JCI table of contents, January 26, 2006EDITOR'S PICK
Low cholesterol cues cataract development
Cataracts are a leading cause of blindness worldwide. Using a rat model of cataract formation, Masayuki Mori and researchers at Shinshu University Graduate School of Medicine in Japan have now found a link between cataracts and cholesterol. The study, appearing online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation reports that a primary genetic defect in cataractogenesis is combined mutation of the lanosterol synthase (Lss) and farnesyl diphosphate farnesyl transferase 1 (Fdft1) genes, both of which function in cholesterol biosynthesis. Cataractous rats with these 2 gene mutations demonstrated reduced cholesterol levels in the eye lens and cerebral cortex, compared to wild-type rats. The researchers also identified a problem with specialized cells of the eye lens, known as epithelial cells. These cells, which require cholesterol for proper development, normally form a thin, single layer across the lens and are responsible for maintaining the transparency of the lens. In cataracts, these cells fail to mature normally, and Mori's group now shows that epithelial cells of cataractous rats with mutations in Lss and Fdft1 also mature abnormally, suggesting that the defect in cholesterol synthesis alters proliferation of these cells and contributes to the lens becoming opaque. The results could have clinical impact in patients taking cholesterol–lowering medications or in individuals with inborn defects in cholesterol synthesis.
TITLE: Lanosterol synthase mutations cause cholesterol deficiency–associated cataracts in the Shumiya cataract rat
Shinshu University Graduate School of Medicine, Matsumoto, Japan
Phone: 81-263-37-2692; Fax: 81-263-37-3428; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=20797
Asian populations less likely to get relief from chest pain with nitroglycerin
Nitroglycerin, also called glyceryl trinitrate (GTN), has been widely used for the management of coronary heart disease, specifically angina and heart failure, for more than 130 years. The efficacy of GTN is determined by the ability of the body to convert it to nitric oxide (NO), a process that requires the enzyme mitochondrial aldehyde dehydrogenase-2 (ALDH2). Li Jin and colleagues at Fudan University in China now show that the reason some Asians have trouble responding to GTN is that 30–50% of this population possess an inactive mutant form of the gene known as ALDH2*2. The study, which appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, examined a total of 111 Chinese coronary heart disease patients who were self-administering GTN under the tongue during acute attacks of angina. Eighty subjects (72%) reported pain relief that occurred in less than 10 minutes (responders) and the remainder had no pain relief (nonresponders). The authors determined that the nonresponders tended to have the ALDH2*2 form of the gene, and they suggest that this genetic factor may warrant consideration when administering nitroglycerin to Asian patients.
TITLE: Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin
Fudan University, Shanghai, People's Republic of China
Phone: 86-21-65642800; Fax: 86-21-55664388; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26564
New clues to how the brain keeps us fat
Individuals (and mice) with loss of function of a gene known as POMC develop early-onset obesity. The POMC protein is broken down into a variety of smaller peptides that have potent action in the body, and if lost, can cause obesity. However, it is unclear whether the POMC peptides from the central nervous system (hypothalamus) or the pituitary are responsible for obesity. To find out, Malcolm J. Low and colleagues at the Oregon Health & Science University attempted to correct the obesity of obese mice lacking POMC by genetically restoring POMC specifically in the pituitary. Surprisingly, instead of making the mice thinner, the pituitary POMC made them eat more, become insulin resistant, and gain fat. In fact, the restored animals gained 30-40% more weight than the POMC-negative animals, and maintained their obesity even when placed on a low-calorie diet. When the researchers examined levels of the stress hormone cortisol, they found that the POMC-corrected animals (particularly males) had greater cortisol fluctuations throughout the day. In addition, levels of leptin, a hormone produced by adipose tissue that increases metabolism and tells the body to stop eating, were higher in the corrected animals, even though they were eating more. The study, which appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, suggests that hypothalamic POMC peptides play a critical role in energy metabolism distinct from pituitary POMC.
TITLE: Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice
Malcolm J. Low
Oregon Health & Science University, Portland, Oregon, USA
Phone: 503-494-4672; Fax: 503-494-4976; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25243
True self-acceptance is the key to fighting multiple sclerosis
Multiple sclerosis (MS) is characterized by loss of the fatty insulation of nerve endings called myelin, a process known as "demyelination". It is thought that a specific part of the immune system, known as the innate immune system, promotes demyelination by tricking the cells of the central nervous system (CNS) into thinking there is an infection, which stimulates the cells to attack and destroy myelin. Researchers now show that an essential event in this process is activation of a special innate cell surface receptor, called Toll like receptor 9 (TLR9) and its partner MyD88, which recognize "danger" signals such as invading bacteria. Using a special animal model of MS known as the EAE mouse, Marco Prinz and colleagues at the Georg-August-University in Germany report that EAE mice that are genetically altered not to express TLR9 or MyD88 are completely resistant to MS. The study, which appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, goes on to show that the protection against MS is due to the failure of the innate immune cells to attack their CNS tissue. The authors show that expression of TLR9 and MyD88 were increased in the diseased spinal cords of EAE mice, revealing that expression of these proteins is involved not only in the defense against invading bacteria, but also in the attack of one's own myelin during MS. The authors suggest that identifying how TLR9 and MyD88 become activated may lead to new therapies for MS.
TITLE: Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis
Georg-August-University, Gottingen, Germany
Phone: 49-551-39-14340; Fax: 49-551-39-8472; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=26078
Fighting airway infection in cystic fibrosis
A bacterium known as Pseudomonas aeruginosa is an important pathogen that is most resistant to therapy when it undergoes a process known as mucoid conversion, forming a biofilm along the airways in cystic fibrosis (CF) patients. In addition, its presence in the lungs of CF patients correlates with markedly reduced lung function. Daniel Hassett and colleagues at the University of Cincinnati College of Medicine in Cincinnati, Ohio found that these microorganisms were killed when exposed to 15 mM nitrite (NO2–) at pH 6.5 under very low oxygen situations, similar to the conditions of CF airways. The authors found that another nitrogen-containing compound, nitrous acid (HNO2), was transformed into toxic chemical species that killed mucoid Pseudomonas aeruginosa, but, importantly, did not adversely affect human airway epithelial cells in culture. The study, which appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, suggests that HNO2 or inhaled NO2– has appeal as a CF therapy and warrants further exploration as a selective killing agent that could eradicate mucoid Pseudomonas aeruginosa from the CF airways.
TITLE: Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions
Daniel J. Hassett
University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Phone: 513-558-1154; Fax: 513-558-8474; E-mail: Daniel.Hassett@uc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=24684
Connecting high blood pressure to the kidney
The kidney is made up of a variety of different cell types that communicate with each other to control blood pressure. It is known that cells use members of a special type of protein family, known as connexins, to communicate, and that one member, connexin43 (Cx43) is increased in the renal blood vessels of mice with high blood pressure. To identify the role of Cx43 in high blood pressure in mice, researchers J.-A. Haefliger and colleagues at the University Hospital in Lausanne, Switzerland, replaced the Cx43 gene normally found in kidney blood vessels with Cx32, a connexin not normally expressed in vessels. These new mice, called KI32 mice, show reduced renal expression of the high blood pressure hormone renin. The study appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation. Next the authors put the normal and KI32 mice on a high-salt diet to increase their blood pressure. Surprisingly, the KI32 mice did not demonstrate elevations in blood pressure. In addition, the KI32 mice were protected from an increase in heart size known as cardiac hypertrophy. The role of Cx43, as suggested by the researchers, is to influence the response of the renal blood vessel wall by allowing adequate communication between cells that line the wall, resulting in renin expression and elevations in blood pressure. The authors state that further work will identify whether it is the loss of Cx43 or the gain of Cx32 that is the critical factor in preventing high blood pressure in this model.
TITLE: Connexin43-dependent mechanism modulates renin secretion and hypertension
University Hospital, Lausanne, Switzerland
Phone: 41-21-314-0926; Fax: 41-21-314-0968;
View the PDF of this article at: https://www.the-jci.org/article.php?id=23327
Paying a complement to prevent kidney damage
Kidney failure leads to the buildup of toxins in the blood. A type of injury known as renal ischemia/reperfusion (I/R) contributes to kidney failure and causes injury to special renal cells called tubular epithelial cells. In mice, acute renal failure (ARF) is associated with activation of a signaling molecule called complement, and mice that are complement-–deficient are protected from renal failure after I/R. Joshua M. Thurman and colleagues at the University of Colorado Health Sciences Center, now show that loss of an inhibitor of complement, known as complement receptor 1–related protein y (Crry), which is found on tubular epithelial cells, protects the kidney from damage. Previous work had shown that renal complement activation occurs via a pathway known as the "alternative" pathway. Mice that were genetically engineered to express low levels of Crry were more sensitive to ischemic injury. In addition, inhibition of Crry in tubular epithelial cells in culture increased alternative pathway–mediated injury. The study, which appears online on January 26 in advance of print publication in the February 2006 issue of the Journal of Clinical Investigation, found that altered expression of Crry by the renal tubular epithelium after I/R permits the activation of complement on the surface of these cells. The results underscore the need for constant complement inhibition by kidney cells, and show that loss of this protection renders cells susceptible to injury.
TITLE: Altered renal tubular expression of the complement inhibitor Crrypermits complement activation after ischemia/reperfusion
Joshua M. Thurman
University of Colorado Health Sciences Center, Denver, Colorado, USA
Phone: 303-315-0171; Fax: 303-315-5540; E-mail: Joshua.Thurman@UCHSC.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24521
Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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