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JCI online early table of contents: March 3, 2008

EDITOR'S PICK: How the drug isotretinoin zaps acne

The most potent drug available for the treatment of acne is 13-cis retinoic acid (13-cis RA; also known as isotretinoin); however, little is known about the mechanism by which it acts. Insight into the mechanisms by which 13-cis RA combats acne has now been provided by Diane Thiboutot and colleagues, from Pennsylvania State University College of Medicine, Hershey, who analyzed skin biopsies from patients with acne before and after 1 week of treatment with 13-cis RA. The authors suggested these data might lead to the development of new treatments for acne, which are badly needed as the use of 13-cis RA is limited by its severe side effects.

Initial analysis confirmed previous observations made using cultured cells that 13-cis RA induces a form of cell death known as apoptosis in sebaceous glands, the parts of the skin that are affected in individuals with acne. Further studies revealed that the gene responsible for making the protein NGAL was highly upregulated in human sebaceous glands by 13-cis RA. As NGAL was found to mediate apoptosis of human sebaceous glands and to be essential for 13-cis RA to mediate apoptosis of human sebaceous glands, the authors suggested that agents that selectively induce NGAL expression in human sebaceous glands might provide a new approach to treating individuals with acne.

TITLE: Neutrophil gelatinase–associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells

Diane M. Thiboutot
Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Phone: (717) 531-7437; Fax: (717) 531-4821; E-mail:

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EDITOR'S PICK: "Female sex hormone" protects against hearing loss in females and males

The "female sex hormone" estradiol is present in both men and women, and is generated from testosterone in men by the protein aromatase. Estradiol plays various roles in addition to its gender-specific ones, including having effects on the hearing (auditory) system. In a new study, Barbara Canlon and colleagues at the Karolinska Institute in Stockholm, Sweden, investigated the role of estradiol-binding proteins, known as estrogen receptors, in response to auditory damage by examining hearing loss recovery in mice with deficiencies in various estrogen receptors. They found that mice deficient in only the estrogen receptor ER-beta had reduced recovery from auditory trauma, and that treatment with ER-beta–binding drugs protected mice from auditory damage. Furthermore, not only was ER-beta found in the ears of both male and female mice, but levels of the nerve-protecting protein BDNF were reduced in mice that lacked either ER-beta or aromatase. The authors therefore concluded that this identification of an auditory-protective role for the estrogen receptor ER-beta may enable the development of new treatments for hearing loss.

TITLE: Estrogen receptor–beta protects against acoustic trauma in mice

Barbara Canlon
Karolinska Institute, Stockholm, Sweden.
Phone: 46-8-524-872-48; Fax: 46-8-327026; E-mail:

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HEMATOLOGY: Role for the serotonin transporter in platelet aggregation

New data, generated by Randy Blakely and colleagues, at Vanderbilt University, Nashville, have established a role for constitutive expression of the protein SERT (the serotonin transporter) in platelet aggregation, a key event in blood clotting. In the study, SERT expression and function were shown to have a role in the aggregation of both mouse and human platelets. Mechanistically, SERT was found to interact directly with the beta-3 component of a protein known as integrin alpha-IIb/beta-3, and this led to increased SERT expression on the surface of the platelet and thereby increased SERT function. Alterations in SERT distribution in platelets was linked to polymorphisms in the beta-3 gene. The interaction of the genes that make beta-3 and SERT has been of substantial clinical interest as they have been implicated in cardiovascular disease and autism. The authors therefore suggested that the demonstration that SERT interacts with integrin beta-3 provides a possible mechanistic basis for these recent genetic associations. In addition, as SERT is the target for the most widely prescribed class of antidepressants (SSRIs), the authors suggest that these data might help explain the recognized comorbidities between cardiovascular disease and depression.

TITLE: Interactions between integrin alpha-IIb/beta-3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

Randy D. Blakely
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: (615) 936-3705; Fax: (615) 936-3040;

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GENETICS: Seeing clearly how genetic mutations cause loss of sight

Retinitis pigmentosa (RP) is a hereditary disease that often results in complete loss of sight as a result of the progressive degeneration of the retina of the eye. Mutations in many different genes are known to cause RP, one of which is PRPF31. New data generated by Carlo Rivolta and colleagues at the University of Lausanne, Switzerland, have provided insight into the effect of several different RP-causing PRPF31 mutations.

The information in genes is translated into protein via an mRNA intermediate. In the study, six different PRPF31 mutations that cause RP were found to generate substantially less mRNA, and therefore dramatically lower amounts of protein, than nonmutated PRPF31. Surprisingly, although blocking a process known as nonsense-mediated mRNA decay, which destroys certain forms of mRNA that would not correctly translate the information in a gene into protein, increased the amount of mRNA generated from the mutated PRPF31, no increase in mutant protein was observed. The authors therefore suggested that most PRPF31 mutations are effectively nonfunctional because surveillance mechanisms destroy any mRNA generated from the mutated genes, and therefore that PRPF31 mutations mediate their RP-causing effect by decreasing the amount of PRPF31 protein present in a cell.

TITLE: Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

Carlo Rivolta
University of Lausanne, Lausanne, Switzerland.
Phone: 41-21-692-5456; Fax: 41-21-692-5455; E-mail:

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MUSCLE BIOLOGY: Why muscle wasting diseases may not require stem cell treatment after all

Muscle wasting, also known as muscle atrophy, can be caused by inactivity, injury, disease, aging, and medication. Many studies have shown that muscle atrophy is accompanied by death of the DNA-containing myonuclei of muscle fibers, which would mean that recovery from muscle atrophy would require replenishment from muscle stem cells. In a new study, Jo Bruusgaard and Kristian Gundersen at the University of Oslo, Norway, used time-lapse microscopy of mouse muscle fibers and myonuclei during atrophy to investigate this process. When mice were subjected to muscle atrophy by various methods, physical evidence of wasting was apparent by significantly decreased muscle fiber areas. However, myonuclei death was not observed in any case during the 28 days of monitoring. The authors concluded therefore that intervention efforts to reverse muscle atrophy should not focus on muscle stem cells.

TITLE: In vivo time-lapse microscopy reveals no loss of murine myonuclei during weeks of muscle atrophy

Kristian Gundersen
University of Oslo, Oslo, Norway.
Phone: (47) 22-85-46-17; Fax: (47) 22-85-46-64; E-mail:

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METABOLIC DISEASE: Learning more about why people with Bardet-Biedl syndrome are obese

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by many features, including obesity and an increased risk of heart disease. Although BBS is a rare disorder, because it is characterized by problems faced by an increasing number of individuals who do not have BBS, much effort is being invested in determining the genes that are mutated in individuals with BBS and how these contribute to obesity and increased risk of heart disease. New data generated by Kamal Rahmouni and colleagues at the University of Iowa Carver College of Medicine, Iowa City, have indicated that sensitivity to the hormone leptin, which suppresses appetite and increases energy expenditure by activating leptin receptors on specific nerves in the brain, is lost in three mouse models of BBS.

In the study, administration of leptin to mice lacking Bbs2, Bbs4, or Bbs6 (proteins made by three of the twelve genes so far identified as being mutated in individuals with BBS) was found to have little effect on body weight and food intake. Further analysis indicated that this resistance to the effects of leptin as an appetite suppressor was associated with a defect in nerves in the brain known as proopiomelanocortin neurons. Although all three strains of mice were resistant to the effects of leptin as an appetite suppressor, only Bbs2-/- mice were resistant to the effects of leptin on arterial blood pressure. As such, Bbs2-/- mice had normal blood pressure, whereas Bbs4-/- mice and Bbs6-/- mice had elevated blood pressure. These data have provided insight into why individuals who have BBS as a result of different genetic mutations might exhibit different clinical symptoms.

TITLE: Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedel syndrome

Kamal Rahmouni
University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Phone: (319) 353-5256; Fax: (319) 353-5350; E-mail:

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ONCOLOGY: Eradicating established tumors in mice

Although an immune response mediated by T cells is mounted toward a tumor, over time the tumor adapts and can escape control by the immune response. Similar problems are an obstacle to T cell–based immunotherapeutic approaches to treating individuals with cancer. Loss of the target of the T cells is one mechanism by which tumors escape immune control. A new study by Bin Zhang and colleagues, at the University of Chicago, has characterized immune pathways that can eradicate established tumors in mice, including variants of the tumor that had lost the target of the antitumor T cells (so called antigen-loss-variants; ALVs). Specifically, in this model, the production of the soluble factors IFN-gamma and TNF by antitumor cytotoxic T cells was required for tumor eradication. For these soluble factors to mediate their antitumor effects both bone marrow and stromal cells had to express IFN-gamma and TNF receptors. These data led the authors to suggest that IFN-gamma and TNF acted on tumor stroma to effect bystander killing of ALVs, and they hope that this insight will aid in the development of effective strategies to eliminate established cancers.

TITLE: IFN-gamma– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers

Bin Zhang
University of Texas Health Science Center, San Antonio, Texas, USA.
Phone: (210) 562-5243; Fax: (210) 562-5292; E-mail:

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MUSCLE BIOLOGY: Learning from a new model for potassium-induced muscle weakness

HyperKPP is a genetic muscle disorder that causes muscle weakness in response to resting after strenuous exercise and to eating potassium-rich foods, among other things. To better understand the mechanisms underlying HyperKPP, Lawrence Hayward and colleagues at the University of Massachusetts Medical School in Worcester, generated a mouse model of the disease by introducing a genetic mutation that causes HyperKPP into the corresponding mouse gene. These mice developed problems similar to individuals with HyperKPP, including abnormally slow muscle relaxation, muscle weakness following potassium exposure at levels typical in human muscle fibers during exercise, and slow recovery from muscle fatigue. The authors therefore hope that this mouse model of HyperKPP may help researchers better understand the human disease and develop better therapies for it and related disorders.

TITLE: Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Lawrence J. Hayward
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Phone: (508) 856-4147; Fax: (508) 856-6778; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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