Stem cell clonality and genotoxicity in hematopoietic cells: gene activation side effects should be avoidable

Two serious adverse events involving activation of the LMO2 oncogene through retrovirus vector insertion in the otherwise extremely successful first gene therapy trial for X-linked severe combined immunodeficieny type 1 (SCID-X1) had initially caused widespread concern in the patient and research communities. Careful consideration 1 year after diagnosis of the second case still finds 12 of the treated patients clearly benefiting from gene therapy (freedom from treatment failure, 80%; survival 100%), a situation that should not portend the end of gene therapy for this disease, and is, in fact encouraging. While current approaches are justified to treat patients with otherwise life-threatening disorders, a broad consensus has developed that systematic basic research is required to further understand the pathophysiology of these serious adverse events and to provide new insights, enabling safer and more effective gene therapy strategies. With the continued success of SCID-X1 gene therapy in the majority of patients treated, it is of even greater importance to understand exactly which vector element or combination of elements predispose to toxicity. An in-depth study of the mechanisms behind the activation of the LMO2 and gammac genes will be highly instructive for the development of safer procedures and vectors. We summarize the central observations, ongoing experimental approaches, new concepts, and developments relevant to understanding, interpreting, and eventually overcoming the real and perceived obstacles posed by insertional mutagenesis due to gene transfer vectors.     

Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.     

The functions of saliva

Oral health is determined to a considerable extent by our ability to produce saliva. Not only must adequate amounts be produced, but a large number of specific proteins also must be secreted for the mouth to function properly. This brief review is directed at describing (1) how saliva is secreted, (2) the consequences of decreased salivary function, (3) the components necessary for oral homeostasis, and (4) the common causes of salivary hypofunction.     

Studies on levamisole--induced agranulocytosis

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet- induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.     

Ultrasonographic Findings with Bleeding and Nonbleeding Esophageal Varices

Real time ultrasonography was carried out in 49 cirrhotic patients within 10 days of esophagoscopy, and in 20 normal subjects. Among the cirrhotic patients, 42 had varices and 18 of these had hematemesis within 3 months of study. The varices were graded 0 to 4+ endoscopically; the diameter of the portal vein, the splenic vein, the hepatic artery, and the maximal length of the spleen were determined on ultrasound. In addition, portal collateral veins and the sudden amputation of portal vein branches in the liver were identified when present. There was a significant correlation of the diameter of the portal vein and the maximal spleen length with the magnitude of varices on endoscopy; there was no significant relationship between the splenic vein or the hepatic artery diameter. Less than half the patients with varices had sonographically demonstrated collaterals or portal vein branch amputation. A sonoscore was derived allotting one point each for enlarged portal vein (greater than 1.3 cm), enlarged spleen, collaterals or two or more amputated veins. The sonoscore correlated better with the endoscopic grade of varices than any other marker. The sonoscore among the patients with varices who bled was significantly higher (p less than 0.01) than any of the other measures. It is concluded that real time ultrasound can be used to screen for varices and to identify the need for endoscopy.     

Prevalence of metabolic syndrome in Chinese women and men: a systematic review and meta-analysis of data from 734 511 individuals

Background

The prevalence of metabolic syndrome is growing because of increasing rates of obesity and sedentary lifestyle. Metabolic syndrome is one of the most important risk factors associated with diabetes, cardiovascular disease, and all-cause mortality. Few studies have examined its sex-specific prevalence in China across time. We compared the prevalences and temporal trends of metabolic syndrome in Chinese women and men.

Systemic and mesenteric O2 metabolism in endotoxic pigs: effect of graded hemorrhage.

Normally, supply-dependency of oxygen uptake (VO2) is not demonstrable unless oxygen delivery (DO2) is less than a critical value (DO2crit) below which VO2 is linearly dependent upon DO2. Because recent evidence suggests that VO2 is pathologically supply-dependent in endotoxic or septic animals and humans, we sought to determine whether 1) pathological systemic and/or mesenteric oxygen extraction (O2EXT) defects occur in a porcine model of endotoxicosis and 2) arterial lactate and ileal intramucosal pH (pHI) serve as useful markers of supply-dependency of VO2 in endotoxic animals. Normal (group I, n = 11) and endotoxic (group II, n = 8) anesthetized pigs were subjected to graded hemorrhage. Endotoxicosis was induced by infusing Escherichia coli lipopolysaccharide (150 micrograms/kg bolus at t = 0 min and 20 micrograms/kg-hr at t = 60 min). From t = 0-60 min, pigs in group II were resuscitated with hetastarch and blood (12 ml/kg each). Hemorrhage was initiated at t = 0 min or t = 70 min in groups I and II, respectively. DO2crit was determined by a modified "dual-line" regression method. Systemic DO2crit was 12.9 +/- 0.9 ml/kg-min in group I and 16.9 +/- 1.3 ml/kg-min in group II (P less than .05). Systemic O2EXT at DO2crit was similar in both groups. Arterial lactate concentration at DO2crit was significantly higher in endotoxic pigs (group I, 2.64 +/- 0.29 mM; vs. group II, 3.88 +/- 0.45 mM; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)