Evan Jacob Lipson, M.D.

• Associate Professor of Oncology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/2194148/evan-lipson

Nevertheless why so much cholesterol in eggs discount simvastatin 40 mg overnight delivery, isolated tubal torsion can occur even with an otherwise normal fallopian tube and without ipsilateral ovarian involvement cholesterol medication flushing simvastatin 40 mg buy lowest price. In general cholesterol test walmart order simvastatin on line, isolated fallopian torsion is rare in a normal fallopian tube cholesterol in shrimp hdl or ldl buy simvastatin 40 mg line, and tubal abnormalities are risk factors for isolated fallopian tube torsions [32 normal cholesterol levels new zealand simvastatin 20 mg fast delivery, 36]. Paraovarian and Paratubal Cysts Paratubal or paraovarian cysts account about 9% to 10% of all adnexal masses. Clinically, it is difficult to distinguish a paraovarian cyst from an ovarian cyst [37, 38]. Torsion of large paraovarian or paratubal cysts has been reported in several studies. These cysts are symptomatic when they become enlarged due to their pressure effect [13, 38­41]. Paratubal cysts should be taken into consideration as one of the differential diagnoses of abdominal pain in prepubertal girls [13]. A retrospective study that was done to compare adnexal torsion characteristics and torsion recurrence rates in a pre- and postmenarchal pediatric and adolescent females <18 years old with surgically diagnosed adnexal torsion found that there was a higher prevalence of paraovarian cysts on preoperative ultrasound in the postmenarchal group compared with the premenarchal group (20. Dysgerminoma is a malignant ovarian tumor that is most frequently seen during adolescence. Unlike most other germ cell tumors, dysgerminoma tends to grow rapidly and has a high risk of torsion [53­55]. The risk of torsion increases by at least eight-fold following tubal sterilization surgery. However, hysterectomy with ovarian conservation is not a risk factor for torsion [3, 23]. Infertility Treatments and Ovarian Torsion Ovulation induction to treat infertility may cause multiple large ovarian follicular cysts, and large cysts carry an increased risk of torsion [47, 59]. Operative laparoscopic conservative treatment (detorsion or unwinding the twisted adnexa) was performed in all of the patients. It is postulated that this is because the ovaries become displaced outside of the lesser pelvis [63]. Adnexal tumors at high risk for torsion and malignancy should be strongly considered for aggressive management during pregnancy [66]. Ovarian masses in pregnant women with adnexal masses 4 cm had a 1% to 6% lower incidence of torsion compared with ovarian masses in nonpregnant women [3, 70]. In a nutshell, pregnancy is a risk factor for torsion even in the absence of a predisposing factor. Ovarian Torsion in Neonates In neonates, complex masses may represent in utero or neonatal torsion; the risk of malignancy is extremely small in this age group. Most neonatal cysts are simple cysts and are mainly follicular cysts that originate as a result of maternal estrogens [71]. Prenatal torsion of the neonate is often diagnosed by routine ultrasonography during pregnancy in the second and third trimesters [73]. However, it is most commonly seen in adolescent (prepubertal) girls during the postovulatory period. In childhood, small cysts due to follicular development and atresia are common and not associated with a pathologic state [71]. However, ovarian tumors must be considered in children, especially in those with a large, persistent complex mass that has solid components. The most common ovarian tumor of childhood is mature cystic teratoma, followed by stromal tumors such as cystadenomas. Ovarian cysts are extremely common in adolescence because of persistent anovulation or ovulation dysfunction. Surgery was done for all patients, and the ovary was necrotic at the time of surgery in all cases. In addition, the associated medical and surgical treatment of the mass in this age group increases mortality. Recurrence of Ovarian Torsion the risk of recurrence is higher in premenarchal girls compared to postmenarchal girls. A common risk factor of recurrence of adnexal torsion in premenarchal girls is the occurrence of a first torsion episode in normal adnexa during the premenarchal period [27]. Another study examined the risk of recurrence of torsion of normal adnexa in postmenarchal women. This study found that torsion recurrence rates were higher in the twisted normal adnexa group compared to the abnormal adnexa group (P <. However, using laparoscopic management of adnexal torsion to spare adnexa by simply untwisting may predispose to recurrent torsion of normal adnexa [42]. Furthermore, torsion of normal adnexa recurs more often on the ipsilateral side [27, 42, 47]. The presentation is often nonspecific; patients my present with a variety of signs and symptoms that are often associated with other causes of acute abdomen, such as appendicitis, pyelonephritis, and nephrolithiasis [9]. Symptoms include acute-onset lower abdominal or pelvic pain; the pain fluctuates and radiates to the loin, back, or thigh. Before the sudden pain (acute), patients may experience an intermittent cramping pain for days or occasionally even for weeks. Premenarchal girls tend to mention a diffuse intermittent abdominal pain as the main presenting symptom because it is difficult for them to localize the pain. In addition, the clinical presentation of adnexal torsion in pregnant and nonpregnant women is the same [20, 23, 60, 80]. On abdominal examination, generalized abdominal tenderness, localized guarding, and rebound and palpable abdominal mass may be found. A clinical/pathologic study of torsion of ovarian tumor found palpable abdominal masses in the majority of cases (79. On vaginal examination, cervical excitation, adnexal tenderness, and adnexal mass may be seen [48]. Diagnosis Torsion of the ovary around its ligamentous supports may result in loss of its blood supply. Delay or misdiagnosis can result in the loss of the affected ovary and subsequent reduced reproductive capacity. Moreover, the diagnosis of this condition can be difficult due to a vague clinical presentation, particularly in intermittent torsion, and the differential diagnosis can include several other gynecologic and surgical emergencies. Adnexal/Ovarian Torsion 141 Clinical Presentation and Differential Diagnosis the ovaries are often difficult to palpate, so physical examination findings often do not suggest the diagnosis. Renal colic typically presents with sudden onset of severe unilateral colicky pain radiating from the loin to the groin, which comes in waves, very similar to torsion. In appendicitis, the pain is localized to the right iliac fossa, with localized guarding and tenderness. A history of sudden-onset, stabbing, sharp pain should raise the suspicion of hemorrhage from a functional cyst. Fibroid degeneration and torsion of pedunculated fibroids are not unusual and should be considered in women known to have fibroids. A rupture of a vessel over a fibroid is also a rare but reported cause of acute abdominal pain and intraperitoneal hemorrhage [83, 84]. Laboratory Investigations Basic laboratory investigations need to be performed to rule out other causes of acute abdominal or pelvic pain and include urine analysis, pregnancy tests, and full blood count. No single or combined markers have been identified that improve diagnostic accuracy in adnexal torsion. Torsion results in an ischemic insult to the ovary, and markers of ischemia or ischemia-reperfusion injury could theoretically be raised in the serum of women with torsion. The most common and easiest marker to examine is C-reactive protein, an acute phase protein that is increased in the presence of inflammation; the white blood cell count is also often measured and is increased in approximately 50% of women with adnexal torsion [88]. Unfortunately, neither of these markers has been found to be useful in the diagnosis of torsion because of low sensitivity and specificity. Several other proinflammatory markers (eg, interleukin-6 and tumor necrosis factor-a33) have been assessed, but again, none have proved to have sufficient diagnostic accuracy for routine use. However, sonographic findings can vary widely depending on the degree of vascular compromise. However, up to 5% of torsed ovaries have been reported as having normal size [30, 91]. Thus, normal ovarian size on gray-scale imaging does not exclude the diagnosis of torsion. In addition, peripherally displaced follicles with hyperechoic central stroma will be seen. The "follicular ring sign" is defined as a hyperechoic ring around the antral follicles compatible with perifollicular edema. There is often hemorrhagic fluid in the pouch of Douglas, but this is not invariable. A long-standing infarcted ovary may have a more complex appearance with cystic or hemorrhagic degeneration [91]. All abnormal sonographic appearances of the ovaries that previously have been attributed to the appearance of torsion in the ovaries, such as the ground-glass and cystic enlargement descriptors, have been found to be nonspecific findings. Endometriosis, hemorrhagic cysts, and tubo-ovarian complexes are often similarly described. The venous flow is more readily affected because of the compressibility of the venous plexus, and the arterial flow to an ovary usually resists torsion due to dual ovarian arterial supply from the aorta and uterine arteries. However, despite its typical high predictive value for most cases, adnexa with incomplete or intermittent torsion may at times still display both venous and arterial flow. Thus, disruption of vascular flow is highly suggestive of torsion, but torsion should not be excluded based on a normal Doppler study alone [97]. The relationship between the duration of pain and vascular flow characteristics was unexpectedly inverse. Other diagnostic criteria that have been described are the twist of the ovarian pedicle, infiltration of pelvic fat, pelvic ascites, and adnexal hemorrhage. Less common findings included hemorrhage in the thickened tube (16% of cases), hemorrhage within the adnexal mass (8%), hemoperitoneum (8%), and engorged vessels on the twisted side [103]. They may manifest as an amorphous, solid mass-like structure, have a target-like appearance, or manifest as a beak-like protrusion extending from the uterus and partially covering the adnexal mass. The twist tube appears as a tubular protrusion from the superiorly located adnexal mass toward the inferiorly located uterus. It allows the distinction between the edema of the ovary appearing hyperintense on T2-weighted images and the adjacent thickness of the fallopian tube [101, 104]. Because the ovary is not involved, a normal ipsilateral ovary does not allow the exclusion of adnexal torsion. Accurate diagnosis is important to maximize the likelihood of fallopian tube salvage. The broad ligament containing the vascular pedicle and fallopian tube appear in a helical configuration that may be best appreciated on the sagittal or coronal planes or on serial audiovisual images. Intravenous contrast agent administration also helps distinguish the ovary and uterus from the thickened swirling configuration of the broad ligament. Subacute hemorrhage is noted as an intraovarian hematoma, hematosalpinx, or hemoperitoneum [106]. The extent of hemorrhage depends on the degree and duration of the torsion, with hemorrhagic infarction occurring at a later stage than edema. The presence of a subacute hematoma is highly associated with infarction and secondary necrosis of the involved ovary [30]. Although subacute hemorrhage can be seen in an ovarian mass without torsion (eg, hemorrhagic cysts, hypervascular or epithelial primary ovarian tumors, and necrotic metastases), the T1-hyperintense rim of a subacute hematoma within an enlarged ovary in a woman presenting with acute pelvic pain should prompt any additional imaging maneuvers necessary to increase diagnostic certainty and initiate the appropriate gynecologic evaluation. Management Torsion of the ovary requires immediate diagnosis, emergency surgery, and treatment to avoid serious complications such as infertility. Traditional management involves oophorectomy, whereas conservative management includes detorsion of the twisted segment. The surgical management of adnexal torsion is clearly determined by many factors in addition to the macroscopic appearance of the adnexa, including age, menopausal status, the presence of preexisting ovarian pathology, and desire to preserve fertility. Because torsion of normal ovaries occurs more commonly in young and adolescent girls than in adult women [8], conservative emergency management becomes the main line of treatment. In addition, the absence of an enlarged ovary in this population contributes to delay in diagnosis. The outcomes, including postoperative ovarian function, were similar in both groups. However, laparoscopy was superior to laparotomy in terms of shorter hospital stay, fewer febrile morbidities, and less analgesic requirements postoperatively [110]. It has been widely accepted as a result of the following factors: the "blue-black" ovaries are nonviable, mere detorsion would trigger possible thromboembolic phenomenon, and there is a fear of leaving malignant tissue behind. Removing the injured organ is now suggested only when there are obvious signs of adnexal disruption, such as ligament detachment or ovarian tissue decomposition. Laparoscopic detorsion is the treatment of choice regardless of the color of the ovaries during the surgery. Within minutes following untwisting, congestion is relieved, and ovarian cyanosis and volume typically diminish. Currently, it is reported to be a safe and effective method in preserving fertility [86, 114, 115]. A persistently black-bluish ovary, however, is not pathognomonic for necrosis, and the ovary may still recover. The black-blue appearance was due to an initial lymphatic and venous stasis rather than significant arterial ischemia. Cohen and associates reviewed 54 cases in which adnexa was preserved regardless of its appearance following detorsion.

Conflict of interest: the authors declare that no conflict of interest or financial relationships exist in accordance with federal regulations cholesterol keto purchase online simvastatin. Pregnancy of unknown location: A consensus statement of nomenclature cholesterol high definition order simvastatin without a prescription, definitions and outcome cholesterol levels uk 6.5 discount simvastatin american express. Ectopic pregnancies in a Caesarean scar: review of the medical approach to an iatrogenic complication cholesterol medication reviews buy simvastatin 10 mg low cost. Failing pregnancies of unknown location: A prospective evaluation of the human chorionic gonadotrophin ratio foods cholesterol is found in generic 20 mg simvastatin free shipping. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: A meta-analysis. The echoic pseudogestational sac of ectopic pregnancy simulating early intrauterine pregnancy. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Transvaginal sonography as the ultimate diagnostic tool for the management of ectopic pregnancy: Experience with 840 cases. Adnexal sonographic findings in ectopic pregnancy and their correlation with tubal rupture and human chorionic gonadotropin levels. The diagnostic effectiveness of an initial transvaginal scan in detecting ectopic pregnancy. Diagnosing ectopic pregnancy and current concepts in the management of pregnancy of unknown location. Laparoscopy versus laparotomy in the management of ectopic pregnancy with massive hemoperitoneum. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: A prospective trial. Comparison of persistent ectopic pregnancy after laparoscopic salpingostomy versus salpingostomy at laparotomy for ectopic pregnancy. Laparoscopic salpingotomy for tubal pregnancy: Comparison of linear salpingotomy with and without suturing. Laparoscopic surgery for distal tubal occlusions: Lessons learned from a historical series of 434 cases. Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management. The overall incidence of ectopic pregnancy in the general population is 1% to 2% and increases to 2% to 5% with assisted reproductive techniques [1]. It is essential to clarify the nomenclature used for different sites of ectopic pregnancy because the terms interstitial pregnancy, angular pregnancy, and cornual pregnancy are often used interchangeably [2]. An interstitial pregnancy is an uncommon type of ectopic pregnancy that results from embryonic implantation in the myometrium surrounding the interstitial part of the fallopian tube and includes 2% to 4% of all ectopic pregnancies [3]. A cornual pregnancy is defined as implantation of the embryo in the fundal intrauterine portion of the anomalous bicornuate or septate uterus. Angular pregnancy is defined as implantation of the embryo into the lateral superior angle of the uterine cavity [3]. The interstitial part of the fallopian tube originates from the tubal ostium and crosses the myometrium of the uterus with a tortuous course eventually arising from the uterine cavity [5]. The interstitial part is relatively thick, with an average diameter of 1 to 2 cm, allowing for a greater capacity of expansion before rupture, generally at 7 to 16 weeks [6]. Due to its high vascular supply from anastomosis of uterine and ovarian arteries, the rupture of the interstitial pregnancy results in catastrophic hemorrhage [7]. Hence, compared to ectopic pregnancies in general, the mortality rate of interstitial pregnancy is seven times greater [7, 8]. Angular pregnancy is differentiated from interstitial pregnancy by its implantation medial to the uterotubal junction. Hence, on laparoscopy, angular pregnancy appears as a bulge medial to the round ligament, while interstitial pregnancy appears lateral to it [3, 7, 9]. Although a normal pregnancy is possible, some of the potential complications of angular pregnancy are miscarriage, persistent pelvic pain, retention of placenta, and rarely, uterine rupture [6]. If pregnancy is implanted in a uterine horn, a great variation is observed in the clinical outcomes of cornual pregnancy contingent on the size and expansibility of the uterine horn [7]. In another case series of interstitial pregnancy in 32 women with mean gestational age of 6. Interstitial line is another sonographic finding used to diagnose interstitial pregnancy, described as an echogenic line extending into the cornual region and abutting the midportion of the interstitial mass or the gestational sac. On sonography, interstitial pregnancy is characterized by a scarcity of the myometrium around the superolateral aspect of the sac, in contrast to angular pregnancy, which is surrounded by at least 5 mm of myometrium on all sides [14]. Cornual pregnancy is essentially ruled out when a structurally normal uterus is identified. Latest techniques, such as 3D high-definition live, render images that provide natural and realistic images of the embryo, may also improve the diagnostic accuracy for interstitial pregnancy [16]. Precise differentiation of interstitial pregnancy from angular pregnancy is essential because management options differ significantly. Moreover, early diagnosis and timely management are essential for successful outcome. However, it may be technically more challenging in presence of hemoperitoneum [18]. Expectant management may be offered, but the patient should be counseled about the possibility of uterine rupture. Patients opting for elective termination of this high-risk pregnancy may be provided with nonsurgical or minimally invasive options [2]. Laparoscopic view during the procedure helps to evaluate the size of the uterus and detects rupture during the procedure. Hysteroscopic view guides the suction tube and confirms complete evacuation of the gestational sac from the uterine cavity and the fallopian tube. This technique verifies that there is no interstitial involvement or perforation [23]. However, there is paucity of reported cases of angular pregnancy and its management. Successful transcervical evacuation is possible in unruptured cases, hemodynamically stable patients, and pregnancies located in the proximal portion of the interstitium with a dilated tubal ostium. The transcervical approach avoids cornual transection, preventing future infertility, tubal blockage, or uterine rupture in subsequent pregnancies. Additional advantages of the procedure include its low cost, short hospital stay, and less invasive nature [21]. Cornuostomy In cornuostomy, the gestational sac is evacuated by an incision on the interstitial pregnancy without removing the surrounding myometrium. This procedure is comparable to salpingostomy performed for ectopic pregnancy in the distal tube [24, 25]. Laparoscopic cornuostomy can be successfully performed by an experienced surgeon, with minimal blood loss and short operative time [26]. Diluted vasopressin is often injected in the myometrium surrounding the gestational sac. The incision can be closed by either interrupted or continuous absorbable sutures [25], suture loop, or purse string sutures [27­30]. The patient presented with rupture of an 8-week interstitial pregnancy after unsuccessful management with methotrexate and was emergently treated with cornuostomy with uneventful postoperative course and successful conception after 6 months followed by cesarean delivery [24]. However, after the advent of laparoscopy, several minimally invasive techniques have been described for cornual resection [31, 32]. The procedure is usually performed by evacuating the gestational sac en bloc with the surrounding cornua through a circumferential incision, followed by closure of the myometrium. Successful laparoscopic cornual excision has been reported in the presence of hemoperitoneum or ruptured interstitial pregnancy [33, 34]. The average interpregnancy interval in this cohort of patients was 4 years and was a possible contributing factor for the absence of uterine rupture [37]. A recent study compared 26 women treated for interstitial pregnancy with either open or laparoscopic cornual resection and 52 parity-matched controls who underwent salpingectomy for noninterstitial ectopic pregnancy. There was no significant difference in spontaneous pregnancy rates beyond 24 weeks of gestation between the two groups (46% cases vs 54% controls, P =. The fear of rupture contributed to higher elective cesarean section rates in patients with previous resection as compared to controls, with no difference in emergency cesarean rates between the two groups [38]. In a retrospective study of 53 interstitial pregnancies, 52 were successfully managed laparoscopically (33 had wedge resection, 13 had cornuostomy, 7 had salpingectomy), whereas only one was converted to a laparotomy [39]. Another retrospective study of 75 interstitial pregnancies compared laparoscopic cornuostomy and cornual resection procedures and found that the mean operative time was shorter for cornuostomy (59. Gestational age, return to operating room, and persistent interstitial pregnancy were comparable between the two groups [34, 40]. They also found the rate of persistent interstitial pregnancy to be higher in ruptured cases (27. Conclusion There has been an increase in the interstitial pregnancy rate due to the use of assisted reproductive techniques. Newer diagnostic techniques permit proper diagnosis and differentiating among interstitial, angular, and cornual pregnancies at an early gestational age. Different minimally invasive techniques can successfully manage interstitial and cornual pregnancies. Incidence of interstitial pregnancy after in vitro fertilization/embryo transfer and the outcome of a consecutive series of 38 cases managed by laparoscopic cornuostomy or cornual repair. Interstitial pregnancy: Results generated from the Society of Reproductive Surgeons registry. Interstitial line: Sonographic finding in interstitial (cornual) ectopic pregnancy. Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. Three-dimensional transvaginal sonographic diagnosis of early and asymptomatic interstitial pregnancy. Diagnosis of interstitial ectopic pregnancy using a three-dimensional high-definition live rendering image. Distinguishing between interstitial and angular pregnancies: Is there a role for saline infusion sonohysterography Laparoscopic management of ectopic pregnancies: A comparison between interstitial and "more distal" tubal pregnancies. Laparoscopic and ultrasound-guided transcervical evacuation of cornual ectopic pregnancy: An alternative approach. Transcervical suction of interstitial pregnancy under laparoscopic and hysteroscopic guidance. Laparoscopic-guided suction curettage of a cornual ectopic pregnancy in a bicornuate uterus. Successful procedure in conservative management of interstitial (cornual) ectopic pregnancy. Laparoscopic diagnosis and treatment of interstitial ectopic pregnancy: A case report. Endoloop technique for laparoscopic cornuectomy: A safe and effective approach for the treatment of interstitial pregnancy. Outcomes in subsequent pregnancies after wedge resection for interstitial ectopic pregnancy: A retrospective cohort study. Comparison of laparoscopic cornual resection and cornuotomy for interstitial pregnancy. Rimawi Introduction Medical providers caring for pregnant women encounter ectopic pregnancies. Ectopic pregnancy occurs in approximately 1% to 2% of all pregnancies, with cervical ectopic pregnancies accounting for <1% of all pregnancies [1]. Cervical ectopic pregnancies have an estimated incidence of one in 2500 to one in 18,000 [1, 2]. This rare type of ectopic pregnancy can result in catastrophic outcomes, specifically significant amounts of hemorrhage, and previously was treated presumptively with hysterectomy. Given the rarity of the condition, even today, the most effective method of its management is under investigation [3­10]. This finding is considered the best diagnostic clue to establish this diagnosis [11]. It is important when locating this specific type of pregnancy that the endocervical canal be visualized separately, which is always adjacent to the sac [11]. In addition, a classic finding with cervical pregnancies is the hourglass-shaped appearance of the cervix. This appearance almost mimics a human waist due to the closed internal os, giving a similar appearance in its shape. To identify the internal cervical os, the bladder neck must be visualized in a sagittal plane, which is considered the anatomic landmark [11]. If an embryo is present, a heartbeat does not need to be present, but often this is seen when diagnosing these types of pregnancies. The use of color Doppler to aid in establishing a diagnosis cannot be emphasized enough because this additive diagnostic modality demonstrates the marked peritrophoblastic flow around the sac embedded in the cervical stroma. However, it may be deceiving when mild vascularity in isolation is visualized without other signs of cervical pregnancy; therefore, color Doppler should be used in conjunction with visualizing a gestational sac within the cervical stroma [12]. Transabdominal ultrasound aids in identifying the appropriate landmarks anatomically. With this method of imaging, the following should be able to be clearly identified: shape of the uterus, position of the uterus, internal cervical os, and bladder and bladder wall [12].

The relationship between podocyte foot process effacement and proteinuria has been questioned cholesterol medication withdrawal symptoms generic simvastatin 40 mg amex,55 and it is clear that there is still much to learn about this long-recognized but still poorly understood ultrastructural phenomenon cholesterol definition simple cheap simvastatin. Confusingly how much cholesterol in eggs benedict purchase simvastatin now, effacement has also been reported (in the absence of proteinuria) in the protein-malnutrition state kwashiorkor cholesterol definition in hindi discount 20 mg simvastatin,56 suggesting that it may be a feature of hypoalbuminemia rather than of proteinuria per se cholesterol levels what is high 20 mg simvastatin purchase free shipping. Therefore teasing out precisely the biologic role of effacement in the development and maintenance of proteinuria may not be important. Several genetic studies in humans have been very instructive in understanding podocyte biology in general and the role of the actin cytoskeleton in particular (reviewed by Wang and von der Lehr). The podocyte slit diaphragm is a major size barrier to albumin and other proteins, and studies have suggested the possibility that this also serves as a charge barrier too. In acquired diseases, either an absolute decrease in their levels or a change in their subcellular location is associated with proteinuria. Another mechanism for proteinuria is a decrease in podocyte number, which simply creates gaps in this layer, enabling proteins to escape through the cellular barrier. A third mechanism underlying proteinuria following podocyte injury is its effect on the glomerular endothelial cell. In general, increased knowledge about genetic causes of nephrotic syndrome has so far had a disappointingly limited impact on understanding, prediction, or management of sporadic cases. Analysis of podocyte genes as predisposing factors for diabetic nephropathy has so far produced negative results. Avoiding these drugs spares patients from unnecessary exposure to toxic therapies. Regrettably, at present such information assists in the management of only a very small proportion of patients. Patterns of glomerulosclerosis histologically include a segmental form (a portion of an individual glomerulus is scarred) and the more extensive global form (the majority of an individual glomerulus scars). There are several mechanisms whereby injury to podocytes leads to glomerulosclerosis. However, because podocytes are terminally differentiated epithelial cells, they are unable to adequately proliferate to replace those lost because of the events described earlier. When podocyte number is reduced by 20% of normal, mesangial cells begin to proliferate and undergo expansion. Studies have suggested that despite a lack of proliferation, podocyte number can be restored following certain therapies such as angiotensin-converting enzyme inhibition. The cellular sources of the increase in extracellular matrix proteins in podocyte diseases derive from podocytes and also from their neighbors, the parietal epithelial cells. Such findings would imply a regenerative pathway or pathways arising from another source. A study of kidneys transplanted from female donors into male recipients identified "male". Experimental data in mice do not support this at the time of writing this chapter. Experimental studies suggest that cells of renin lineage, normally residing in the juxtaglomerular compartment, might also serve as adult podocyte progenitors in states of podocyte depletion. An elegant study showed that the effects of cyclosporine on proteinuria are independent of its effects on the immune system and defined the calcineurin-dependent dephosphorylation of synaptopodin, which in turn leads to destabilization of the podocyte actin cytoskeleton, as the key reaction in podocytes that is inhibited by cyclosporine. However, several therapies have, in addition to their systemic effects, direct biologic actions on podocytes. The specific anti­B cell monoclonal antibody rituximab, increasingly thought to be effective in proteinuric diseases even when they are not all obviously immune mediated, has been shown to have direct effects on podocytes, including stabilizing their actin cytoskeleton. The identification of the podocyte as the key cell type in proteinuric disease made it logical to examine whether effects of glucocorticoids on podocytes could explain their efficacy in nephrotic syndrome. Initial reports in murine89 and human90 podocytes showed that dexamethasone had potent biologic effects directly on podocyte structure and function. These include limiting podocyte apoptosis,91 enhanced nephrin transport,92 and effects on the actin cytoskeleton. For these reasons, inhibition of the renin angiotensin aldosterone system is currently the standard of care for lowering proteinuria. For example, hepatocyte growth factor appears to have reparative effects in podocytes injured by Adriamycin in vivo and in vitro101 and in the glomerular injury induced by lipopolysaccharide. In experimental diabetic nephropathy, blockade of the cannabinoid receptor 1 reduces albuminuria. Moreover, these proteins are constantly communicating with one another through elaborate signaling pathways to ensure that they function properly to limit the passage of proteins from the blood compartment to the urinary space, while also maintaining a normal shape. Thus, when injured, they cause changes to other glomerular cells and structures to some extent, depending on the glomerular disease type. Perhaps one of the biggest is podocyte regeneration, because these cells are simply unable to proliferate successfully or adequately to replace any depletion in their overall number. Designing and delivering therapeutic agents specific to podocytes is actively being pursued, both to enhance efficacy and to reduce systemic side effects. Noninvasive diagnostic testing is being keenly studied, such as measuring podocyte products in the urine, and markers in the serum and urine. Live video imaging is significantly advancing our understanding of the movement and behavior of podocytes under normal and stressed conditions beyond the traditional "fixed" pictures using conventional microscopy. Urinary and plasma biomarkers are being identified that it is hoped will translate into clinical practice. The past 2 decades have witnessed phenomenal advances in understanding podocyte biology in health and disease, and the future looks ever so bright too. The generation of "podocytespecific" transgenic mice, as well as the development of several cell lines, has enabled investigators to better understand this dynamic and highly specialized, terminally differentiated epithelial cell. Sachs N, Sonnenberg A: Cell-matrix adhesion of podocytes in physiology and disease. Reiser J, von Gersdorff G, Loos M, et al: Induction of B7-1 in podocytes is associated with nephrotic syndrome. Hohne M, Ising C, Hagmann H, et al: Light microscopic visualization of podocyte ultrastructure demonstrates oscillating glomerular contractions. Jeansson M, Gawlik A, Anderson G, et al: Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. Gagliardini E, Conti S, Benigni A, et al: Imaging of the porous ultrastructure of the glomerular epithelial filtration slit. Asanuma K, Yanagida-Asanuma E, Faul C, et al: Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Ronco P, Debiec H: Target antigens and nephritogenic antibodies in membranous nephropathy: of rats and men. Romagnani P, Lasagni L, Remuzzi G: Renal progenitors: an evolutionary conserved strategy for kidney regeneration. Smeets B, Kuppe C, Sicking E-M, et al: Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. Ohashi T, Uchida K, Uchida S, et al: Dexamethasone increases the phosphorylation of nephrin in cultured podocytes. Uchida K, Suzuki K, Iwamoto M, et al: Decreased tyrosine phosphorylation of nephrin in rat and human nephrosis. Faul C, Donnelly M, Merscher-Gomez S, et al: the actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Kato T, Mizuno S, Nakamura T: Preservations of nephrin and synaptopodin by recombinant hepatocyte growth factor in 54. Lowik M, Levtchenko E, Westra D, et al: Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis. Kriz W: Podocyte is the major culprit accounting for the progression of chronic renal disease. Barutta F, Corbelli A, Mastrocola R, et al: Cannabinoid receptor 1 blockade ameliorates albuminuria in experimental diabetic nephropathy. Saito D, Maeshima Y, Nasu T, et al: Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis. This article is dedicated to one aspect of kidney metabolism-namely the storage, release, and utilization of energy by the nephron as it transforms the glomerular filtrate into urine. Of the major body organs, the kidney consumes the second highest amount of oxygen per gram of tissue (2. It has been asserted that because the kidney reabsorbs 99% of the glomerular filtrate, it must use a lot of energy-but this logic is incorrect. The minimum net energy required for reabsorption does not depend on the amount of fluid that is reabsorbed. On the other hand, energy is required to form a urine that differs in solute composition from that of the body fluids. To appreciate this, consider that the hypothetical remixing of urine with plasma would cause the formation of entropy, known as mixing entropy. The minimum amount of energy required for this is equal to the temperature multiplied by the decrease in mixing entropy associated with the differential solute composition of urine versus plasma. The theoretical minimum amount of energy required to make urine was determined from the laws of equilibrium thermodynamics nearly a century ago. For a human in balance on a typical diet, the cost of converting the glomerular filtrate into urine by an idealized process that is 100% efficient, infinitely slow, completely reversible, involves no backleak, and generates no entropy and heat is about 0. On this basis alone, one might argue that the kidney is horribly inefficient, even after one subtracts the cost to the kidney of maintaining itself. On the other hand, added costs are imposed by the requirement to make urine in a finite amount of time, need for flexibility to alter the volume and composition of the urine rapidly, stoichiometric constraints of biochemistry, known limits on the thermodynamic efficiency of oxidative phosphorylation, and intrinsic permeabilities of tissues to electrolytes, gases, and urea. The thermodynamic requirement may be a small fraction of the actual expenditure, but before one concludes that the body is unconcerned with thermodynamics, it may be noted that the thermodynamic energy required of the kidney to maintain salt and nitrogen balance with consumption of a typical diet is minimized with the usual water intake of 1 to 2 L/day. This is consistent with an evolutionary process geared to minimize the thermodynamic energy requirements of the kidney. Using a classic thermodynamic approach, Newburgh suggested that the composition of the urine and body fluids in kidney disease are determined by the available free energy and noted that the declining flexibility of the diseased kidney to vary the urine composition could be predicted from the reduced free energy available for transport. The first law of thermodynamics states that total energy is conserved during any process that occurs in a closed system. When a system is open to its environment, the combined energy of the system plus environment remains constant. When the total internal energy, temperature, pressure, and volume of a system remain constant, any process that yields a change in free energy also yields a reciprocal change in entropy. Doing work on the system is equivalent to adding free energy to the system, which determines the upper limit of how much useful work the system can do against its environment. The first law of thermodynamics stipulates that total energy is conserved throughout any process, but provides no other indication of whether a given process will occur spontaneously. The urine has a different ratio of urea to salt than the reabsorbate, so the entropy has decreased. However, the total internal energy of the combined urine and reabsorbate is the same as the original filtrate. Hence, the first law would be satisfied if the urine were to form spontaneously from the filtrate. The fact that NaCl and urea never sort themselves spontaneously into regions of higher and lower concentration is a consequence of the second law of thermodynamics, which states that all spontaneous processes generate entropy. Conversely, all spontaneous processes dissipate free energy and will cease when the supply of free energy is exhausted. It is possible to reduce entropy or elevate free energy in a system, but only if the system imports energy from its surroundings, in which case there will be an increase in entropy of the surroundings that exceeds the decrease in entropy of the system. Other processes, such as the countercurrent multiplier, are inefficient and generate a lot of entropy. The laws of equilibrium thermodynamics determine the direction of any spontaneous process, but they do not address the rate of change. Hence, the laws of equilibrium thermodynamics are not adequate for a full description of a living system that is displaced from equilibrium and characterized by flow of matter and energy within the system itself, as well as between the system and its environment. Thermodynamic principles are extended to incorporate time as a variable by the theory of nonequilibrium thermodynamics. Nonequilibrium thermodynamics entails certain assumptions and approximations that make it more of a tool and less of a foundation than classic equilibrium thermodynamics, but the theory performs well in many areas of physiology, including transport physiology. In this process, there is almost full conversion from chemical to mechanical energy, with minimal dissipation. Although this energy could be dissipated through subsequent collisions, such events are unlikely over very short time scales and short distances. If no other collisions occur in that short time interval, the phosphate can then transfer its entire kinetic energy to the sodium pump in the form of a molecular strain. If the permeability to one ion dominates the others, then the membrane voltage approaches the Nernst potential for that ion, and the free energy is transferred to the electrochemical potential of the other ions. If chloride is not actively transported, then the second law of thermodynamics dictates that no free energy exists in the chloride gradient. Thus, for a membrane that actively transports Na and K and is primarily permeable to K, the membrane voltage approaches the Nernst potential for K, and the free energy provided by active transport is all transferred to the transmembrane Na difference. The negative cell voltage, in turn, neutralizes the net driving force for further potassium egress and augments the net driving force for sodium entry. This allows the transmembrane concentration differences for sodium and potassium to remain almost equal and opposite in spite of the much greater permeability to potassium. In the proximal tubule, the energy for apical chloride entry is derived circuitously via sodium-hydrogen exchange, which is coupled to oxalate, formate, or hydroxyl ion transport. In each case, raising cell chloride above equilibrium provides a driving force for chloride to diffuse out of the cell across the basolateral membrane, which is permeable to chloride. Raising cell chloride also makes the basolateral membrane voltage less negative, as is apparent from the Goldman equation. Because luminal voltage is the sum of voltage steps across the basolateral and apical membranes, raising cell chloride in a cell with basolateral chloride conductance will raise the lumen voltage.

Syndromes

• Acute renal failure
• Short-term use of systemic steroids
• Ascites and varices
• Extreme tiredness (lethargy)
• Abnormal Pap smears
• Bronchoscope: Used to look in the airways and lungs
• Constipation
• Kidneys (renal vein thrombosis)
• Twitching in face

Occasionally cholesterol levels chart south africa order cheap simvastatin, or in more severe cases cholesterol levels with age discount simvastatin 40 mg with mastercard, mineralization cholesterol medication chart simvastatin 10 mg purchase visa, eosinophilic intranuclear (pseudo) inclusion bodies cholesterol hair treatment 40 mg simvastatin purchase mastercard, believed to be caused by invagination of the cytoplasm into the enlarged nuclei cholesterol score of 7 order simvastatin 10 mg without a prescription, and within the hypertrophic cardiac myofibers (Jasty et al. Although quite rarely, some early lesions may present as myocardial necrosis and hemorrhage in the subendocardium or papillary muscle (Chamanza et al. Such lesions present perhaps the greatest interpretative challenge for cardiovascular findings in toxicity studies in non-human primates. The etiology of the spontaneous lesions in monkeys is not clear, and there is debate as to whether the morphologic features are comparable to chronic catecholamine-induced experimental cardiomyopathy or stress-induced cardiomyopathy (Nyska and Gruebbel 2010; Vidal et al. Biochemical measurements would be required to support the catecholamine/stressrelated hypothesis. However, findings similar to those described above, such as cardiac myofiber hypertrophy, karyomegaly, and vacuolation, were observed in a rhesus macaque with an active angiomatous pheochromocytoma (Vogel and Fritz 2003) and in animals directly injected with catecholamines (Khullar et al. Therefore, it is possible that myocardial degeneration with karyomegaly is at least in part, associated with stress and the release of catecholamines. However, due to the propensity of this lesion to occur at higher frequency in particular groups or batches of animals, supplier or source (geographic region) (Vidal et al. Three main types of ectopic cyst have been described in the macaques and marmosets (Chamanza et al. Insert shows medial and adventitial inflammation, in addition to splitting of the internal elastic lamina. The Cardiovascular System 755 keratinized cysts may be associated with a foreign-body inflammatory reaction where the epithelial wall breaks and the keratin is in direct contact with adjacent tissues (Chamanza et al. Squamous plaques are incomplete cysts with no central lumen and are thought to represent tangential sections of walls of squamous cysts. Ectopic thyroid follicle-like structures on the other hand are mainly observed in the subepicardial areas at the base of the heart, including atrial appendages and walls of the great vessels, and are not readily identified at necropsy. It has been suggested that squamous cysts and squamous plaques could be of foregut origin while ectopic thyroid tissue could be of thyroglossal duct origin (Elwell and Mahler 1999; Kaspareit et al. Other very common congenital findings in laboratory animals are valvular hematocysts or angiectasis of valvular vessels (also incorrectly referred to as valvular haematoma) seen in young beagles (and ruminants). They are spontaneously regressing, bulging blood-filled cysts with no functional consequence, although in some cases, hemorrhage, thrombosis with organization/fibrosis, and hemosiderin may be present. Minimal to mild grades of spontaneous valvular myxomatous change characterized by accumulation of loose mucinous substance and slight thickening of valves can be observed occasionally in young dogs, and rarely in young primates (Chamanza et al. Mineralization and extramedullary hematopoiesis occur more commonly in marmosets than other laboratory species. The lesion is believed to be linked to vitamin D3 oversupply, since marmosets have a special requirement for dietary vitamin D3 (Lowenstine 2003), and the presence of minimal mineralization in other organs such as adrenal glands is suggestive of metastatic calcification. Similarly, myocardial extramedullary hematopoiesis in the heart and other organs is considered to be related to the nutritionally associated anemia in the captive common marmoset (Zuhlke and Weinbauer 2003). This finding should not be confused with myocardial inflammatory cell infiltration. In control, purpose-bred beagle dogs, 9­20 months of age, and using standard histologic sections of all cardiac chambers, myocardial inflammation has been reported in 2% females and 5% males (Keenan and Vidal 2006). Small foci of myocardial degeneration and necrosis, with or without inflammation and fibrous scar tissue, can be seen in routine heart sections from toxicology studies. This may or may not be associated with mineralization, and the lesion is considered to be a spontaneous incidental finding, and has no specific anatomical predilection (Keenan and Vidal 2006). Focal myocardial necrosis may be due to stenosis of small intramyocardial or large branches of the coronary arteries (Luginbühl and Detweiler 1965); or infection with canine parvovirus which, in older dogs, can cause cardiac inflammation and/or fibrosis (Robinson et al. Physiologic factors such as blood pressure and genetic factors can also contribute to cardiac size and the potential for cardiac enlargement (Tanase et al. However, using parameters not affected by body condition such as brain weight may be more meaningful (Sellers et al. Generally, dilation and hypertrophy can be an adaptive response to mechanical, hemodynamic, hormonal, or pathological stimuli (Greaves 2007). An acute increase in volume overload of a chamber will 756 Toxicologic Pathology lead to expected physiological dilation, while a chronic volume overload stimulus can result in hypertrophy (Berenji et al. Increased diastolic workload from valvular insufficiencies can also cause dilation (Hunter and Chien 1999). Dilation is a response to an increased workload in both the physiologic and pathologic states (Grossman 1980). This increased volume causes stretching of myofibers and increased contractile force of the heart, resulting in increased stroke volume and cardiac output. Chronic dilation can result in hypertrophy and change in heart shape (Dorn 2005; Grossman 1980). A reversible increase in cardiomyocyte mass, but not myocyte number, is termed cardiac hypertrophy. The initiating stress factor determines the pattern of the hypertrophic (concentric or eccentric) response, and compounds that cause systemic hypertension affect the left ventricle, while pulmonary hypertension affects primarily the right ventricle. Eccentric cardiac hypertrophy occurs in a pattern similar to normal growth and is driven primarily by volume overload due to an increase in end diastolic volume and a dilated chamber (Grant et al. In eccentric hypertrophy and dilation, even though there is increase in muscle mass, the walls are usually thin and the heart tends to be globose (Grant et al. Concentric hypertrophy is a disproportionate increase in ventricular wall thickness with a normal or reduced end-diastolic and chamber volume. The increased thickness of the ventricular walls will normalize the wall stress during systole because of the addition of new myofibrils (Grant et al. In ventricular volume overload, there is increased wall stress during diastole which leads to the addition of sarcomeres, fiber elongation, and chamber enlargement (Grossman 1980; Grossman et al. Chronic chamber enlargement increases systolic pressure that produces ventricular wall thickening in an attempt to normalize systolic stress. Grossly, the hypertrophic endocardium may appear opaque due to subendocardial fibrosis (Greaves 2007). Cardiac hypertrophy develops subsequent to abnormal systolic and diastolic stresses on the cardiac myofiber. The increase in mass and size of the heart is driven by mechanical and trophic stimuli. There is recent evidence that the mechanical stresses activate growth factor-related surface receptors that induce transcription of embryonic and immediate early-response genes that influence growth and differentiation (Akazawa and Komuro 2003; Cooper 1997; Dorn 2005; Hunter and Chien 1999). Gene expression can change the phenotype of the myocyte by induction of atrial, natriuretic peptides, and switching from adult to fetal forms of myosin and skeletal actin (Maxie and Robinson 2007). Signal transduction also plays an important role in the cardiac hypertrophy remodeling process because, in response to systemic hypertension, mice lacking gp130 cytokine receptor in myocytes do not develop cardiac hypertrophy, but instead have marked increase in cardiomyocyte apoptosis, dilated cardiomyopathy, and heart failure (Hirota et al. It is generally accepted that hypertrophy is an adaptive, compensatory response that diminishes wall stress and oxygen consumption (Berenji et al. In humans, ventricular hypertrophy is a marker of increased risk for development of heart failure (Berenji et al. Data from some studies in humans suggest that there are clear differences between physiological and pathological hypertrophy (Pelliccia et al. Experimental myocardial hypertrophy has been produced as a compensatory response to exercise, hypertension, and myocardial infarction. Chronic administration of anabolic steroids, testosterone, catecholamines, thyroxine, and growth hormones can also produce a similar response (Craft-Cormney and Hansen 1980; Gilbert et al. Although a variety of factors including endocrine, paracrine, or autocrine effects may contribute to growth in cardiac mass, it is not clear how hemodynamic stress and these interactions determine cardiac hypertrophy. Interstitial cells also play an important role in the process of cardiac enlargement, and increased fibrosis has been reported as a contributory source of dysfunction (Weber et al. Morphologically and morphometrically, fibroblast proliferation was associated with increased abnormal collagen deposition that may account for the increased stiffness of the myocardium, and ultimate dysfunction (Findikli et al. This includes compounds that are active pharmacologically as antiarrhythmics, sympathomimetics, calcium channel blockers, vasodilating antihypertensive drugs, and adrenergic blockers, and agents that perturb energy metabolism of cardiac myoctes such as oxfenicine (Case et al. Many of these drugs have logged significant patient years and have not been reported to cause adverse cardiac effects or increased risk of diastolic heart failure in humans (Greaves 2007). Conversely, a direct effect on the myocardial structure and/or function must also be taken into consideration and, if necessary, conduct special investigative studies. Pharmacologically, compounds that cause perturbation of cardiomyocyte energy metabolism have been reported to increase cardiac weight. The weight of evidence from these data suggested that exaggerated pharmacology in the dog and rat was responsible for this adaptive response (Bachmann et al. Increases in cardiac weight, myocardial discoloration, dilated and flabby ventricles were observed in rats following administration of methyl2-tetradecylglycidate (Bachmann et al. Based on these findings, it was concluded that this cardiac effect was a result of direct effect on cardiomyocyte energy metabolism (Zbinden 1986). Light and transmission electron microscopy did not show any evidence of cell injury or damage. The effects were fully reversible after two weeks in the off treatment phase (Greaves 2007). Administration of and 2 adrenoreceptor blockers did not prevent cardiac effects, but these effects were prevented when sympatholytics (non-selective, and 1 adrenoreceptor blockers) were administered (Greaves 2007). In nonclinical toxicology studies, administration of troglitazone was associated with cardiac hypertrophy in rats and mice, but not monkeys (Breider et al. There was no evidence of cardiac effects with troglitazone in human clinical trials, which may be due to withdrawal from the market before sufficient post-marketing data became available. In contrast, the cardiac effect of rosiglitazone in humans remains controversial (Delea et al. Cardiac hypertrophy and peripheral edema are the two major safety concerns for this class of drug. These nonclinical observations translated into clinical edema in patients, which may or may not contribute to cardiotoxicity (Peraza et al. Approved small molecule drugs associated with this adverse effect include sunitinib, dasatinib, and sorafenib. The molecular mechanism underlying cardiotoxicity has not been elucidated, but mitochondrial perturbation and modulation of adenosine monophosphateactivated protein kinase activity have been implicated (Mellor et al. This complex interaction and overlap makes predicting clinical cardiotoxicity from nonclinical toxicology data very difficult. Developing a clear picture of the important signaling pathways for members of the kinome for therapeutic target selection, and secondary pharmacology screening to improve the safety profile for cardiotoxicity, is a major hurdle. Because kinases are important regulatory proteins that act through a vast, interconnected network of cellular processes, toxicity can arise from intended or unintended "bystander" targets that have no role in the desired biologic effect. Determining which of these off target kinases play a role in the maintenance of normal cardiac physiology and function will aid in selection of pharmacologically active targets and/or molecules with a low risk for cardiotoxicity. Identification of these signaling pathways will enable development and utilization of secondary pharmacology screens in nonclinical toxicology studies and this investment could reduce attrition significantly. Drug-Induced Myocardial Degeneration and Necrosis, Inflammation, and Fibrosis the myocardium can be damaged by a wide variety of insults including infectious, ischemia, anoxia, chemical, or physical agents; however, the pattern of response to injury by cardiomyocytes is very limited. Some of these responses, such as cytoplasmic vacuolation, may be reversible, but persistence of these cytoplasmic changes will result in degeneration, necrosis, inflammation, and eventually repair with fibrous connective tissue because cardiomyocytes lack the ability to regenerate. The degree and severity of inflammation depends on the agent causing the insult, and continued contraction of myocytes plays an important role in formation of the scar tissue (Vracko et al. In general, myocardial necrosis, myocarditis, and myocardial infarction are recognizable histologic patterns of damage that can be seen in the heart. Use of the term "necrosis" is non-specific and is applicable to many different types of myocardial damage, while myocardial infarction implies necrosis as a result of underlying ischemia. The use of the term myocarditis suggests an infectious cause; however, drugs and toxins may be associated with this response though the causation may be unclear (Feldman and McNamara 2000). In toxicology studies, spontaneous, age-related changes in the myocardium often manifest as inflammation, and this can confound interpretation in chronic toxicity studies because a clear underlying etiology is unknown. In non-human primates, infiltration of inflammatory cells in the myocardium is fairly common in control animals routinely used in toxicology studies. The most common cardiac findings include inflammatory cell infiltrates, focal myocarditis, myocardial fibrosis, endocarditis, and pericarditis (Chamanza et al. Non-inflammatory findings that have been reported include anisokaryosis, karyomegaly, mineralization, squamous cysts, and ectopic thyroid tissue (Chamanza et al. Spontaneous cardiomyopathy, characterized by cardiomyocyte disarray, cytoplasmic pallor, karyomegaly, vacuolization of the perimyseal connective tissue and perivascular fibrosis, have been reported (Zabka et al. The etiology of these spontaneous lesions in monkeys is not clear, and there is debate as to whether the morphologic features are comparable to chronic catecholamine-induced experimental cardiomyopathy or stress-induced cardiomyopathy (Nyska and Gruebbel 2010; Vidal et al. Biochemical measurements would be required to support the catecholamine/stress-related hypothesis. Of relevance to toxicology, inhibition or deficiency of Vitamin K activity in mice can induce multifocal myocardial hemorrhage with secondary edema and inflammation (Allen et al. Myocardial necrosis can be the result of cardiac ischemia and the outcome of cardiac ischemic events depends not only on the intensity, size, and duration of the ischemic stimulus, but also on the intrinsic defense mechanisms of the myocardium (Ravingerova 2007). The inherent protective mechanisms provide a so-called "tolerance" to myocardial ischemia/perfusion, and limit the degree and magnitude of myocardial injury during ischemic events (Peart and Headrick 2008). This protective mechanism is termed "ischemic tolerance" and is induced by ischemic preconditioning, an adaptive response. Classic preconditioning is the first phase, and begins minutes after the "stimulus," lasting up to 2 hours (Murry et al. Late preconditioning, or "second window of preconditioning," is the second phase, and begins 24 hours post-preconditioning stimulus, lasting up to 96 hours (Marber et al. Ischemic post-conditioning can also occur after a period of prolonged ischemia (Zhao et al. Cardiac ischemic tolerance reflects myocardial functional reserves that are not used when the tissue is oxygenated appropriately, and is modulated by signal transduction pathways, transcription factors, and cellular enzymes that all converge on the main effector target, the mitochondria (Golomb et al. Therefore, drugs and/or chemicals that perturb these pathways may impair cardiac ischemic tolerance without affecting myocardial integrity, or functions under normal, well-oxygenated conditions (Dzeja et al.

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