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Stenosis or occlusion of central veins in hemodialysis patients is common, especially with previous intravascular catheter or device use. Superior vena cava (SVC) obstruction is emerging as a frequent chronic complication of central vein cannulation that not only jeopardizes the availability of vascular access for hemodialysis, but can become a life-threatening emergency. Clinical features of SVC syndrome can be subtle or dramatic, including facial swelling and shortness of breath, which require expeditious attention and intervention. The approach to SVC syndrome involves judicious use of imaging techniques to define the cause and location. Early management with endovascular intervention with angioplasty and stent placement is the usual first choice. The occlusion can often be recanalized using new techniques such as radiofrequency wire and then salvaged with stents, providing prompt resolution of symptoms. Limitations to interventions include requirement of cutting-edge equipment, expertise, expense, and the usually temporary nature of the resolution. Surgery is considered the treatment of last resort for refractory cases. SVC syndrome can be prevented by minimizing catheter and intravascular device use through early recognition of patients with chronic kidney disease, early referral for education about all choices for kidney replacement modalities, and early placement of arteriovenous access prior to the onset of dialysis therapy.

Introduction Chronic central venous catheters (CVC) for dialysis lose patency and deliver lower blood flow over time, often due to fibrous sheathing that covers the lumen tips. The CentrosFLO central venous catheter has a shape that directs the arterial and venous tips away from the walls of the vena cava and right atrium, making sheathing of the tips less likely. Methods A prospective, multicenter, single arm, non-controlled, observational study was conducted at eight sites in the United States. All consenting dialysis patients receiving CentrosFLO catheters through the right or left internal jugular veins were accepted in the study, as long as the catheter was expected to be used for 45 days and was not an over-the-wire replacement for a previous CVC. Data were automatically collected on initial and average dialysis blood flow rate and initial arterial and venous pressures, for up to 26 weeks of dialysis therapy. Findings 75 patients were enrolled. Kaplan-Meier analysis indicated that 87% of patients maintained blood flow rate over 300 mL/min throughout 26 weeks of follow-up. There was no decline in average dialysis blood flow rate and no significant change in hydraulic resistance of the arterial or venous lumens of the catheters during the study. Discussion The CentrosFLO catheter demonstrates long term patency with good flow rates on dialysis, which, by comparison with previous studies, shows a clinically significant improvement in blood flow rate vs. other catheters. Stable hydraulic resistance of the catheter lumens showed no evidence of tip encroachment by fibrous sheaths.

Over the past several years, many more isoforms for the same enzymes, specifically for 1-acylglycerol-3-phosphate O-acyltransferases (AGPATs), have been cloned and studied. In this review, we summarize their biochemical features and discuss their functional role.The most significant role of these AGPATs appeared from our observation of AGPAT2 in the biology of adipose tissue (adipocytes) in humans and mice. Other isoforms are shown to be implicated in lung, reproductive and cardiac muscle function and in the cause of cancer. In-vitro substrate specificities of these AGPATs also suggest the in-vivo role of these AGPATs in remodeling of several of the glycerophospholipids.Despite significant progress in understanding the role of these AGPATs, much is still to be discovered in terms of how each of these AGPATs function in the presence or absence of other AGPATs and what their functional role might be.

ObjectivesTraditionally, a gallbladder removed for presumed benign disease has been sent for histopathological examination (HPE), but this practice has been the subject of controversy. This study was undertaken to compare patients in whom gallbladder cancer (GBC) was diagnosed after cholecystectomy on HPE with GBC patients in whom the gallbladder was not sent for HPE and who therefore presented late with symptoms.MethodsA retrospective analysis of prospectively collected data for 170 GBC patients diagnosed after cholecystectomy was conducted. All patients presented to one centre during 2000–2011. These patients were divided into two groups based on the availability of histopathology reports: Group A included patients who presented early with HPE reports (n=93), and Group B comprised patients who presented late with symptoms and without HPE reports (n=77).ResultsThe median time to presentation in Group A was significantly lower than in Group B (29days vs. 152days; P

Loss-of-function mutations in 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 in humans and mice result in loss of both the white and brown adipose tissues from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue, or lipodystrophy, results in hyperinsulinemia, diabetes mellitus, and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and we studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2−/− mice. The in vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by overexpression of either AGPAT1 or AGPAT2 in Agpat2−/− mice failed to ameliorate the hepatic steatosis. From these studies, we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2−/− mice.

Hydatid disease of the liver is endemic in India and is a common health problem. Although various treatment options have been described ranging from pharmacotherapy to radiological interventions and surgical procedures (both conservative and radical), the best treatment option in an individual case continues to be debated. We did a retrospective analysis of patients with hydatid disease of the liver who were managed at our centre between January 2000 and December 2009. All cysts were classified as per the Gharbi’s classification. The various treatment options used to treat hydatid cysts of the liver included percutaneous aspiration, injection and reaspiration (PAIR) or PAIR with drainage (PAIR-D) and surgery (both conservative and radical). The immediate and long-term outcomes following such management were analysed. During the study period, 128 patients with hydatid cyst of the liver were managed with PAIR/PAIR-D (n = 52), radical/excisional surgery (n = 61) and conservative surgery (n = 33). In ten patients, the PAIR procedure was abandoned due to either bile or pultaceous material aspirated after the initial puncture and these patients subsequently underwent surgical management. The PAIR was unsuccessful in eight of the 42 patients in whom it was attempted and these subsequently underwent surgery. The mean intraoperative blood loss and the duration of surgery were comparable in patients who underwent either conservative or radical surgery (p = 0.35 and 0.19, respectively). Postoperative bile leaks and cavity abscesses were significantly higher in patients who underwent conservative surgery (p = 0.032 and p = 0.001, respectively). Five patients (one following a radical operation and four following a conservative surgery, p = 0.05) developed recurrence in a mean follow-up period of 28 months and these were managed medically. Several treatment options are available for the management of hydatid disease of the liver and the treatment modality chosen should be tailored to the individual patient. While percutaneous drainage (with PAIR/PAIR-D) is reserved for more favourable cases of type I and II cysts, the others are best managed surgically. Complete excision (cystopericstectomy or resection) of the hydatid cyst is the preferred approach and 61 of the 94 patients who were managed surgically were suitable for it. Although excisional surgery minimizes the risk of long-term recurrence and cavity-related complications, it may be hazardous in cysts located close to major biliovascular channels. In these cases (considering that it is benign disease), a drainage operation is preferable. Both conservative and radical surgery can be safely performed laparoscopically.

The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA). In this study, we show enzymatic properties, tissue distribution, and subcellular localization of human AGPAT3 and AGPAT5. In cells overexpressing these isoforms, the proteins were detected in the nuclear envelope and the endoplasmic reticulum. AGPAT5-GFP fusion protein was localized in the mitochondria of both Chinese hamster ovary and human epithelial cervical cancer cells. Using lysates of AD293 cells infected with AGPAT3 and AGPAT5 recombinant adenovirus, we show that AGPAT3 and AGPAT5 proteins have AGPAT activity. Both the isoforms have similar apparent V(max) of 6.35 and 2.42 nmol/min/mg protein, respectively, for similar LPA. The difference between the two isoforms is in their use of additional lysophospholipids. AGPAT3 shows significant esterification of lysophosphatidylinositol (LPI) in the presence of C20:4 fatty acid, whereas AGPAT5 demonstrates significant acyltransferase activity toward lysophosphatidylethanolamine (LPE) in the presence of C18:1 fatty acid. The AGPAT3 mRNA is ubiquitously expressed in human tissues with several-fold differences in the expression pattern compared with the closely related AGPAT4. In summary, we show that in the presence of different fatty acids, AGPAT3 and AGPAT5 prefer different lysophospholipids as acyl acceptors. More importantly, localization of overexpressed AGPAT5 (this study) as well as GPAT1 and 2 (previous studies) in mitochondria supports the idea that the mitochondria might be capable of synthesizing some of their own glycerophospholipids.

Background and Aim: Persistent infection with hepatitis B virus (HBV) is a major etiological risk factor for hepatocellular carcinoma (HCC). The host cellular components involved in the progression of the carcinoma are still unclear. In the present study we aimed to evaluate Ras mediated signaling in hepatocellular carcinoma with persistent HBV infection. Methods: To gain insight into the role of Ras mediated signaling in HBV mediated carcinogenesis we evaluated Ras functionality by mutation analysis, reverse transcription-polymerase chain reaction, immunohistochemistry (IHC), Ras-guanosine triphosphate bound functionality assay and Ras-mediated downstream signaling in a cohort of primary HCC tissues positive for HBV-DNA. Results: Mutation in codon 12 of K-ras appeared to be an uncommon event in the pathogenesis of HCC. We found unusually low levels of Ras expression in HCC compared with those with normal liver and chronic liver disease (cirrhosis and chronic hepatitis). Considerable heterogeneity was found with respect to Ras-mediated signaling events (pRaf, pMAPK and pAKT). The hepatoma cell line (Hep3B) with integrated HBV showed upregulation in expression and activation of Ras and its downstream signaling in comparison to HBV a negative cell line (HepG2). The contrasting result between the cell lines and primary tumors is worthy of note. Conclusions: The unusual finding on downregulation of Ras expression in primary HCC tumors in the present study together with tumor heterogeneity with respect to Ras-mediated signaling events prompts a new role of the wild type K-Ras as a possible growth suppressor and a stochastic model for progression of hepatic cancer.

We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called β5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.

Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the 'o' position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020GA (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020GA ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.

A 43-year-old woman presented with right upper abdominal pain, on and off for 3–4 years. One year prior to her presentation, a space-occupying lesion was found in the right lobe of the liver, which was suspected to be hemangioma, as the patient had history of combined oral contraceptive pill use for the last 15 years. On examination, she was thinly built and had pallor; abdominal examination revealed tender hepatomegaly 3 cm below the costal margin, smooth surface, sharp regular edge with left lobe enlargement, and no bruit. All routine biochemical and hematologic investigations were normal, except hemoglobin of 7.6 gm/dl. On triple-phase CT scan, there were hypodense ill-defined lobulated area in right lobe of liver; similar lesions were also seen in segments V and VII of liver along with a few sub-diaphragmatic and para-aortic nodes. Liver biopsy showed features suggestive of hemangioendothelioma, and immunohistochemistry showed CD 31 and CD 34 positivity but negative for estrogen receptors. Laparoscopy revealed presence of multiple deposits on left lobe of liver and ascites. Tumor was unresectable, and the patient was found to be a candidate for liver transplant. Chemoembolization was tried as a palliation awaiting transplant, but the procedure was unsuccessful due to the hypovascular nature of the tumor. The patient died within 4 months of diagnosis due to liver failure, awaiting liver transplant, as a suitable donor was not available. A clinical suspicion based on demographics, risk factors and imaging, familiarity with the pathologic findings, and utilization of advanced imaging techniques may allow early diagnosis of these tumors and hence their appropriate management.

The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARgamma and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation.

Anemia of chronic kidney disease due to deficiency of erythropoietin is common and has clinical consequences. Erythropoiesis stimulating agents including darbepoetin alfa (DA) are effective in correcting anemia. DA is generally well tolerated and has side effect profile similar to recombinant human erythropoietin. It has a long half-life permitting infrequent dosing. DA has been tested extensively in preclinical and clinical studies and significant experience has accumulated in clinical practice. Global safety profile of DA must consider recent data indicating worse survival, poor cardiovascular outcomes and thrombotic risks of targeting near normal hemoglobin levels and administering high doses of erythropoiesis stimulating agents. Strategies to achieve and maintain a reasonable, individualized target hemoglobin level with minimal variations in hemoglobin level are needed.

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

Congenital generalized lipodystrophy (CGL) is a rare auto-somal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth, acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia, dyslipidemia, and insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with CGL3. They also had generalized muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.

Background Splenic vein thrombosis leading to sinistral portal hypertension and variceal bleeding is a complication of chronic pancreatitis. The management of these patients without variceal bleeding remains controversial. Methods A total of 157 patients with chronic pancreatitis were managed consecutively in our center between January 1996 and December 2005. Thirty-four patients with chronic pancreatitis were diagnosed to have splenic vein thrombosis. Results The incidence of splenic vein thrombosis in patients with chronic pancreatitis was 22%. Fifteen percent of patients with chronic pancreatitis and splenic vein thrombosis presented with gastroesophageal variceal bleeding. Nine patients underwent splenectomy along with pancreatic procedures and 21 patients underwent pancreatic procedures only. Adding splenectomy to the pancreatic procedure did not lead to increased morbidity or mortality. Conclusion Splenectomy should be added to the pancreatic procedure in patients who have evidence of portal hypertension on preoperative evaluation, especially if gastric varices are found.

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract. Though traditionally considered to be an aggressive disease with rapid progression and dismal outcome, several recent reports have suggested that aggressive surgical resection improves survival. Adenocarcinoma is the most common histological type; squamous cell carcinoma, adenosquamous carcinoma, neuroendocrine carcinoma, and carcinosarcoma are the rare histological variants. According to the recent AJCC/UICC TNM staging system, T1 and T2 GBC includes patients with carcinoma limited to the mucosa (T1a) or muscularis proper (T1b) or invading the perimuscular connective tissue (T2) without liver infiltration. T1a tumors are difficult to diagnose preoperatively and are usually diagnosed after histopathology of the cholecystectomy specimen. Simple cholecystectomy is sufficient for cure in these patients, provided that the cystic duct margin is free of tumor and there is no intraoperative bile spillage. According to the National Comprehensive Cancer Network (NCCN) guidelines, a radical cholecystectomy is recommended for patients with a lesion T1b and beyond.

Patients with advanced chronic kidney disease are at a high risk of cardiovascular events. Patients with end-stage renal disease have a particularly high morbidity and mortality, in part attributed to the complications and dysfunction related to vascular access in this population. Creation of an arteriovenous access for HD is considered standard of care for most patients and has distinct advantages including less likelihood of infections, less need for intervention, and positive impact on survival as compared with usage of a catheter. However, creation of an arteriovenous shunt incites a series of events that significantly impacts cardiovascular and neurohormonal health in both positive and negative ways. This article will review the short- and long-term effects of dialysis access on cardiovascular, neurohormonal, and pulmonary systems as well as a brief review of their effect on survival on HD. Presence of other comorbidities in a patient with dialysis access can amplify these effects, and these considerations are of paramount importance in individualizing the approach to not only the choice of vascular access but also the modality of kidney replacement therapy.

Background: Idiopathic, benign, non-traumatic, non-inflammatory strictures of bile ducts are rare. We report cases with benign non-traumatic, non-inflammatory strictures of bile ducts diagnosed on histopathology of endoscopic tissue specimens and managed with endoscopic therapy. Methods: Eight patients with benign non-traumatic, non-inflammatory strictures of bile ducts were studied. Diagnosis of benign stricture was based on imaging studies (ultrasound and CT scanning), normal CA 19–9 levels, negative brush cytology and histopathology, endoscopic retrograde cholangiopancreatography (ERCP) and no evidence of malignancy on follow up. Endoscopic balloon dilatation of stricture was performed and biliary stent was placed. Results: Median age was 42 years and five patients were males. Clinical presentation included jaundice (5), abdominal pain (7), fever (2) and pruritus (6). Liver function tests and imaging studies revealed features of obstructive jaundice. ERCP revealed smooth concentric and tapering stricture in all patients. Brush cytology and histopathological specimen revealed cubocolumnar epithelium surrounded by fibrous tissue without inflammation and negative for malignant cells. All patients got relief of fever, jaundice, pain and pruritus after balloon dilatation and stenting. Symptoms completely resolved in a median of 24 days. Liver function tests normalized in a median of 36 days. Follow up ERCP after 6 months did not show evidence of stricture and stent could be removed successfully in all patients. Thereafter, for a median follow up of 19 months, patients remained asymptomatic and their liver function tests and ultrasound were normal. Conclusions: Benign strictures of extrahepatic bile ducts can be non-traumatic and non-inflammatory without any cause and can be managed successfully with endoscopic balloon dilatation and biliary stenting.

Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A. Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24, causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A. Whereas the loss of function mutation of ZMPSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.

We present an anatomic variation of type IIIA thumb hypoplasia in which a tendinous interconnection between the flexor pollicis longus and the extensor pollicis longus occurred on the ulnar aspect of the thumb. Interconnection between extrinsic flexor and extensor systems is well known in type IIIA thumb hypoplasia and has been reported on the radial side (pollex abductus). In our patient the ulnar location of the interconnection remained unrecognized until recurrence of the deformity in adolescence.

Selective loss of body fat is the hallmark of patients with lipodystrophies. Among genetic lipodystrophies, fat loss is observed either from birth, as in congenital generalized lipodystrophy, or later in life, as in familial partial lipodystrophy. The extent of fat loss also varies among subtypes of lipodystrophies. Patients develop hyperinsulinemia, acanthosis nigricans, hypertriglyceridemia, diabetes mellitus, and hepatic steatosis. Defects in several genes, such as those encoding an enzyme (AGPAT2), a nuclear receptor (PPARγ), a nuclear lamina protein (LMNA) and its processing endoprotease (ZMPSTE24), a kinase (AKT2), and a protein of unknown function (BSCL2), have been found in patients with genetic lipodystrophies. Additional loci remain to be discovered. We discuss features of autosomal recessive and dominant types of lipodystrophies and therapeutic interventions available for these patients.

Context:A heterozygous missense mutation substituting arginine at position 133 to leucine in the lamin A/C protein has been reported in two young women with clinical features of short stature, bird-like faces, and early onset of aging processes. Objective: The objective of the study was to carry out detailed phenotyping of these two women by evaluating the pattern of fat loss using anthropometry, dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI) and study metabolic abnormalities in glucose and lipid metabolism. Design: The study consisted of descriptive case reports. Setting: The study was conducted at a referral center. Patients: Patient 1 was a 23-yr-old African-American female with progeroid features. Patient 2 was a 24-yr-old Caucasian female with generalized lipodystrophy, hypertriglyceridemia, and severe insulin resistance diabetes who required more than 200 U of insulin daily. Interventions: There were no interventions. Main Outcome Measures: Body fat distribution to characterize pattern of lipodystrophy and nuclear morphology abnormalities in skin fibroblasts were studied. Results: Patient 1 had normal body fat (27%) by DEXA. However, MRI revealed relative paucity of sc fat in the distal extremities, with preservation of sc truncal fat. She had impaired glucose tolerance and elevatedpostprandialseruminsulinlevels.Patient2,incontrast,had only 11.6% body fat as determined by DEXA and had generalized loss of sc and intraabdominal fat on MRI. Skin fibroblasts from patient 2 showed marked abnormal nuclear morphology, compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope, and the nuclear DNA remained within the nucleus. Conclusions: Atypical Werner’s syndrome associated with Arg133Leu mutation in the LMNA gene presents with a phenotypically heterogeneous disorder. Furthermore, the severity of metabolic complications seems to correlate with the extent of lipodystrophy. (J Clin Endocrinol Metab 90: 6699–6706, 2005)

Hydroxysteroid dehydrogenases (HSDs) interconvert potent and relatively inactive forms of individual steroid hormones using nicotinamide cofactors NADPH/NADP+ and NADH/NAD+ [nicotinamide adenine dinucleotide (phosphate), reduced/oxidized forms]. Although reactions with purified enzymes in vitro may be driven in either direction depending on the assay conditions, HSD enzymes appear to function in one direction or the other in intact cells. At least for some of these enzymes, however, the apparent unidirectional metabolism actually reflects bidirectional catalysis that reaches a pseudoequilibrium state with a strong directional preference. This directional preference, in turn, derives from intracellular concentration gradients for the nicotinamide cofactors and the relative affinities of each HSD for these cofactors. Because the concentrations of free cofactor exceed those of steroids by many orders of magnitude, the activities of these enzymes are predominantly driven by cofactor abundance, which is linked to intermediary metabolism. Consequently, the amount of active steroids in cells containing HSDs may be modulated by cofactor abundance and, hence, intracellular redox state. We will review the evidence linking cofactor handling and HSD activity, speculate on additional ways that intracellular metabolism can alter HSD activity and, thus, hormone potency, and discuss fruitful avenues of further investigation.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Recently, mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) genes were reported in pedigrees linked to chromosomes 9q34 and 11q13, respectively. There are limited data regarding phenotypic differences between the various subtypes of CGL. Furthermore, whether there are additional loci for CGL remains unknown. Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes. Twenty-six pedigrees harbored mutations, including seven novel variants, in the AGPAT2 gene, and 11 pedigrees harbored mutations in the BSCL2 gene, including five novel variants. Eight pedigrees had no substantial alterations in either gene. Of these, three informative pedigrees showed no linkage to markers spanning the AGPAT2 and BSCL2 loci, and in six of the affected subjects, the transcripts of AGPAT2 and BSCL2 were normal. All subtypes of CGL showed high prevalence of diabetes, hypertriglyceridemia, and acanthosis nigricans. However, patients with BSCL2 mutations had lower serum leptin levels, an earlier onset of diabetes, and higher prevalence of mild mental retardation compared with other subtypes. We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity.

Mandibuloacral dysplasia (MAD; OMIM 248370) is a rare, genetically and phenotypically heterogeneous, autosomal recessive disorder characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis, cutaneous atrophy and lipodystrophy. A homozygous missense mutation, Arg527His, in the LMNA gene which encodes nuclear lamina proteins lamins A and C has been reported in patients with MAD and partial lipodystrophy. We studied four patients with MAD who had no mutations in the LMNA gene. We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy. ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A in two steps to form mature lamin A. Deficiency of Zmpste24 in mice causes accumulation of prelamin A and phenotypic features similar to MAD. The yeast homolog, Ste24, has a parallel role in processing of prenylated mating pheromone a-factor. Since human ZMPSTE24 can also process a-factor when expressed in yeast, we assessed the functional significance of the two ZMPSTE24 mutations in the yeast to complement the mating defect of the haploid MATa yeast lacking STE24 and Ras-converting enzyme 1 (RCE1; another prenylprotein-specific endoprotease) genes. The ZMPSTE24 mutant construct, Phe361fsX379, was inactive in complementing the yeast a-factor but the mutant, Trp340Arg, was partially active compared to the wild type ZMPSTE24 construct. We conclude that mutations in ZMPSTE24 may cause MAD by affecting prelamin A processing.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes.

OBJECTIVES—Familial partial lipodystrophy, Dunnigan variety (FPLD), is an autosomal dominant disorder due to missense mutations in the lamin A/C (LMNA) gene encoding nuclear lamina proteins. It is characterized by loss of subcutaneous fat from the extremities and trunk and accumulation of fat in the head and neck region beginning at puberty. Patients with FPLD are predisposed to metabolic complications of insulin resistance such as diabetes. We sought to identify risk factors for diabetes in patients with FPLD. RESEARCH DESIGN AND METHODS—A cross-sectional study comparing clinical, biochemical, and anthropometric variables and LMNA genotypes in FPLD patients with and without diabetes. RESULTS—We studied 52 women and 24 men with FPLD from 18 different families. Twenty-eight women (54%) but only four men (17%) had diabetes (P < 0.001); therefore further comparisons were mostly limited to women. Compared with women without diabetes, those with diabetes had higher BMI (median values 23 vs. 24 kg/m2, respectively; P = 0.03), increased chin skinfold thickness (10 vs. 20 mm; P = 0.001), lower rates of nulliparity (60% vs. 28%; P = 0.04), and higher levels of fasting serum triglycerides (2.4 vs. 3.5 mmol/l; P < 0.001) but similar serum leptin levels (3.4 vs. 3.6 ng/ml; P = 0.9). The prevalence of diabetes was not related to age, menopausal status, family history of type 2 diabetes in unaffected relatives, or LMNA genotype. CONCLUSIONS—We conclude that increased adiposity as reflected by excess subcutaneous fat accumulation in the chin region and parity may predispose women with FPLD to develop diabetes.

UNLABELLED Pain syndromes of Guillain-Barre are neuropathic as well as nociceptive in origin. We aimed to evaluate the therapeutic efficacy of gabapentin in relieving the bimodal nature of pain in Guillain-Barre syndrome in a randomized, double-blinded, placebo-controlled, crossover study in 18 patients admitted to the intensive care unit for ventilatory support. Patients were assigned to receive either gabapentin (15 mg. kg(-1). d(-1) in 3 divided doses) or matching placebo as initial medication for 7 days. After a 2-day washout period, those who previously received gabapentin received placebo, and those previously receiving placebo received gabapentin as in the initial phase. Fentanyl 2 micro g/kg was used as a rescue analgesic on patient demand or when the pain score was >5 on a numeric rating scale of 0-10. The numeric rating score, sedation score, consumption of fentanyl, and adverse effects were noted, and these observed variables were compared. The numeric pain score decreased from 7.22 +/- 0.83 to 2.33 +/- 1.67 on the second day after initiation of gabapentin therapy and remained low during the period of gabapentin therapy (2.06 +/- 0.63) (P < 0.001). There was a significant decrease in the need for fentanyl from Day 1 to Day 7 during the gabapentin therapy period (211.11 +/- 21.39 to 65.53 +/- 16.17 [ micro g]) in comparison to the placebo therapy period (319.44 +/- 25.08 to 316.67 +/- 24.25 [ micro g]) (P < 0.001). IMPLICATIONS Gabapentin, an antiepileptic drug, has been used effectively for different types of pain management. This study demonstrates that gabapentin has minimal side effects and is an alternative to opioids and nonsteroidal antiinflammatory drugs for management of the bimodal nature of pain of Guillain-Barre Syndrome patients.

Presence of portal hypertension (PH) adversely affects perioperative and long-term outcome in patients with post-cholecystectomy benign biliary stricture (PCBBS). Identification of factors related to the development of PH will help to prevent this complication.From September 2010 to December 2012, 30 patients with PCBBS were studied prospectively for correlation of portal pressure (PP) with injury repair interval (IRI), biliary pressure (BP), severity of hepatic fibrosis (FS), severity of hepatic inflammation (IS) and obstructive biliary pathology score (OBPS). Appropriate statistical methods employed and P ≤ 0.05 (two-sided) was considered statistically significant.Mean PP, mean BP and median IRI were 19.4 ± 4.74 mmHg, 20.1 ± 3.99 mmHg and 145 days, respectively. Spearman's rank correlation coefficients (P-value) of PP with IRI, FS, IS and OBPS were 0.564 (0.001), 0.502 (0.004), 0.752 (0.0001) and 0.242 (0.19), respectively. Pearson correlation of PP with BP was r = 0.383 (r(2) = 0.146, P = 0.03). Spearman's rank correlation coefficients (P-value) of FS with IS and OBPS were 0.561 (0.003) and 0.371 (0.04), respectively. Spearman's rank correlation coefficient of serum bilirubin with OBPS was 0.550 (P = 0.001). Incidence of PH was 33.3% and mean fall of PP following biliary repair was 6.2 ± 1.98 mmHg (P 0.0001).PP in patients with PCBBS has a good correlation with IS, and a fair correlation with both FS and IRI whereas PP was not directly related to BP and OBPS; further prospective trials are mandatory to confirm this correlation, and to evaluate mechanism of fall in PP following biliary decompression.

Lipodystrophy, a disease characterized by lack of adipose tissue, is either due to genetic defects or acquired. Genetic lipodystrophies are inherited both in an autosomal dominant or recessive fashion. Several genetic loci have been identified affecting differentiation of adipose tissue or lipid storage. Although it appears counterintuitive, lack of adipose tissue results in the same clinical burden seen in subjects with obesity, chiefly, insulin resistance, hypertriglyceridemia, fatty liver, and diabetes. This implies a role for adipose tissue at the center of energy homeostasis. Study of human lipodystrophies has provided a rich trove of genetic loci which affect adipogenesis and/or lipid storage (adipose tissue dysregulation) as illustrated by mutations in AGPAT2, BSCL2, LMNA, or ZMPSTE24 genes. Thus, identifying additional genetic loci in patients with lipodystrophies will continue to be a rich source of biological material to study loss of both white and brown adipose tissues. In this review I discuss the recent findings which have occurred over the last 5 years.

Background: In endemic areas, gallbladder cancer (GBC) and tuberculosis may coexist. This study aimed to ascertain the impact of coexistent tuberculosis on the management of patients with GBC. Methods: Data of patients with proven GBC with coexistent tuberculosis managed at our centre between January 2003 and December 2007 were analysed from a prospective gallbladder cancer database to highlight the management issues and ascertain the impact that coexistent tuberculosis had on the outcome in these patients. Results: Of the 340 patients of GBC evaluated at our centre, 7 patients had concomitant tuberculosis and constituted the study group. All the patients were women (mean age 56.3 years). The commonest presenting symptoms were abdominal pain, decreased appetite and significant weight loss. Two patients were found to have tuberculosis on preoperative evaluation on a fine-needle aspiration cytology from the left supraclavicular lymph nodes; 3 patients were detected intraoperatively (1 had peritoneal tuberculosis on staging laparoscopy and 2 had tubercular lymphadenitis on interaortocaval lymph node sampling) and 2 were detected postoperatively with histopathological examination showing GBC with tubercular lymphadenitis of the hepatoduodenal lymph nodes. Six of these 7 patients underwent surgery with curative intent and 1 underwent a surgical bypass. Conclusion: Five of the 7 patients of GBC with coexistent tuberculosis could have been denied the chance of curative surgery had a preoperative/intraoperative biopsy confirmation not been done. Thus, histopathological confirmation is mandatory before labelling a cancer as metastatic and denying the patient a chance for cure.

Background Although thought to have common immunopathological processes, concomitant occurrence of allergic bronchopulmonary aspergillosis (ABPA) and allergic Aspergillus sinusitis (AAS) appears to be rarely reported as to date only five detailed case reports are available. Objective To present a review of seven cases of concomitant ABPA and AAS, three of whom were earlier reported for their unusual presentations. Methods Patients with ABPA with nasal symptoms were evaluated radiologically. Consent was taken for antral wash and/or Caldwell-Luc operation in those with radiological evidence of sinusitis and the material was sent for histopathological and mycological studies. Results Of the 95 patients with ABPA, 22 had radiological evidence of sinusitis. Nine consented to surgery, seven of whom were diagnosed as concomitant AAS. Nasal symptoms preceded chest symptoms in two patients, vice versa in one and occurred simultaneously in four. Familial occurrence of ABPA, middle lobe syndrome and collapse with effusion along with an operated aspergilloma were seen in one patient each. Transient pulmonary infiltrates and central bronchiectasis were seen in all patients. Computed tomography of the paranasal sinuses, carried out in six patients, revealed mucosal thickening with hyperdense lesions, without any bony erosion or destruction. All patients had positive skin tests, positive precipitin study and raised total and specific IgE. Allergic mucin was seen in all patients, fungal hyphae in five, and culture grew Aspergillus spp. in four. All patients responded favourably to oral prednisolone. Conclusion Concomitant occurrence of ABPA and AAS seems to be infrequently recognized. Since asthma and sinusitis are often seen by two different specialities, the occurrence of AAS in ABPA and ABPA in AAS may easily be overlooked.

OBJECTIVE The HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11β-hydroxysteroid dehydrogenase is mutated in the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of salt-sensitive hypertension. This gene is thus a logical candidate locus for risk of essential hypertension. DESIGN AND METHODS Because hypertension in Black people tends to be of the low-renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro-American (59 kindreds) and Afro-Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0·84) CA repeat polymorphism in the first intron of HSD11B2. Linkage was assessed by the affected pedigree member method. RESULTS No linkage of hypertension to this locus could be demonstrated, but statistically significant allelic associations were noted. CONCLUSIONSHSD11B2 does not have a strong influence on the development of essential hypertension in Black people, but weaker effects on blood pressure cannot be ruled out.

Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with a homozygous null mutation in ZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near-normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed a lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from a single RD patient's fibroblasts also suggest that prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype.

Alternating purine-pyrimidine (APP) sequences which might assume left handed DNA helical structures (Z-DNA) could influence the expression of genes in which they were located. There are two such repeat elements in the HSD11B2 (11beta-hydroxysteroid dehydrogenase) gene. First, a CA repeat is located in the first intron. Deletion of this element in a minigene construct leads to a significant decrease (40%) in the expression of the HSD11B2 message in human cortical collecting duct cells. The second APP tract is located approximately 0.9 kb from the last exon or 4.8 kb from the intronic CA repeat element. Deleting this APP tract in a minigene decreases gene expression by 30%. The CA repeat along with its flanking sequences increases luciferase reporter gene expression if placed 5' of the HSD11B2 promoter but not when placed downstream of the reporter gene. Similarly the second APP tract increases luciferase reporter gene expression when placed 5' of the HSD11B2 promoter in an antisense orientation but not in a sense orientation. These results suggests that these dinucleotide repeats influence expression of the HSD11B2 gene in a manner dependent on position and orientation.

The HSD11B2 and VPATPD genes encoding the human kidney isozyme of 11β-hydroxysteroid dehydrogenase (11-HSD2) and subunit D of the vacuolar proton ATPase, respectively, are located on chromosome 16q22. They are transcribed from complementary DNA strands and their 3′ ends are only 0.5 kilobase apart. Because polymorphisms in HSD11B2 have been associated with hypertension and salt sensitivity, we characterized the human VPATPD gene. It spans 19 kb and consists of 8 exons. The encoded protein is 99.5% identical to mouse subunit D at the amino acid level. An alternating purine-pyrimidine tract is located in the 3′-untranslated region of VPATPD. On genotyping 17 hypertensive subjects, no length polymorphism was found. Although VPATPD and HSD11B2 are both expressed in kidney and placenta, they are regulated differently; forskolin upregulates HSD11B2 but not VPATPD in human choriocarcinoma JEG3 cells. The functional significance of the proximity of these two genes remains to be established.

The melanocortin-4 receptor (MC4R) is part of an important pathway regulating energy balance. Here we report the existence of autoantibodies (autoAbs) against the MC4R in sera of obese patients.The autoAbs were detected after screening of 216 patients' sera by using direct and inhibition ELISA with an N-terminal sequence of the MC4R. Binding to the native MC4R was evaluated by flow cytometry, and pharmacological effects were evaluated by measuring adenylyl cyclase activity.Positive results in all tests were obtained in patients with overweight or obesity (prevalence, 3.6%) but not in normal weight patients. The selective binding properties of anti-MC4R autoAbs were confirmed by surface plasmon resonance and by immunoprecipitation with the native MC4R. Finally, it was demonstrated that these autoAbs increased food intake in rats after passive transfer via intracerebroventricular injection.These observations suggest that inhibitory anti-MC4R autoAbs might contribute to the development of obesity in a small subpopulation of patients.

Whereas aldosterone is normally a much stronger mineralocorticoid than cortisol in vivo, mineralocorticoid receptors have identical in vitro affinities for these hormones. The in vivo specificity of the receptors is, at least in part, the result of activity of 11-HSD, an enzyme located in most mineralocorticoid target tissues that converts cortisol to cortisone. Cortisone is not a ligand for the receptor, whereas aldosterone is not a substrate of the enzyme. The syndrome of AME is a rare form of juvenile hypertension in which 11-HSD is defective. This deficiency allows mineralocorticoid receptors to be occupied by cortisol, leading to hypertension, because plasma concentrations of cortisol are much higher than those of aldosterone. Licorice, which contains 11-HSD inhibitors, causes a similar syndrome. There are two known isozymes of 11-HSD. The liver or type I isozyme is expressed at high levels in the liver, has a relatively low affinity for steroids (micromolar Km), catalyzes both dehydrogenation and the reverse reductase reaction, and utilizes NADP+ or NADPH as cofactors. The kidney or type 2 isozyme is expressed at high levels in the kidney and placenta, has a high affinity (nanomolar Km) for steroids, catalyzes only dehydrogenation, and utilizes NAD+ as a cofactor. Mutations in the HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11-HSD have been detected in all kindreds with AME studied thus far. This gene represents a candidate locus for the common, "essential" form of hypertension.

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal tubules and cortical collecting ducts, where it acts to increase sodium resorption from and potassium excretion into the urine. Excess secretion of aldosterone or other mineralocorticoids, or abnormal sensitivity to mineralocorticoids, may results in hypokalemia, suppressed plasma renin activity, and hypertension. The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. Because mineralocorticoid receptors themselves have similar affinities for cortisol and aldosterone, it is hypothesized that the deficiency allows these receptors to be occupied by cortisol, which normally circulates at levels far higher than those of aldosterone. We cloned cDNA and genes encoding two isozymes of 11 beta-HSD. The liver (L) or type 1 isozyme has relatively low affinity for steroids, is expressed at high levels in the liver but poorly in the kidney, and is not defective in AME. The kidney (K) or type 2 isozyme has high steroid affinity and is expressed at high levels in the kidney and placenta. Mutations in the gene for the latter isozyme have been detected in all kindreds with AME. Moreover, the in vitro enzymatic activity conferred by each mutation is strongly correlated with the ratio of cortisol to cortisone metabolites in the urine [tetrahydrocortisone (THF) +allo-THF]/THE. This suggests that the biochemical phenotype of AME is largely determined by genotype.

The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11β-hydroxysteroid dehydrogenase (11-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. The deficiency allows mineralocorticoid receptors to be occupied by cortisol, because these receptors themselves have similar affinities for cortisol and aldosterone. There are two isozymes of 11-HSD, a liver (L) or type 1 isozyme with a relatively low affinity for steroids, and a kidney (K) or type 2 isozyme with high steroid affinity. Mutations in the gene for the kidney isozyme of 11-HSD have been detected in all kindreds with AME. We expressed enzymes carrying all known missense mutations in cultured cells and determined their activity. For each patient with AME, we compared the enzymatic activity predicted by the genotype with the ratio of cortisol to cortisone metabolites in the urine, (THF + aTHF) THE . These were strongly correlated, suggesting that the biochemical phenotype of AME is largely determined by genotype. The K isozyme of 11-HSD is also expressed in high levels in the placenta, where its function is unclear. AME patients often have low birth weight. By analogy with AME, low placental 11-HSD K activity in humans might be a risk factor for low birth weight and subsequent hypertension. However, we found that there was no significant correlation between 11-HSD activity, mRNA levels, and either fetal or placental weight.

This study was conducted to determine the occurrence of menstrual-linked asthma (MLA) in India in 100 consecutive female asthmatics in the reproductive age group. The patients were required to respond to a questionnaire concerning the relationship between their asthma and the menstrual cycle. Twenty-three patients had subjective perception of deterioration in symptoms of asthma in relation to the menstrual cycle. Ten patients from both groups were also required to maintain a daily peak expiratory flow rate (PEFR) diary for 2 consecutive menstrual cycles. The mean total duration of illness in patients with MLA was significantly longer than in patients without cyclic exacerbation. Cough and breathlessness were also significantly more severe as was the disease. This was evidenced by the more frequent emergency room visits and hospitalizations in these patients. Menstrual-linked worsening of asthma was most common in the premenstrual week (17 patients), in 8 of these 17 patients, this phenomenon continued to occur during the menstrual week also. Interestingly, 1 patient complained of deterioration of asthma 2 days after menstruation was over. Such an observation is yet to be recorded. Fourteen patients reported an increase in symptoms with almost every cycle while 3 had worsening related to specific season only. Sixteen patients often required extra medication during the premenstrual and/or menstrual weeks. A significant association was also observed between severity of premenstrual syndrome and MLA. The mean PEFR values over 2 cycles revealed a significant fall in the morning as well as evening values in the premenstrual and menstrual weeks as compared to the midcycle week in patients with MLA. This fall was maximal in the premenstrual week. Such a fall was not observed in asthmatics without menstrual exacerbation of symptoms. MLA was detected in about a fourth of the female asthmatics in India and it appears to represent a more severe form of the disease. This study also documented that MLA was associated with an increase in airway resistance and was not simply due to an increased perception of symptoms during the premenstrual or menstrual weeks.

Acute decompensated heart failure (ADHF) with associated volume overload is the most common cause of hospitalization in heart failure patients. When accompanied by worsening renal function, it is described as a cardiorenal syndrome and is a therapeutic challenge. Initial treatment commonly encompasses intravenous diuretics however, suboptimal results and high rehospitalization rates have led experts to search for alternative therapeutic strategies. Recent technological advances in extracorporeal therapies have made ultrafiltration a feasible option for treatment of hypervolemia in ADHF. Recent large randomized trials have compared the efficacy and safety of ultrafiltration with diuretics. Additionally, the benefits of novel pharmacologic approaches, including combining hypertonic saline with diuretics, have recently been studied. The aim of this review is to discuss the developments in both pharmacologic and extracorporeal methods for treating hypervolemia in ADHF and acute cardiorenal syndrome.