Biochemical Manifestations Research Articles

Circadian rhythms in acute intermittent porphyria--a pilot study.

Acute intermittent porphyria (AIP) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen (PBG) deaminase (PBGD) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid (ALA) synthase-1 (ALAS1) with over-production of ALA and PBG. The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls. Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP. This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP.

When Schwann Cells Conspire with Mitochondria, Neighboring Axons Are under Attack by Glia-Derived Neurotoxic Lipids

In this issue of Neuron, Viader etal. (2013) report on the production of toxic lipids by Schwann cells deficient in mitochondrial respiration, which are capable of destroying neighboring axons. This may have implications for understanding the neurobiology and treatment of mitochondrial neuropathies.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

BackgroundThe use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive.Methods30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch.Results66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model.ConclusionsSirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Clinical, biochemical, and radiological manifestations of vitamin D deficiency in newborns presented with hypocalcemia

Introduction:The Clinical and radiological manifestations of newborns with severe VDD have not been studied well.Materials and Methods:We studied the clinical, biochemical, and radiological manifestations of 10 full-term (FT) newborns (6: M, 4: F) infant presented to with symptomatic hypocalcemia (seizure) secondary to vitamin D deficiency (VDD) during the first 10 days of life are described. All were exclusively breastfed since birth. All their mothers have low 25 hydroxy vitamin D (25OHD) level <10 ng/mL and were not taking vitamin supplements during pregnancy.Results:FT newborns with hypocalcemia secondary to VDD presented with generalized convulsions (10/10) and craniotabes (8/10), but none had rachitic chest rosaries or joint broadening. Cranial ultrasonographic evaluation was normal. Serum 25OHD concentrations were low in these newborns (13.2 ± 3.8 ng/mL) and their mothers (8.1 ± 1.5 ng/mL). A total of 60% of them had increased parathormone (PTH) concentrations (>60 ng/mL) and 60% had decreased magnesium (Mg) concentrations (<0.7 mmol/L). Their alkaline phosphatase (ALP) concentrations were significantly higher than normal newborns. All other laboratory results (liver function tests, urea and electrolytes, C reactive protein, lumbar puncture, blood culture, and lactate) were normal. In all patients, seizures ceased within 2 days of starting treatment with alphacalcidol and calcium. Radiological manifestations included metaphyseal band of relative lucency (osteopenia), just under the line of provisional calcification, within distal radius (7/10), femur (4/10), and tibia (3/10), mild cupping and haziness of distal radius (2/10).Discussion:Newborns with VDD had significantly lower serum calcium, ALP and PTH and higher phosphate concentrations, compared to older infants with VDD rickets. In newborns with VDD, serum calcium levels were correlated significantly with 25OHD (r = 0.597, P < 0.001), Mg concentrations (r = 0.436, P < 0.001) and negatively with ALP concentrations (r = −0.451, P < 0.001). Serum PTH concentrations were correlated significantly with serum Mg (r = 0.78, P < 0.0001) but not with serum calcium (r = −0.103, P = 0.3) or 25OHD (r = −0.03, P = 0.7) concentrations.Conclusion:The clinical, biochemical, and radiological manifestations of VDD in newborns indicate that they are less adapted to VDD compared to older infants. VD supplementation for mothers and newborns should be considered to avoid short-term complications of VDD in the neonatal period and on the growing infants especially in countries with high prevalence of VDD.

Asymptomatic Primary Hyperparathyroidism

The clinical profile of primary hyperparathyroidism (PHPT) as it is seen in the United States and most Western countries has evolved significantly over the past half century. The introduction of the multichannel serum autoanalyzer in the 1970s led to the recognition of a cohort of individuals with asymptomatic hypercalcemia, in whom evaluation led to the diagnosis of PHPT. The term “asymptomatic primary hyperparathyroidism” was introduced to describe patients who lack obvious signs and symptoms referable to either excess calcium or parathyroid hormone. Although it was expected that asymptomatic patients would eventually develop classical symptoms of PHPT, observational data suggest that most patients do not evolve over time to become overtly symptomatic. In most parts of the world, the asymptomatic phenotype of PHPT has replaced classical PHPT. This report is a selective review of data on asymptomatic PHPT: its demographic features, presentation and natural history, as well as biochemical, skeletal, neuromuscular, psychological, and cardiovascular manifestations. In addition, we will summarize available information on treatment indications and options for those with asymptomatic disease.

Obscurin: A New Player in Cardiac Hypertrophy

Obscurins, encoded by the single OBSCN gene, comprise a family of giant (∼890-810 kDa) and small (∼550-50 kDa) proteins of vertebrate striated muscles composed of adhesion and signaling motifs. Giant obscurins intimately surround sarcomeres at the level of M-bands and Z-disks where they participate in the assembly, stabilization, and integration of the contractile cytoskeleton with other sarcoplasmic structures. Consistent with this, the immunoglobulin (Ig) domains 58 and 59 of obscurins interact directly with Ig domains 9 and 10 of titin located at the periphery of Z-disks. Genomic linkage analysis has recently revealed a missense mutation (R4344Q) in obscurin Ig58 that is causally linked to hypertrophic cardiomyopathy (HCM). To examine how the R4344Q mutation leads to the development of HCM, we generated two animal models: a knock-in model that contains full length obscurins carrying the R4344Q mutation, and a partial knock-out model that lacks Ig 58 and 59. Immunoblot and immunofluorescence analysis indicated that both mutant and truncated obscurins are readily expressed in cardiac muscles, and properly incorporated into sarcomeres. Homozygous partial knock-out mice developed overt cardiac hypertrophy by 12 months of age, as measured by echocardiography; notably, hypertrophy was exacerbated in the female homozygous animals. While a hypertrophic trend was apparent in homozygous knock-in animals, phenotypic and functional alterations of the affected hearts were not statistically significant from those of wild-type animals. Importantly, trans-aortic constriction of ∼2 months old knock-in and partial knock-out male and female mice led to severe cardiac hypertrophy within 4-8 weeks post-surgery, as evaluated by echocardiography. We are currently examining the cellular and biochemical manifestations of mutant and truncated obscurins, as related to the development of HCM. Our studies provide the first in vivo models to study the molecular defects that underlie HCM due to altered obscurins.

Malignant Catatonia Mimicking Pheochromocytoma

Malignant catatonia is an unusual and highly fatal neuropsychiatric condition which can present with clinical and biochemical manifestations similar to those of pheochromocytoma. Differentiating between the two diseases is essential as management options greatly diverge. We describe a case of malignant catatonia in a 20-year-old male who presented with concurrent psychotic symptoms and autonomic instability, with markedly increased 24-hour urinary levels of norepinephrine at 1752 nmol/day (normal, 89–470 nmol/day), epinephrine at 1045 nmol/day (normal, <160 nmol/day), and dopamine at 7.9 μmol/day (normal, 0.4–3.3 μmol/day). The patient was treated with multiple sessions of electroconvulsive therapy, which led to complete clinical resolution. Repeat urine collections within weeks of this presenting event revealed normalization or near normalization of his catecholamine and metanephrine levels. Malignant catatonia should be considered in the differential diagnosis of the hypercatecholamine state, particularly in a patient who also exhibits concurrent catatonic features.

Molecular genetic testing for mitochondrial disease: from one generation to the next.

Molecular genetic diagnostic testing for mitochondrial disease has evolved continually since the first genetic basis for a clinical mitochondrial disease syndrome was identified in the late 1980s. Owing to global limitations in both knowledge and technology, few individuals, even among those with strong clinical or biochemical evidence of mitochondrial respiratory chain dysfunction, ever received a definitive molecular diagnosis prior to 2005. Clinically available genetic diagnostic testing options improved by 2006 to include sequencing and deletion analysis of an increasing number of individual nuclear genes linked to mitochondrial disease, genome-wide microarray analysis for chromosomal copy number abnormalities, and mitochondrial DNA whole genome sequence analysis. To assess the collective effect of these tests on the genetic diagnosis of suspected mitochondrial disease, we report here results from a retrospective review of the diagnostic yield in patients evaluated from 2008 to 2011 in the Mitochondrial-Genetics Diagnostic Clinic at The Children's Hospital of Philadelphia. Among 152 patients aged 6 weeks to 81 years referred for clinical evaluation of multisystem presentations concerning for suspected mitochondrial disease, a genetic etiology was established that confirmed definite mitochondrial disease in 16.4% and excluded primary mitochondrial disease in 9.2%. Substantial diagnostic challenges remain owing to the clinical difficulty and frank low yield of a priori selecting individual nuclear genes to sequence based on particular symptomatic or biochemical manifestations of suspected mitochondrial disease. These findings highlight the particular utility of massively parallel nuclear exome sequencing technologies, whose benefits and limitations are explored relative to the clinical genetic diagnostic evaluation of mitochondrial disease.

Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice.

We studied mice with or without heterozygous deletion of the Casr in the parathyroid gland (PTG) [(PTG) CaSR(+/-)] to delineate effects of age and sex on manifestations of hyperparathyroidism (HPT). In control mice, aging induced a left-shift in the Ca(2+) /parathyroid hormone (PTH) set point accompanied by increased PTG CaSR expression along with lowered serum Ca(2+) and mildly increased PTH levels, suggesting adaptive responses of PTGs to aging-induced changes in mineral homeostasis. The aging effects on Ca(2+) /PTH set point and CaSR expression were significantly blunted in (PTG) CaSR(+/-) mice, who showed instead progressively elevated PTH levels with age, especially in 12-month-old females. These 12-month-old knockout mice demonstrated resistance to their high PTH levels in that serum 1,25-dihydroxyvitamin D (1,25-D) levels and RNA expression of renal Cyp27b1 and expression of genes involved in Ca(2+) transport in kidney and intestine were unresponsive to the rising PTH levels. Such changes may promote negative Ca(2+) balance, which further exacerbate the HPT. Skeletal responses to HPT were age-, sex-, and site-dependent. In control mice of either sex, trabecular bone in the distal femur decreased whereas cortical bone in the tibiofibular junction increased with age. In male (PTG) CaSR(+/-) mice, anabolic actions of the elevated PTH levels seemed to protect against trabecular bone loss at ≥ 3 months of age at the expense of cortical bone loss. In contrast, HPT produced catabolic effects on trabecular bone and anabolic effects on cortical bone in 3-month-old females; but these effects reversed by 12 months, preserving trabecular bone in aging mice. We demonstrate that the CaSR plays a central role in the adaptive responses of parathyroid function to age-induced changes in mineral metabolism and in target organ responses to calciotropic hormones. Restraining the ability of the PTG to upregulate CaSRs by heterozygous gene deletion contributes to biochemical and skeletal manifestations of HPT, especially in aging females.

Metabolic response to Klebsiella pneumoniae infection in an experimental rat model.

Bacteremia, the presence of viable bacteria in the blood stream, is often associated with several clinical conditions. Bacteremia can lead to multiple organ failure if managed incorrectly, which makes providing suitable nutritional support vital for reducing bacteremia-associated mortality. In order to provide such information, we investigated the metabolic consequences of a Klebsiella pneumoniae (K. pneumoniae) infection in vivo by employing a combination of 1H nuclear magnetic resonance spectroscopy and multivariate data analysis. K. pneumoniae was intravenously infused in rats; urine and plasma samples were collected at different time intervals. We found that K. pneumoniae-induced bacteremia stimulated glycolysis and the tricarboxylic acid cycle and also promoted oxidation of fatty acids and creatine phosphate to facilitate the energy-demanding host response. In addition, K. pneumoniae bacteremia also induced anti-endotoxin, anti-inflammatory and anti-oxidization responses in the host. Furthermore, bacteremia could cause a disturbance in the gut microbiotal functions as suggested by alterations in a range of amines and bacteria-host co-metabolites. Our results suggest that supplementation with glucose and a high-fat and choline-rich diet could ameliorate the burdens associated with bacteremia. Our research provides underlying pathological processes of bacteremia and a better understanding of the clinical and biochemical manifestations of bacteremia.

Allogeneic Hematopoietic Cell Transplantation for Severe Epidermolysis Bullosa: Impact of Conditioning Regimen and Stem Cell Source On Outcomes

AbstractAbstract ▪965▪This icon denotes a clinically relevant abstractIt is becoming clear that bone marrow (BM) and umbilical cord blood (UCB) cells can engraft in extramedullary tissues after hematopoietic cell transplantation (HCT). On the basis of preclinical testing in an animal model of recessive dystrophic epidermolysis bullosa (RDEB, an incurable, often fatal blistering genodermatosis), we evaluated the effectiveness of allogeneic HCT in ameliorating the biochemical and clinical manifestations of the disease in humans. RDEB is due to deficiency of type VII collagen (C7), which causes a lack of attachment between the epidermal basement membrane and the dermal matrix, and which results in a poor quality of life and early death as a result of chronic mucocutaneous blistering. Between 2007 and 2012, 18 patients with severe generalized RDEB have undergone allogeneic HCT at the University of Minnesota. Thirteen patients were treated with myeloablative (MA) conditioning (busulfan IV 0.8 mg/kg for >12 kg and 1.1 mg/kg for those <12 kg of body weight every 6 hours on days -9 to -6, with pharmacokinetic targeting 1,000 mmol/min for the area under curve; fludarabine [FLU] IV 25 mg/m2/day on days -5 to -3; and cyclophosphamide [CY] IV 50 mg/kg/day on days -5 to -2). Five patients were treated with non-MA conditioning (CY IV 50 mg/kg/day on day -6; FLU IV 40 mg/m2/day on days -6 to -2; anti-thymocyte globulin IV 30 mg/kg/day on days -4 to -2; and total body irradiation 200 cGy on day -1), with cyclosporine A and mycophenolate mofetil as GVHD prophylaxis. Patients were transplanted with either BM from an HLA-matched sibling (n=10) or HLA-matched unrelated donor (n=3), or with partially matched UCB (n=5) when a matched marrow donor was not available. In addition to the hematopoietic graft, a single infusion of third-party, HLA-mismatched mesenchymal stromal/stem cells (MSCs, dose: 2 × 106/kg) was administered on day 0 to 12 of the 18 RDEB individuals (7 with MA and 5 with non-MA conditioning). The primary endpoint of the analysis was survival with skin improvement. Importantly, non-MA conditioning was well tolerated, with a marked reduction in risk of infection, and of pulmonary and renal toxicity. Thus far, for the entire cohort, the overall probability of survival is 73% (95% CI, 49–96%), with 11 patients demonstrating partial-to-marked biochemical and clinical improvement in mucocutaneous disease as evaluated by protein expression and resistance to blistering. There are no significant differences yet in beneficial or adverse effects in patients treated with or without MSC co-infusion. Transplant outcomes are shown in the Table.GraftNRegimenNC7 Protein ExpressionSkin Healing1Skin Chimerism, N (range)3GvHD Acute/ChronicAliveAlive and EngraftedUCB5MA4211 (11–30%)1/121RIC10000/010BM13MA96727 (2–97%)1/077RIC41322 (3–23%)0/044Total18181011102/11411We conclude that BM is the preferred source of HSC (BM: 11 of 13 alive and engrafted [85%] versus CB: 1 of 5 alive and engrafted [20%], p-value = 0.02). Also, early results with the non-MA conditioning are promising in terms of toxicity profile and engraftment. Overall, HCT can result in significant skin engraftment, restoration of the missing C7 protein, and clinical improvement in RDEB. HCT has the potential of being a durable, systemic therapy for many people with different forms and severities of EB, and sets the stage for using BM cells in the treatment of a broad spectrum of extracellular matrix disorders.1Defined as a change in the amount of skin covered with blisters and erosions from >50% before HCT to <10% after HCT.2Remarkably, significant clinical improvement can be achieved even in the absence of any detectable C7 early after HCT.3Approximately 30% of wild-type levels of C7 are believed to be sufficient to protect from extensive blistering. Disclosures:No relevant conflicts of interest to declare.

Evidence of apoptosis in some cell types due to pentachlorophenol (PCP) in Heteropneustes fossilis

The study aimed to clarify the role of apoptosis in pentachlorophenol (PCP) induced testicular, ovarian and renal cell genotoxicity of Heteropneustes fossilis. It was further intended to find the target germ cell type and assess the cellular and nuclear damage. Treatment of PCP was used for multiduration on the germinal tissues and they were processed to detect structural changes by light and electron microscopic evaluation and kidney cells for subsequent detection of DNA fragmentation by agarose gel electrophoresis. Findings suggest functional and morphological changes in the tissues are due to apoptosis, as evidenced by some biochemical and cytological signs. Histological observation on germinal epithelium reveals cell suicidal symptoms such as vacuolization, liquefied regions in the cytoplasm of oocytes, margination of nuclei, clumping of chromatin, and compaction of cytoplasmic organelle. Biochemical manifestation concurrent to this, is; cleavage of kidney cell DNA into low molecular weight fragments confirming apoptosis. Subsequently, it is further cleaved into nucleosome size fragments or its multiples. Ultra-structural histopathology and DNA studies conclusively lead to the PCP induced apoptosis in the exposed cell types. Results further support the usefulness of this assay in the related studies and its feasibility in generating a base line data.

Erythrocyte density in sickle cell syndromes is associated with specific clinical manifestations and hemolysis

AbstractDense, dehydrated red blood cells (DRBCs) are a characteristic feature of sickle-cell disease (SCD). DRBCs play a role in the pathophysiology of SCD acute and chronic organ damage because of heightened tendency to undergo polymerization and sickling because of their higher hemoglobin S concentration. Relations between red cell density (assessed with phthalate density-distribution profile method) and several hematologic, biochemical, genetic parameters, and clinical manifestations were studied in a large cohort of homozygous patients. The percentage of DRBCs was significantly higher in patients who experienced skin ulcers, priapism, or renal dysfunction. Presence of α-thalassemia deletions was associated with fewer DRBCs. A multivariable analysis model showed DRBCs to be positively associated with hemolytic parameters such as lactate dehydrogenase and bilirubin and negatively with fetal hemoglobin. The percentage of DRBCs decreased by 34% at 6 months of hydroxycarbamide (xydroxyurea) therapy. Thus, DRBCs are associated with specific clinical manifestations and biologic markers and may be a useful addition to the biologic and clinical evaluation of patients with SCD, because they can easily be measured in a hematocrit tube.

Criteria of clinic diagnosis and effectiveness of biological therapy in viral hepatitis A

The clinical trial of 60 patients (mean age (28.5 ± 0.9) years) with moderate severity hepatitis A (VHA) has been performed. The diagnosis in all patients was verified by detection of IgM to VHA by ELISA. In the course of the disease clinical symptoms and functional status of the liver were evaluated. We determined the activity of alanine transaminase, aspartate transaminase, gammaglutamyl transferase, alkaline phosphatase, and the content of bilirubin. Malondialdehyde (MDA) level in blood serum was determined as a laboratory indicator of endogenous intoxication. Main group consisted of 30 patients treated with antigomotoxic therapy, whereas in the control group (30 patients) the common therapy was carried out. A faster elimination of clinical and biochemical manifestations of the acute phase of VHA was established in the main group compared with the patients of the control group. In contrast to the latter, the average MDA in the main group patients 3 and 6 months after treatment did not differ significantly from the normal values.

Conjugated Hyperbilirubinemia in Children

A variety of anatomic, infectious, autoimmune, and metabolic diseases can lead to conjugated hyperbilirubinemia, both in the newborn period and later in childhood. The pediatric practitioner is most likely to encounter conjugated hyperbilirubinemia in the neonatal period.It is crucial to maintain a high degree of suspicion for cholestasis in the persistently jaundiced newborn. The goal is recognition of conjugated hyperbilirubinemia between 2 and 4 weeks after birth, allowing for the prompt identification and management of infants who have biliary atresia, which remains the most common cause of neonatal cholestasis.

P-0139 Xelox Regimen in Treatment of Neuroendocrine Tumors of Gastrointestinal Tract (Preliminary Results)

ABSTRACT Introduction To evaluate the effectiveness of XELOX in patients with disseminated neuroendocrine tumors (NET) of gastrointestinal tract. Methods 50 patients with morphologically verified NET of gastrointestinal tract,17 (34%) men and 33 (66%) women aged 19-75, mean age 55.5±11.8 years. Among them 2 patients (4%) had gastric NET, 18 (36%) - pancreatic NET, 18 (36%) - intestinal NET, in 12 patients (24%) the primary tumor was not identified. G1 tumor was verified in one case (8%), G2 – in 31 patients (62%), G3 – in 10 patients (20%), in 5 patients (10%) the tumor was only verified by cytological study. Thirty-three patients (66%) had liver metastatic disease. Clinical manifestations of carcinoid syndrome with elevation of serum chromogranin A and serotonin and urinary 5-HIAA levels were seen in 31 (62%) patients with well-differentiated tumors. Additional therapy by somatostatin analogs received 30 patients (60%). Chemotherapy regimen: oxaliplatin 120 mg/m2 day 1, capecitabine 2000 mg/m2 days 1-14. Mean follow-up time was 28 months. Results The overall number of chemotherapy courses was 242. Stabilization was seen in 44 patients (88%), progression - in 6 patients (12%). Biochemical effect confirmed by decrease in chromogranin and/or serotonin serum level was observed in 28 patients (44%). Median progression-free survival time was 14 months, 60% of patients showed no signs of progression for one year. Patients with clinical and biochemical manifestations of carcinoid syndrome receive additional treatment with somatostatin analogs or interferons. Median survival is not reached. Conclusion ХELOХ regimen may be used for disease control in patients with disseminated well- and poorly differentiated NET of gastrointestinal tract in first and following treatment lines.

Development of an animal model for assessment of primary end-to-end biliary reconstruction

BACKGROUND: Bile duct anastomotic stricture after bile duct injury or liver transplantation remains as the most formidable clinical problem. Here, we attempt to describe the natural course of healing following experimental end-to-end anastomosis (EEA) and to evaluate the efficacy and safety of EEA in a rabbit model. METHODS: New Zealand rabbits were divided into experimental groups with complete transection of the common bile duct (CBD) and control group with CBD mobilization. Clinical, laboratory biochemical and cholangiographical manifestations were compared between the groups. At intervals postoperatively healing course of the bile duct was judged by macroscopic, microscopic and transmission electron microscope examination. The diameters of CBD were measured by sliding caliper. RESULTS: Serum concentrations of alkaline phosphatase, alanine aminotransferase and total bilirubin were significantly higher in experimental groups than those in control group (P < 0.05). The cholangiogram showed that anastomotic stricture and markedly dilated biliary tree were observed at varying time postoperatively. Inflammatory reactions, cicatricial stricture and fibrosis in the bile duct wall were observed in the experimental groups. In addition, biliary fibroblast increased and collagen deposition was observed in the anastomotic scar tissue. We observed that 3 (6%) rabbits had formed gallstones within 1–3 months after injury EEA. CONCLUSIONS: This study demonstrated that microsurgical techniques could achieve successful primary end-to-end biliary repair in the rabbit. Anastomotic tension, surgical technology and fibrotic healing may be the most important causes of stricture formation. Additionally, this model may allow for researching the pathologic changes in the healing process of the bile duct and the mechanisms of stricture formation.

An Interleukin-10 Gene Promoter Polymorphism (−592A/C) Associated with Type 2 Diabetes: A North Indian Study

In this first report on the association of an IL-10 promoter polymorphism with type 2 diabetes mellitus in a North Indian population, the -592A/C SNP (rs1800872) was genotyped by PCR-RFLP and the IL-10 level measured using ELISA. Although no significant difference was observed in the genotypic frequencies (P = 0.657), diabetes patients carried a significantly higher number of A alleles at the -592 position, 25.6% (P < 0.001, odds ratio 0.887, 95% CI 0.670-1.184). Significant correlations were detected in postprandial glucose levels of CC-genotype patients and controls (P = 0.025), age and waist-hip ratio of CA patients and controls (P ≤ 0.001), and fasting glucose (P = 0.045) and low-density lipoprotein (P = 0.049) in all patients and controls. The serum IL-10 level was significantly higher in patients than in controls (P = 0.033). The polymorphism was significantly associated with disease incidence and its biochemical manifestations.

Biochemical features of hepatic dysfunction in Nigerians with Sickle Cell Anaemia

This study seeks to document the biochemical manifestations of liver dysfunction in Nigerians with sickle cell anaemia with the aim of alerting physicians on the need to consider these changes in the overall management of the disease condition. Serum total proteins, albumin, bilirubin, alkaline phosphatase (ALP), alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels were estimated in 150 patients with sickle cell anaemia (HbSS) and 100 control (HbAA) subjects. The serum total proteins and albumin levels were found to fall within the reference intervals in both the HbSSpatients and the controls. However, the mean bilirubin (total and conjugated) levels and the activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were significantly higher (P<0.05) in the HbSSpatients than the control subjects. This study demonstrated elevated levels of serum bilirubin, ALP, ALT and AST in patients with sickle cell anaemia.

Biochemical Manifestation of HIV Lipodystrophy Syndrome

Highly active anti-retroviral therapy (HAART), including protease inhibitors (PI) have led to dramatic improvements in the quality and quantity of life in patients with acquired immunodeficiency syndrome (AIDS). However, a significant number of AIDS patients on HAART develop characteristic changes in body fat redistribution referred to as lipodystrophy syndrome (LDS). Features of LDS include hypertrophy in the neck fat pad (buffalo hump), increased fat in the abdominal region (protease paunch), gynecomastia and loss of fat in the mid-face and extremities. The aim of this paper is to review the current knowledge regarding this syndrome. This article reviews the published investigations on biochemical manifestation of HIV lipodystrophy syndrome. It is estimated that approximately 64% of patients treated with PI will experience this syndrome. Biochemically, these patients have increased triglycerides (Trig), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and extremely low high-density lipoprotein-cholesterol (HDL-C). It is hoped that awareness of this syndrome would aid in early diagnosis and better patient management, possibly leading to a lower incidence of cardiovascular complications among these patients.