Complicated polycystic liver disease with intracystic hemorrhage and obstructive jaundice

Polycystic liver disease, which is generally part of the autosomal dominant polycystic kidney disease, is often asymptomatic. We report a case of obstructive jaundice caused by compression of the biliary tract by a large haemorrhagic liver cyst. The patient was a man with sporadic polycystic liver disease without polycystic kidney disease and with normal renal function for his age. Ultrasound combined with cholangio-MRI provided non-invasive confirmation of intracystic bleeding and intrahepatic biliary dilatation. Obstructive jaundice was confirmed by cyst puncture-aspiration which resolved symptoms and normalized biology. The initial treatment of haemorrhagic liver cyst complicating polycystic liver disease must be medical with cyst aspiration-drainage and sclerotherapy to avoid surgery in these fragile patients.     

Intervertebral disc disorganization is related to trabecular bone architecture in the lumbar spine.

Cancellous bone morphometry was investigated in the sagittal plane of lumbar vertebrae using histoquantitation. The aim of this study was to identify variations in cancellous bone architecture at increasing states of intervertebral disc (IVD) disorganization after age adjustment and to investigate regional variations within the whole vertebral body. Measurements were taken of the ratio of bone volume (BV) to total volume (TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and trabecular number (Tb.N). Lumbar spines (T12-L5) of 19 men and 8 women were removed at autopsy from an adult sample with no clinical history of bone-related disease or histologically identifiable bone disease. It was found that degeneration of the IVD becomes more common with increasing age. After age-adjustment, significant increases in the proportion of BV/TV were observed in the presence of advancing IVD disorganization. Significant architectural changes were observed in the anterior regions of the vertebral body with increases in Tb.Th and Tb.N and decreases in Tb.Sp. Minimal alterations were found at posterior regions. Bone loss was observed in central regions (most distant from the cortex) as IVD disorganization increased through reduction in both Tb.N and Tb.Th. The BV/TV increase in anterior areas of the centrum may be a response to a redistribution of load to the vertebral body periphery as a result of IVD disorganization. It appears that trabecular morphology is related to the condition of the associated IVD, rather than being the sole consequence of a loss of BV/TV with age. This relationship could influence the occurrence of vertebral body crush fracture.     

The JNK inhibitor D-JNKI-1 blocks apoptotic JNK signaling in brain mitochondria

Kainic acid (KA) induced seizures provokes an extensive neuronal degeneration initiated by c-Jun N-terminal kinases (JNK) as central mediators of excitotoxicity. However, the actions of their individual isoforms in cellular organelles including mitochondria remain to be elucidated. Here, we have studied the activation of JNK1, JNK2 and JNK3 and their activators, mitogen-activated protein kinase kinase (MKK) 4/7, in brain mitochondria, cytosolic and nuclear fractions after KA seizures. In the mitochondrial fraction, KA significantly increased the presence of JNK1, JNK3 and MKK4 and stimulated their phosphorylation i.e. activation. The pro-apoptotic proteins, Bim and Bax were induced and, consequently, the ratio Bcl-2-Bax decreased. These changes were paralleled by the release of cytochrome c and cleavage of poly(ADP-ribose)-polymerase (PARP).The JNK peptide inhibitor, D-JNKI-1 (XG-102) reversed these pathological events in the mitochondria and almost completely abolished cytochrome c release and PARP cleavage. Importantly, JNK3, but not JNK1 or JNK2, was associated with Bim in mitochondria and D-JNKI-1 prevented the formation of this apoptotic complex.Apart from of the attenuation of c-Jun phosphorylation in the nucleus, D-JNKI-1 did not affect the level of JNK3 isoform in the nuclear and cytosolic fractions. These findings provide novel insights into the mode of action of individual JNK isoforms in cell organelles and points to the JNK3 pool in mitochondria as a target of the JNK inhibitor D-JNKI-1 to confer neuroprotection.     

Perspectives on hand function in girls and women with Rett syndrome

Objective: Rett syndrome is a rare neurodevelopmental disorder that is usually associated with a mutation on the X-linked MECP2 gene. Hand function is particularly affected and we discuss theoretical and practical perspectives for optimising hand function in Rett syndrome.

Methods: We reviewed the literature pertaining to hand function and stereotypies in Rett syndrome and developed a toolkit for their assessment and treatment.

Results: There is little published information on management of hand function in Rett syndrome. We suggest assessment and treatment strategies based on available literature, clinical experience and grounded in theories of motor control and motor learning.

Conclusion: Additional studies are needed to determine the best treatments for hand function in Rett syndrome. Meanwhile, clinical needs can be addressed by supplementing the evidence base with an understanding of the complexities of Rett syndrome, clinical experience, environmental enrichment animal studies and theories of motor control and motor learning.     

Identification of the Human P-450 Enzymes Responsible for the Sulfoxidation and Thiono-Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P-450 Enzymes in Disulfiram Bioactivation

Diethyldithiocarbamate methyl ester (DDTC-Me) is a precursor to the formation of S-methyl-N,N-diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P-450 (CYP) enzymes in sulfoxidation and thiono-oxidation of DDTC-Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P-450 enzyme(s) involved in the sulfoxidation and thiono-oxidation of DDTC-Me. These approaches included the use of cDNA-expressed human P-450 enzymes, correlation analysis with sample-to-sample variation in human P-450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P-450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC-Me, as determined with cDNA-expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC-Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC-Me sulfoxidation and testosterone 6β-hydroxylation; (2) increased DDTC-Me sulfoxidation in the presence of α-naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC-Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono-oxidation of DDTC-Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA-expressed enzymes; (2) a high correlation between DDTC-Me thiono-oxidation and testosterone 6β-hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti-CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC-Me thiono-oxidation by furafylline and anti-CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC-Me thiono-oxidation by DDTC and anti-CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC-Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC-Me thiono-oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.     

Immunologic response to Haemophilus influenzae type b (Hib) conjugate vaccine and risk factors for carriage among Hib carriers and noncarriers in Southwestern Alaska

Continued Haemophilus influenzae type b (Hib) carriage in rural Alaska contributes to the ongoing risk of invasive disease. Community-wide Hib carriage surveys were conducted in three villages in southwestern Alaska. Sixteen carriers and 32 age- and village-matched controls were enrolled and were vaccinated with Hib oligosaccharide-CRM(197) conjugate vaccine. Serum immunoglobulin G (IgG) concentration, antibody avidity, and serum bactericidal activity (SBA) were measured prior to Hib vaccination and 2 and 12 months after vaccination. We identified no demographic or behavioral factors associated with Hib colonization. Prior to vaccination, Hib carriers had a higher IgG geometric mean concentration than controls did (8.2 versus 1.6 microg/ml; P < 0.001) and a higher SBA geometric mean titer (7,132 versus 1,235; P = 0.006). Both groups responded to vaccination with increased IgG and SBA. These data illustrate the role of Hib colonization as an immunizing event and show that Hib carriers in communities with ongoing transmission have no evidence of reduced immune responsiveness that may have put them at risk for colonization.     

The effect of menarcheal age on anthropometric,limb length,and bone measures in Hutterite and non‐Hutterite women

The age women reach menarche may affect bone length and mass. Some studies show an earlier menarcheal age (MA) results in a shorter stature and increased body fat. We hypothesized that Hutterite women have a shorter height and limb length, but greater bone mass and areal bone mineral density (aBMD) than non‐Hutterites. Results are from a secondary analysis of 344 (198 Hutterite) healthy, pre‐menopausal women aged 20?40 years who participated in the South Dakota Rural Bone Health Study. Bone measures were obtained by DXA (spine, hip and total body) and pQCT (4 and 20% distal radius). MA correlated with year of birth (r = ?0.10, P = 0.08) indicating a trend toward a younger MA for women born in more recent years. MA was inversely associated with current weight (r = ?0.11, P < 0.05), percent body fat (r = ?0.16, P < 0.01), femoral neck BMC (r = ?0.18, P = 0.003), femoral neck aBMD (r = ?0.21, P < 0.001), hip aBMD (r = ?0.22, P < 0.001) and trabecular volumetric BMD (vBMD) (r = ?0.14, P = 0.03). Hutterite women had a younger MA than non‐Hutterite women (12.3 ± 1.3 vs. 13.0 ± 1.3 yr, P < 0.001). In final regression models controlling for diet and activity patterns, Hutterite compared to non‐Hutterite women had shorter standing height (162 ± 0.4 vs. 166 ± 0.4 cm, P < 0.001), forearm length (258 ± 0.8 vs. 261 ± 0.9 mm, P = 0.04); and leg length (76 ± 0.2 vs. 77 ± 0.3 cm, P < 0.01) as hypothesized, but MA did not predict these outcomes. In conclusion, younger MA in Hutterite women did not explain their shorter standing height and limb lengths, but total hip aBMD was inversely associated with MA and greater in Hutterite than non‐Hutterite women. Am. J. Hum. Biol., 2008. © 2008 Wiley‐Liss, Inc.