Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise

The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors

Doctrine Formulation and Distrust

Legal scholars exhaustively debate the substantive wisdom of Supreme Court decisions and the appropriate methods for interpreting legal texts but rarely consider the more pragmatic need to craft rules that will be faithfully implemented by the lower court judges who have the last word in the overwhelming majority of cases. Political scientists, in contrast, invest tremendous effort seeking to determine whether lower courts “comply” with Supreme Court directives, but find themselves unable to explain why their own studies generally find high levels of compliance. This Article argues that part of the answer lies in the Court\u27s ability to craft legal doctrines that both shape a trial court\u27s initial decision and increase the efficacy of appellate monitoring. After identifying numerous strategies for increasing lower court control, this Article argues that appreciating the links between them helps illuminate recent developments in three areas of public law: the constitutional law of punitive damages;the rules governing “officer suits” brought under 42 U.S.C. § 1983;and the concept of “reasonable” searches and seizures under the Fourth Amendment. Reprinted by permission of the publisher

Exertional rhabdomyolysis and heat stroke : beware of volatile anesthetic sedation

In view of the enormous popularity of mass sporting events such as half-marathons, the number of patients with exertional rhabdomyolysis or exercise-induced heat stroke admitted to intensive care units (ICUs) has increased over the last decade. Because these patients have been reported to be at risk for malignant hyperthermia during general anesthesia, the intensive care community should bear in mind that the same risk of life-threatening rhabdomyolysis is present when these patients are admitted to an ICU, and volatile anesthetic sedation is chosen as the sedative technique. As illustrated by the three case studies we elaborate upon, a thorough diagnostic work-up is needed to clarify the subsequent risk of strenuous exercise, and the anesthetic exposure to volatile agents in these patients and their families. Other contraindications for the use of volatile intensive care sedation consist of known malignant hyperthermia susceptibility, congenital myopathies, Duchenne muscular dystrophy, and intracranial hypertension

Exertional rhabdomyolysis : relevance of clinical and laboratory findings, and clues for investigation

Some degree of exertional rhabdomyolysis (ER), striated muscle breakdown associated with strenuous exercise, is a well-known phenomenon associated with endurance sports. However in rare cases, severe and/or recurrent ER is a manifestation of an underlying condition, which puts patients at risk for significant morbidity and mortality. Selecting the patients that need a diagnostic work up of an acute rhabdomyolysis episode is an important task. Based on the diagnostic work up of three illustrative patients treated in our hospital, retrospectively using the 'RHABDO' screening tool, we discuss the clinical and biochemical clues that should trigger further investigation for an underlying condition. Finally, we describe the most common genetic causes of this clinical syndrome

Doctrine Formulation and Distrust

Legal scholars exhaustively debate the substantive wisdom of Supreme Court decisions and the appropriate methods for interpreting legal texts but rarely consider the more pragmatic need to craft rules that will be faithfully implemented by the lower court judges who have the last word in the overwhelming majority of cases. Political scientists, in contrast, invest tremendous effort seeking to determine whether lower courts “comply” with Supreme Court directives, but find themselves unable to explain why their own studies generally find high levels of compliance. This Article argues that part of the answer lies in the Court\u27s ability to craft legal doctrines that both shape a trial court\u27s initial decision and increase the efficacy of appellate monitoring. After identifying numerous strategies for increasing lower court control, this Article argues that appreciating the links between them helps illuminate recent developments in three areas of public law: the constitutional law of punitive damages;the rules governing “officer suits” brought under 42 U.S.C. § 1983;and the concept of “reasonable” searches and seizures under the Fourth Amendment. Reprinted by permission of the publisher

Enhancement of Neoangiogenesis and Follicle Survival by Sphingosine-1-Phosphate in Human Ovarian Tissue Xenotransplants

Ovarian transplantation is one of the key approaches to restoring fertility in women who became menopausal as a result of cancer treatments. A major limitation of human ovarian transplants is massive follicular loss during revascularization. Here we investigated whether sphingosine-1-phosphate or its receptor agonists could enhance neoangiogenesis and follicle survival in ovarian transplants in a xenograft model. Human ovarian tissue xenografts in severe-combined-immunodeficient mice were treated with sphingosine-1-phosphate, its analogs, or vehicle for 1–10 days. We found that sphingosine-1-phosphate treatment increased vascular density in ovarian transplants significantly whereas FTY720 and SEW2871 had the opposite effect. In addition, sphingosine-1-phosphate accelerated the angiogenic process compared to vehicle-treated controls. Furthermore, sphingosine-1-phosphate treatment was associated with a significant proliferation of ovarian stromal cell as well as reduced necrosis and tissue hypoxia compared to the vehicle-treated controls. This resulted in a significantly lower percentage of apoptotic follicles in sphingosine-1-phosphate-treated transplants. We conclude that while sphingosine-1-phosphate promotes neoangiogenesis in ovarian transplants and reduces ischemic reperfusion injury, sphingosine-1-phosphate receptor agonists appear to functionally antagonize this process. Sphingosine-1-phosphate holds great promise to clinically enhance the survival and longevity of human autologous ovarian transplants