer after severe necrotizing pancreatitis than after edematous pancreatitis. However, the ultimate resolution of secretory function was remarkable, in particular after severe hemorrhagic pancreatitis. In all four models, secretory capacity became indistinguishable from normal before the morphological alterations had completely resolved. The present experimental data suggest that pancreatic secretion, and particularly pancreatic secretory response to cholecystokinin, may also be reduced in patients early after the onset of acute pancreatitis.

The effects of alpha‐thalassaemia in HbSC disease

In HbSC disease, as in sickle cell anaemia, there is a spectrum of clinical severity. A reduced mean corpuscular volume and haemoglobin concentration, traits typical of thalassaemia, might retard sickling. We therefore ascertained the prevalence of alpha-thalassaemia in 53 adults with HbSC disease and related alpha-globin gene deletion to the haematologic and clinical findings. Alpha-globin genotype was identified by restriction endonuclease gene mapping. Indirect ophthalmoscopy and fluorescein angiography were used to document the presence of proliferative retinopathy. Bone necrosis and infarction were determined roentgenographically or by radionuclide scanning. Either heterozygous or homozygous alpha-thalassaemia-2 was present in 26% of patients. There was no relationship between alpha-globin genotype and haematocrit, pain crises, bone lesions, proliferation retinopathy or clinical severity score.

Chronic eosinophilic pneumonia.

Chronic eosinophilic pneumonia is a clinical, radiographic, and histologic entity of unknown etiology, occurring predominantly in young women with an allergic history. A wide spectrum of clinical severity has been reported. Blood eosinophilia greater than 6% and characteristic peripheral pulmonary infiltrates suggest the diagnosis. Biopsy is confirmatory with a distinctive histologic picture. Response to steroids is dramatic and of diagnostic value, probably making biopsy unnecessary in some instances. Two cases with histologic proof are reported, in one of which the diagnosis was suggested pre-operatively.

Anticoagulant and Thrombolytic Drugs1 II

Since platelets have a dominant role in the early stages of thrombosis, interference with fibrin formation by anticoagulant drugs can have only a limited place in the prevention or treatment of thrombosis. The precise indications for the use of anticoagulant drugs are not yet defined: there is evidence for their value in the prophylaxis and treatment of deep venous thrombosis and pulmonary embolism, in transient cerebral ischaemic attacks, to prevent emboli in rheumatic heart disease, and in ischaemic heart disease. Sensitivity reactions to the indanedione derivatives are relatively frequent: coumarin derivatives are therefore preferred for oral anticoagulant therapy. Heparin is valuable for the rapid induction of an anticoagulant effect. The place of ancrod is not established, but it holds promise as an agent in the management of thrombotic disease. Most surgical procedures can be carried out in patients under treatment with coumarinindanedione drugs, but heparin must be neutralised if surgery becomes necessary. In pregnancy coumarin-indanedione drugs should probably be avoided and heparin used if anticoagulant therapy is indicated. Breast-feeding should be stopped if oral anticoagulants are required in the post-partum period. Thrombolytic therapy has been used in a wide variety of thrombo-embolic disorders, but adequate evaluation in specific conditions is largely lacking. Disseminated intravascular coagulation presents a wide spectrum of clinical severity: treatment must take account of both the cause and the effects of the process and includes the elimination of the source of coagulant material and, where appropriate, the use of heparin, the replacement of depleted coagulation factors and treatment of the underlying disease. Difficulty in the maintenance of a stable therapeutic level of anticoagulant effect with the coumarin-indanedione derivatives may be due to erratic ingestion of the tablets, intercurrent illness, or the concurrent therapy with drugs which potentiate or decrease the anticoagulant effect of the coumarin drugs. The side-effects of the oral anticoagulant drugs fall into two groups: (i) haemorrhagic side-effects due to over-dosage and (ii) non-haemorrhagic side-effects. Non-haemorrhagic side-effects are rare with coumarin derivatives, but sensitivity reactions to indanedione derivatives are not uncommon and may be severe. Anticoagulant therapy is contra-indicated, unless reliable control can be maintained; in patients who have lesions of the gastrointestinal or renal tracts which are liable to bleed; in patients in whom there is danger of bleeding into the central nervous system (severe hypertension, previous cerebrovascular accident or recent surgery or trauma); and in patients with chronic renal failure.