ACARDIAC TWIN FETUS WITH SEVERE HYDROPS FETALIS AND BILATERAL TALIPES VARUS DEFORMITY

Twin reversed-arterial-perfusion syndrome (TRAPS) is a rare complication of monochorionic twin pregnancies. TRAPS is characterized by the hemodynamic dependence of a “recipient” twin from a “pump” twin. The “recipient” twin exhibits lethal abnormalities, such as acardia and acephaly. Circulatory failure of the normal twin derives from the existence of arterio-arterial and veno-venous anastomoses within the placenta that allow retrograde perfusion of the acardiac twin by blood coming from the normal twin. Acardiac twinning is the most extreme manifestation of the twin-twin transfusion syndrome. This occurs in 1 in 100 monozygotic twin pregnancies and 1 in 35,000 births. We report a case of diamnionic monochorionic female twins in which the acardiac twin demonstrated severe hydrops fetalis and bilateral talipes varus deformity. Cesarean section was performed on a 27-year-old hypertensive gravida 2, para 1 mother for fetal indications at 32 6/7 weeks gestation. The acardiac fetus had a two-vessel umbilical cord measuring 43.5 cm in length and 0.8 cm in diameter. The proximal end inserted into the root of the normal twin's umbilical cord in an acute angle forming a “v” close to the placental disc. Structures rostral to the thorax were absent except for a round mass of flesh with three small buds in place of the head and neck, and bilateral upper extremities. Only the kidneys, right adrenal, small and large intestine, and rudimentary urinary bladder were present. Both feet demonstrated talipes varus deformity. The fetus was severely hydropic. The subcutaneous fat measured 4.5 cm in maximum thickness. The normal twin had a protracted course complicated with respiratory distress syndrome, moderate secundum atrial septal defect with left to right shunt, and thrombocytopenia of prematurity. The baby was eventually discharged after approximately 1 month. At the time of this report, 5 months postpartum, the neonate is growing and developing normally. To our knowledge, this is the first report of severe hydrops fetalis and talipes varus deformity in an acardiac twin.     

Role of apoptosis in HIV disease pathogenesis

After approximately one and a half decades of intensive studies, the exact mechanisms to explain HIV-mediated cytopathicity are still enigmatic and need closer scrutiny. There has been a dichotomy between virological and immunological viewpoints in understanding HIV-mediated cytopathicity, the former emphasizing a killing of infected cells by HIV-1 and the latter emphasizing indirect mechanisms wherein HIV or its soluble component(s) alter CD4 T-cell function and induce susceptibility to apoptosis. Accumulating evidence points to the notion that apoptosis might be a major contributor to the depletion of CD4 T-cells in HIV infection. This review summarizes current information about the regulatory mechanisms of T-cell apoptosis and the role of apoptosis in HIV pathogenesis with the goal of providing an integrated view of HIV cytopathicity.     

Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies

Mutations in alpha-synuclein (alpha S) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited alphaS-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and alphaS inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that alphaS and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, alpha S-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with alphaS in subcellular compartments of normal brain and that parkin frequently co-localizes with alpha S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.     

Reliability of CD4 quantitation in human immunodeficiency virus-positive children: implications for definition of immunologic response to highly active antiretroviral therapy

Our objective was to develop data-based algorithms for definition of immunologic response to AIDS therapies in pediatric patients, taking account of T-cell subset measurement errors. The study design involved cross-protocol analysis of 2,148 enrollees in six completed Pediatric AIDS Clinical Trials Group trials. We used standard quantitation of T-cell subsets; linear modeling with mean-dependent measurement error variance was used to develop 95% tolerance limits for change in CD4%. For individuals with a CD4% of approximately 25%, the measurement error-based 95% tolerance interval ranges from 15% to 35%, whereas for individuals with a CD4% of approximately 5%, the tolerance interval ranges from 3% to 7%. When pairs of CD4% measures taken within a time interval of less than 30 days are averaged to estimate steady-state CD4%, tolerance interval width decreases by approximately 30%. A simple graphical tool that provides a data-based criterion for immunologic response over and above variation ascribable to T-cell measurement error is provided. Variability in CD4% due to measurement error is substantial, increases with level of CD4%, and complicates assessment of immunologic response to therapy. Replicates of CD4% measures could be used to improve precision of interpretation of CD4% measures.     

Inhibition of hepatitis C virus nonstructural protein, helicase activity, and viral replication by a recombinant human antibody clone

Hepatitis C virus (HCV) nonstructural protein 3 (NS3), with its protease, helicase, and NTPase enzymatic activities, plays a crucial role in viral replication, and therefore represents an ideal target for the development of anti-viral agents. We have developed a recombinant human antibody (Fab) that reacts with the helicase domain of HCV NS3. The affinity-purified Fab antibody completely inhibited the helicase activity of HCV NS3 at equimolar concentration. To evaluate the effect of the Fab on HCV replication, the clone encoding the Fab gene was put into an expression vector, which converts Fab into a complete IgG1 antibody. Using a DNA-based transfection model, we demonstrated that intracellular expression of this antibody resulted in significant reduction of HCV-negative strand RNA synthesis. Intracellular expression of this antibody into either a stable cell line replicating subgenomic RNA, or a transient full-length HCV replication model, reduced both HCV RNA and viral protein expression. These results support the use of recombinant antibody fragments to inhibit NS3 enzyme as a novel, feasible, and effective approach for inhibiting HCV replication.     

Body weight and abdominal fat gene expression profile in response to a novel hydroxycitric acid-based dietary supplement

Obesity is a global public health problem, with about 315 million people worldwide estimated to fall into the WHO-defined obesity categories. Traditional herbal medicines may have some potential in managing obesity. Botanical dietary supplements often contain complex mixtures of phytochemicals that have additive or synergistic interactions. The dried fruit rind of Garcinia cambogia, also known as Malabar tamarind, is a unique source of (-)-hydroxycitric acid (HCA), which exhibits a distinct sour taste and has been safely used for centuries in Southeastern Asia to make meals more filling. Recently it has been demonstrated that HCA-SX or Super Citrimax, a novel derivative of HCA, is safe when taken orally and that HCA-SX is bioavailable in the human plasma as studied by GC-MS. Although HCA-SX has been observed to be conditionally effective in weight management in experimental animals as well as in humans, its mechanism of action remains to be understood. We sought to determine the effects of low-dose oral HCA-SX on the body weight and abdominal fat gene expression profile of Sprague-Dawley rats. We observed that at doses relevant for human consumption dietary HCA-SX significantly contained body weight growth. This response was associated with lowered abdominal fat leptin expression while plasma leptin levels remained unaffected. Repeated high-density microarray analysis of 9960 genes and ESTs present in the fat tissue identified a small set (approximately 1% of all genes screened) of specific genes sensitive to dietary HCA-SX. Other genes, including vital genes transcribing for mitochondrial/nuclear proteins and which are necessary for fundamental support of the tissue, were not affected by HCA-SX. Under the current experimental conditions, HCA-SX proved to be effective in restricting body weight gain in adult rats. Functional characterization of HCA-SX-sensitive genes revealed that upregulation of genes encoding serotonin receptors represent a distinct effect of dietary HCA-SX supplementation.