Severe unresolving Plasmodium falciparum malaria following artemisinin combination therapy: Emergence of drug resistance in Saudi Arabia.

A 5-year-old female child presented with fever of 1-week duration after visiting a malaria endemic zone without antimalarial prophylaxis. The patient presented with respiratory distress, decreased level of consciousness and high-grade fever. An elevated parasitaemia reaching 800,000/µl was observed. Antimalarial therapy was initiated with artesunate being administered intravenous (IV) along with IV clindamycin. Contrary to the expectations, there was no resolution of fever. Following a week of unresolved fever, the drug therapy was revised and altered to IV quinine dihydrochloride and IV clindamycin. Emergence of non-responsiveness to artesunate in Saudi Arabia is an alarming sign and requires revision of management protocols.

Classification of papulo-squamous skin diseases using image analysis.

INTRODUCTION: Papulo-squamous skin diseases are variable but are very close in their clinical features. They present with the same lesions, erythematous scaly lesions. Clinical evaluation of skin lesions is based on common sense and experience of the dermatologist to differentiate features of each disease. AIM: To evaluate a computer-based image analysis system as a helping tool for classification of commonly encountered diseases. MATERIALS AND METHODS: The study included 50 selected images from each of psoriasis, lichen planus, atopic dermatitis, seborrheic dermatitis, pityrasis rosea, and pitryasis rubra pilaris with a total of 300 images. The study comprised three main processes peformed on the 300 included images: segmentation, feature extraction followed by classification. RESULTS: Rough sets recorded the highest percentage of accuracy and sensitivity of segmentation for the six groups of diseases compared with the other three used techniques (topological derivative, K-means clustering, and watershed). Rule-based classifier using the concept of rough sets recorded the best percentage of classification (96.7%) for the six groups of diseases compared with the other six techniques of classification used: K-means clustering, fuzzy c-means clustering, classification and regression tree, rule-based classifier with discretization, and K-nearest neighbor technique. CONCLUSION: Rough sets approach proves its superiority for both the segmentation and the classification processes of papulo-squamous skin diseases compared with the other used segmentation and classification techniques.

Association between dialysis dose improvement and nutritional status among hemodialysis patients.

BACKGROUND: Several studies suggest an association between improved survival and better nutritional status. It has been suggested that there is a correlation between dose of dialysis and nutritional status. However, in spite of the current practice, there are conflicting reports regarding the relationship between dose of dialysis or malnutrition, and biochemical outcome. In this article, we will discuss the impact of dose of dialysis on nutritional status and biochemical outcome in hemodialysis patients. We will also mention the interrelationships of dialysis dose, malnutrition, and biochemical outcome with respect to these patients. METHODS: Data were processed on 134 dialysis patients (mean age 48.21 +/- 13.38, 69 male, 65 female) on 3-times-per-week dialysis regimens. The overall study period was 3 months from June 1, 2005 to August 31, 2005. The patients were divided into two groups: the baseline group and the intervention group. The data of the baseline group were collected in June, 2005 and the data of the intervention group were collected in August, 2005 after applying the intervention or a protocol for dialysis adequacy improvement. RESULTS: The statistical analysis demonstrated that there was a significant improvement in mean URR and Kt/V from the baseline to the intervention group. The intervention group had a considerably higher rate than the baseline group for all nutritional and biochemical outcome parameters. The study showed a strong positive correlation between nPCR and Kt/V (p = 0.0001) and also a strong positive correlation between serum albumin and Kt/V (p = 0.00001). No correlations were found between Kt/V and biochemical outcomes such as hemoglobin (p = 0.4922), calcium (p = 0.650), phosphate (p = 0.508), and phosphatase (p = 0.091). CONCLUSION: All the available evidence in hemodialysis patients confirms the close association between dialysis dose and biochemical outcome. A body of evidence also highlights the existence of relationship between malnutrition and outcome among these patients. Dose of dialysis and nutrition are considered to be interrelated.

Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder present in 1 in 8000 people and associated with arteriovenous malformations. Genetic testing can identify individuals at risk of developing the disease and is a useful diagnostic tool. OBJECTIVE: To present a strategy for mutation detection in families clinically diagnosed with HHT. METHODS: An optimised strategy for detecting mutations that predispose to HHT is presented. The strategy includes quantitative multiplex polymerase chain reaction, sequence analysis, RNA analysis, validation of missense mutations by amino acid conservation analysis for the ENG (endoglin) and ACVRL1 (ALK1) genes, and analysis of an ACVRL1 protein structural model. If no causative ENG or ACVRL1 mutation is found, proband samples are referred for sequence analysis of MADH4 (associated with a combined syndrome of juvenile polyposis and HHT). RESULTS: Data obtained over the past eight years were summarised and 16 novel mutations described. Mutations were identified in 155 of 194 families with a confirmed clinical diagnosis (80% sensitivity). Of 155 mutations identified, 94 were in ENG (61%), 58 in ACVRL1 (37%), and three in MADH4 (2%). CONCLUSIONS: For most missense variants of ENG and ACVRL1 reported to date, study of amino acid conservation showed good concordance between prediction of altered protein function and disease occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too complex or difficult to detect, or mutations in genes yet to be identified.

Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by epistaxis, telangiectases, and multiorgan vascular dysplasia. The two major types of disease, HHT1 and HHT2, are caused by mutations in the ENG (endoglin) and ACVRL1 genes, respectively. The corresponding endoglin and ALK-1 proteins are specific endothelial receptors of the transforming growth factor beta superfamily essential for maintaining vascular integrity. Many mutations have been identified in ENG and ACVRL1 genes and support the haploinsufficiency model for HHT. Two more genes have recently been implicated in HHT: MADH4 mutated in a combined syndrome of juvenile polyposis and HHT (JPHT), and an unidentified HHT3 gene linked to chromosome 5. Current knowledge on the genetics of HHT is summarised, including the pathways that link the genes responsible for HHT and the potential mechanisms underlying the pathogenesis of the disease.

Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia.

Primary pulmonary hypertension (PPH) is a rare but severe and progressive disease characterised by obstructive lesions of small pulmonary arteries. Patients with PPH often have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, whereas some carry mutations in the activin receptor-like kinase 1 (ALK-1) gene, generally associated with hereditary haemorrhagic telangiectasia (HHT) type 2, a vascular dysplasia affecting multiple organs. The aim of this study was to determine whether members of families with PPH and confirmed or probable HHT had ALK-1 mutations. ALK-1 and BMPR2 mutation analysis was performed on deoxyribonucleic acid from affected members of four families with PPH and confirmed or suspected HHT. ALK-1 mutations were identified in all four families and three novel mutations found in exon 10, leading to truncated proteins. In the fourth family, a missense mutation, previously reported in four independent HHT families, was detected in exon 8. Analysis of the BMPR2 gene revealed no exonic mutations in the probands with both PPH and HHT. The present data bring to 10 the number of reported families with primary pulmonary hypertension and hereditary haemorrhagic telangiectasia type 2, representing 16% of the 61 families with known activin receptor-like kinase 1 mutations. Such mutations might predispose to primary pulmonary hypertension, and specialists should be aware of the potential link between these two disorders.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Visceral manifestations in hereditary haemorrhagic telangiectasia type 2.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by epistaxis, telangiectases, and visceral manifestations. The two known disease types, HHT1 and HHT2, are caused by mutations in the endoglin (ENG) and ALK-1 genes, respectively. A higher frequency of pulmonary arteriovenous malformations (AVMs) has been reported for HHT1 while HHT2 is thought to be associated with a lower penetrance and milder disease manifestations. In this study, we present 10 families with an ALK-1 genotype. Visceral manifestations were detected in 24 (26%) of the 93 HHT2 patients from nine of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and AVMs in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in six of the 10 families, mostly in patients over the age of 50. These patients also had frequent epistaxis and suffered from anaemia, often requiring blood transfusions. The identification of ALK-1 mutations in subjects with a suspected diagnosis and without clinical signs of HHT argue in favour of a molecular diagnosis. We also analysed the data published on 44 families with HHT2 and conclude that visceral manifestations occur in 26 of these families and affect 30% of HHT2 patients. This is considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centres. These findings, however, stress the need for an early diagnosis of HHT that can be useful for the early control of associated visceral involvement.

Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2.

ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-beta superfamily, is the gene mutated in hereditary hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels. ALK-1 levels were specifically reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two newborns not carrying the missense mutations present in the clinically affected relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function of the mutant allele due to a reduction in either protein level or activity. We also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-beta1 and -beta3 receptor complexes in association with endoglin and TbetaRII, but not in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not detectable in the TGF-beta1 or -beta3 receptor complexes. However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients. Our data suggest a transient association between these two proteins of the TGF-beta superfamily, both required at a critical level to ensure vessel wall integrity.

Prognostic relevance of microvessel density in colorectal tumours.

The importance of angiogenesis as a prognostic marker has been examined in 111 colorectal cancer patients with a minimum follow-up of 5 years. Tumour sections were immunostained with pan-endothelial antibody to CD31. Microvessels were identified and counted in 5 separate areas of highest vascularity (). Analysis of the data showed that the survival was not significantly affected by tumour site, size, grade, patients' age or gender. However, a statistically significant correlation was found between microvessel density (MVD) and survival: patients with an increased number of microvessels survived longer than those with a low number of microvessels (p=0.0007). Therefore, paradoxically, unlike other tumour types, in colorectal cancer MVD appears to be an indicator of good prognosis. The reasons that MVD correlates with good or poor prognosis are likely to vary in different tumours. For instance a frequent difficult issue in colon cancer is the presence of ulceration and adjacent severe inflammation which by itself can increase vascularity. Furthermore, overall prognosis will also depend on other factors, such as oncogenes, extracellular matrix components, adhesion molecules, growth factors, degree of apoptosis and the mode of metastatic spread.

The novel combination of fat clearance and immunohistochemistry improves prediction of the outcome of patients with colorectal carcinomas: a preliminary study.

To evaluate the significance of micrometastases in relation to survival rate, specimens from 48 colorectal carcinoma patients were analysed after fat clearance. The number and size of the lymph nodes harbouring metastases and the significance of micrometastases for patients' survival were assessed. We found that although the majority of metastatic lymph nodes (71.8%) were 5 mm or less in diameter, their size had no effect on survival. Immunohistochemical staining of lymph nodes revealed that 15 of 25 patients with Dukes' stage B diagnosed by routine staining had micrometastases, 86% of these lymph nodes being less than 5 mm in diameter. The survival rate of this subgroup was found to be considerably poorer than that of Dukes' stage B patients with no micrometastases. None of the three patients with Dukes' stage A carcinoma had micrometastases. Since most of the metastases and micrometastases occur in lymph nodes of 5 mm and less and can be easily missed by routine examination, we suggest that fat clearance and routine immunohistochemical analysis of Dukes' stage B improve the prediction of outcome of colorectal cancer patients.

Effect of subdermal levonorgestrel contraceptive implants, Norplant, on serum lipids.

Forty-seven normal non-smoking parous women were enrolled in a longitudinal study of the effect of use of the subdermal levonorgestrel implants, NORPLANT, on serum lipids. Blood samples were collected after an overnight fast before insertion and after three, six, nine and twelve months of use. The high-density lipoprotein cholesterol showed no change until the twelfth month when it was increased (P less than .05). Total cholesterol, low-density lipoprotein cholesterol and triglyceride levels decreased significantly during NORPLANT use.