bluuebunny/crossref_metadata_2025 huggingface dataset:
The estimation of the basic reproduction number for infectious diseases
Authors: Dietz K.
Published: November 2007

The basic reproduction number Ro is the number of secondary cases which one case would produce in a completely susceptible population. It depends on the duration of the infectious period, the probability of infecting a susceptible individual during one contact, and the number of new susceptible individuals contacted per unit of time. Therefore Ro may vary considerably for different infectious diseases but also for the same disease in different populations. The key threshold result of epidemic theory associates the outbreaks of epidemics and the persistence of endemic levels with basic reproduction numbers greater than one. Because the magnitude of R0 allows one to determine the amount of effort which is necessary either to prevent an epidemic or to eliminate an infection from a population, it is crucial to estimate Ro for a given disease in a particular population. The present paper gives a survey about the various estimation methods available.
Review papers : Variance components for statistical genetics: applications in medical research to characteristics related to human diseases and health
Authors: Hopper JL
Published: November 2007

RA Fisher introduced variance components in 1918. He synthesized Mendelian inheritance with Darwin's theory of evolution by showing that the genetic variance of a continuous trait could be decomposed into additive and non-additive components. The model can be extended to include environmental factors, interactions, covariation, and non-random mating. Identifiability depends critically on design. Methods of analysis include modelling the mean squares from a fixed effects analysis of variance, and covariance structure modelling, which can be extended to multivariate traits and has been used to study ordinal traits by reference to postulated, unmeasured, latent 'liabilities'. These methods operate on dependent observa tions within independent groups of the same size and structure, and therefore require balanced designs ('regular' pedigrees). A multivariate normal model handles data in its generic form, utilizes data efficiently from all members of pedigrees of unequal size or varying structure, accommodates individuals missing at random, and allows flexible modelling with tests of distributional assumptions and fit. Most analytical methods use least squares or maximum likelihood under normal theory. Robust methods, scale transforma tion, ascertainment, path diagrams and correlational path models (popular in behavioural genetics through addressing nonrandom mating and social interactions), 'heritability', and the contribution and limitations of statistical modelling to the 'nature-nurture' debate, are discussed.
Forensic inference from genetic markers
Authors: Devlin B.
Published: November 2007

This review provides an overview of forensic inference from genetic markers. Because the judge and jurors are charged with decision-making, the forensic expert's job is to provide a useful summary of the evidence to the court. Hence, this review focuses on the likelihood ratio as a means of summarizing the genetic data for either criminal or civil cases. The properties of the genetic markers frequently used in today's court cases, those being VNTR loci, are discussed in detail. Unlike traditional markers, the data from VNTR loci are complicated because current molecular methods generate data that follow a finite mixture distribution. Critical ancillary issues are also covered, though not in detail.
Generalizations and applications of frailty models for survival and event data
Authors: Pickles Andrew , Crouchlev Robert
Published: November 2007

A variety of survival models with both discrete and continuously distributed frailty is considered within a framework that involves the specification of three sub-models. An intensity sub-model specifies how the intensity is related to values of covariates and frailty; a measurement sub-model specifies how fallible measures of frailty are related to it; and an exposure sub-model specifies how frailty is distributed within the population. The models include those in which frailty is due to omitted covariates and those where it represents a covariate that has been measured subject to error. Multivariate frailty is also considered, with particular emphasis on models suitable for application to genetically related individuals, notably twins. A numerical example illustrates the use of a model with multivariate frailty for data on repeated exercise times.
Second-order analysis of space-time clustering
Authors: Diggle PJ , Chetwynd AG , Häggkvist R. , Morris SE
Published: November 2007

We consider the problem of detecting and describing space-time interaction in point process data. We extend existing second-order methods for purely spatial point process data to the spatial-temporal setting. This extension allows us to estimate space-time interaction as a function of spatial and temporal separation, and provides a useful reinterpretation of a popular test, due to Knox, for space-time interaction. Applications to simulated and real data indicate the method's potential.
The Watery Diarrhea-Colitis Syndrome
Authors: Saul Scott H.
Published: November 2007

Collagenous and lymphocytic/microscopic colitis represent a distinct histopathologic spectrum of findings, with occasional transition, observed in patients with normal or near-normal colonoscopic findings and chronic watery diarrhea (watery diarrhea- colitis syndrome). Biopsies are characterized by surface epithelial damage, an increased number of chronic inflamatory cells in the lamina propria, intraepithelial lymphocyto sis, intact crypt architecture, and in the cases of collagenous colitis, a thickened subepi thelial collagen layer (SCL). While their precise interrelationship is unclear, as their clinicopathologic similarities far outweigh their differences, it appears reasonable for pathologists and clinicians to consider them conceptually together as part of a syn drome of chronic watery diarrhea and colitis distinct from other forms of chronic inflammatory bowel disease. The etiology and pathogenesis of this syndrome are un clear. Colorectal surface epithelial damage appears to be for the most part responsible for the secretory diarrhea, while the thickened SCL appears to be a variable response to the surface epithelial damage. Why the thickened SCL occurs only in some cases, why it does not occur in other forms of colitis, and whether it functions as a diffusion barrier are unknown. The propensity of the watery diarrhea-colitis syndrome to pref erentially affect middle-aged and elderly women, an association with autoimmune disorders, and clinicopathologic similarities to celiac disease suggest that host immune factors are important. Other dietary factors, medications, or other agents may also play a role, and this is currently under investigation. Small bowel villous atrophy appears to account for the presence of steatorrhea noted in some reports. Definitive diagnosis is facilitated by the procurement of multiple, well-oriented biopsies, prefera bly extending at least into the proximal left colon. A thickened SCL occasionally can only be demonstrated in biopsies from the right colon. An appreciation of the normal variation found in colorectal biopsies and recognition of artifactual thickening of the subepithelial basement membrane in maloriented sections and in relation to bowel preparation will eliminate overdiagnosis of normal biopsies, while the absence of fea tures typical for other forms of inflammatory bowel disease facilitates differential diag nosis. Patients may respond dramatically to therapeutic intervention with drugs often used for ulcerative colitis and Crohn's disease, however, spontaneous remissions are well documented. A colitis-dysplasia-carcinoma sequence has not as yet been docu mented to occur in this patient population. In just over one decade the morphologic features of the watery diarrhea-colitis syndrome have come to be recognized. Hope fully, the next decade of observation and investigation will help to clarify the precise relationship between cases with and without a thickened SCL, as well as the etiology and pathogenesis of the secretory diarrhea. Int J Surg Pathol 1 (1): 65-82, 1993
Paragangliomas
Authors: Lam K.Y. , Chan Alexander C. L.
Published: November 2007

Eleven Chinese patients with paragangliomas were studied to evaluate the clinicopath ological features in detail. Their age ranged from 19 to 68 years with a mean of 41.7 years. Carotid body paragangliomas were the most common, followed by jugulotym panic paragangliomas. The patients with carotid body tumors were younger than the other patients in the group (eg, those with retroperitoneal paragangliomas). Retroperi toneum tumors were typically larger (the largest one was 8 cm in diameter), while tumors in the middle ears were smaller (0.5 to 1 cm in diameter). All the paraganglio mas were tested by a panel of panneuroendocrine markers (neuron-specific enolase, synaptophysin, and chromogranin), and they all stained strongly with synaptophysin. Thus, synaptophysin was shown to be a useful neuroendocrine marker for paraganglio mas. Int J Surg Pathol 1 (1):111-116, 1993
Ki67 Immunoreactivity Is Retained in Acetone-fixed Cryostat Sections Stored at - 20°C
Authors: Buckley Colm , Magee Hilary M. , Dervan Peter A.
Published: November 2007

The authors studied the retention/loss of immunoreactivity in frozen tissue over a period of 8 weeks using a variety of storage strategies. Ki67 immunoreactivity is com monly used to assess the growth fraction of tumors in frozen histopathology sections. Many antigens are lost with prolonged storage, even in frozen specimens. To evaluate the loss of Ki67 in frozen tissue, 30 tumors were studied over a storage period of 8 weeks. Cryostat sections, acetone-fixed and stored at — 20°C for 8 weeks, showed identical immunoreactivity to tissue stained immediately on arrival in the laboratory. The other methods gave less satisfactory results. The authors conclude that routine acetone-fixed frozen sections provide excellent results for up to 8 weeks when stored at - 20°C. Int J Surg Pathol 1(2):135-138, 1993
Invited Review : Three New Vascular Tumors—Tufted Angioma, Kaposiform Infantile Hemangioendothelioma, and Proliferative Cutaneous Angiomatosis
Authors: Allen P.W.
Published: November 2007

The features of tufted angioma (Nakagawa), Kaposiform infantile hemangioendotheli oma, and proliferative cutaneous angiomatosis are reviewed. Tufted angioma, which usually appears before the age of ten years, is a large, poorly demarcated, macular, cutaneous and subcutaneous lesion most commonly located on the neck or trunk. Histologically, there is a "cannon ball" pattern of concentrically whorled lobules and tufts of endothelial and perithelial cells. Tufted angioma is difficult to excise and usually persists throughout life but causes no serious symptoms. Kaposiform infantile heman gioendothelioma is a rare, aggressive vascular tumor of the deep soft tissues, bone, and skin that presents during the first year of life and is often complicated by Kasabach- Merritt syndrome. Histologically, there is a Kaposiform pattern, but some cells may be arranged in nodules and tufts indistinguishable from tufted angioma. Kaposiform infantile hemangioendothelioma responds to interferon therapy. On the basis of the few cases so far recognized, proliferative cutaneous angiomatosis is a large, diffuse, mainly superficial angioma that grows insidiously and is biopsied in the second or third decade of life. Histologically, there are irregular, interconnecting cords and sheets of endothelial cells that form anastomosing spaces. Extravasated red cells and endothe lial hemosiderosis are prominent. The superficial location, older age, and the distinctive histology suggest that proliferative cutaneous angiomatosis differs from Kaposiform infantile hemangioendothelioma. Int J Surg Pathol 2(1):63-72, 1994
Tracheobronchial Inflammatory Myofibroblastoma
Authors: Altman Howard , Pietra Giuseppe G. , LiVolsi Virginia A. , Kelley Mark A. , Unger Michael , Hayden Richard
Published: November 2007

Clinicopathologic findings in three cases of inflammatory myofibroblastomas (so-called inflammatory pseudotumors) of the trachea and bronchi are reported. In all cases the myofibroblastic nature of the spindle cell proliferation was revealed using electron microscopic and immunohistochemical methods. In two of these cases, in which the lesions were incompletely excised to conserve the wall of the airways and the normal lungs, several recurrences over a period of many years were successfully managed endoscopically. These potentially recurring and locally invasive myofibroblastic lesions should be treated as low-grade neoplasms rather than reactive processes. However, if complete excision is not feasible, lung-sparing management is warranted because myofibroblastomas progress slowly and recurrences can be readily detected by bron choscopy. Int J Surg Pathol 2(2):93-98, 1994.
Peripheral Neuroectodermal Tumor-Ewing's Sarcoma of the Thumb With Local Recurrences and Pleural Metastases After 17 Years
Authors: Volkan Adsay N. , Bansal Manjula , DaSilva Moacyr , Inglis Allen E. , Saltz Leonard
Published: November 2007

We report a case of an 8-year-old boy who initially presented with a painful subungual mass that was diagnosed as a "glomus tumor" largely based on the clinical presenta tion. Local excision was performed, and the patient remained tumor free for 17 years, after which he experienced three local recurrences and massive pleural metastases within the next 2 years. The tumor was poorly differentiated with small round cells and increased mitotic activity on light microscopy. The precise nature of the tumor was difficult to characterize and was unraveled primarily by immunoperoxidase studies, particularly the diffuse strong positivity of HBA-71 (MIC 2) antibody, also called pe ripheral neuroectodermal tumor-Ewing's sarcoma antigen, which is reported to be fairly specific for these tumors, and the expression of neural markers Leu-7 (HNK-1 ) and neuron-specific enolase. In addition, ultrastructural examination revealed imma ture cell junctions, cell processes, and abundant pools of intracytoplasmic glycogen. Metastatic pleural tumor recurred very rapidly after excision, but showed a dramatic, although short-lasting, response to chemotherapy with cisplatin and etoposide. The thumb is an uncommon location for peripheral neuroectodermal tumor-Ewing's sar coma, and a 17-year, disease-free interval is most unusual for a malignant tumor of this nature. We discuss this case with respect to its unique clinical behavior and in the context of the differential diagnosis of small, round cell neoplasms. Int J Surg Pathol 2(2):147-156, 1994
Solitary Fibrous Tumor of the Orbit
Authors: Lucas David R. , Campbell R. Jean , Fletcher Christopher D. M. , Garrity James A. , Nascimento Antonio G. , McCartney Alison C. E.
Published: November 2007

We report three cases of solitary fibrous tumor (SFT) arising in the orbit. All patients presented with nontender swelling of the affected eye, and one patient presented with nasolacrimal duct obstruction. All three patients had well-circumscribed tumors that had histologic features identical to those of SFT of the pleura (fibrous mesothelioma). The neoplastic cells were purely fibrogenic. They were reactive with antivimentin and CD-34 and demonstrated no smooth muscle or neural differentiation (nonreactive with antibodies to actin, desmin, and S 100 protein). KP-1 (CD-68) immunoreactivity was present focally within the neoplastic cells in all three tumors; however, it was strongly positive within tumor infiltrating macrophages. Electron microscopy per formed on one tumor showed fine fibroblastic differentiation with phagocytic activity confined to infiltrating macrophages. SFT of the orbit is a distinct pathologic entity that merits distinction within the broad group of orbital fibrous tumors. Int J Surg Pathol 2(3):193-198, 1995
Effects of Sotalol on His-Purkinje Conduction and Refractoriness in Humans
Authors: Nademanee Koonlawee , Noll H. Elizabeth , Feld Gregory K.
Published: November 2007

Background: The effects of sotalol on refractoriness in human ventricular and atrial muscles have been well established, but the drug's effect on the electrical properties of the His- Purkinje system in humans is not known, especially whether sotalol's effect is due solely to its action on prolonging repolarization or in combination with its beta-blocking properties. We studied the electrophysiologic effects of intravenous sotalol and propranolol in patients undergoing electrophysiologic studies of cardiac arrhythmias.

Methods and Results: We studied 22 patients (19 men, 3 women; mean age, 60 ± 6 years) who had coronary artery disease and assessable anterograde, retrograde, or both, His-Purkinje system function. Fifteen patients underwent electrophysiologic studies before and after intra venous sotalol (1.5 mg/kg), and 7 patients underwent electrophysiologic studies before and after intravenous propranolol (0.15 mg/kg). Both sotalol and propranolol had no signilicant effect on the H-V interval, but sotalol significantly increased ventricular refractoriness and His-Purkinje refractoriness, both in anterograde and retrograde conduction, whereas propra nolol did not. Sotalol's effect on His-Purkinje refractoriness also caused alrioventricular block distal to the His bundle during atrial pacing at a moderately fast rate. Sotalol was not effec tive in preventing bundle branch re-entry tachycardia, nevertheless. it increased cycle length of bundle branch re-entry tachycardia by increasing refractoriness.

Conclusions: Sotalol increased His-Purkinje refractoriness in humans but had no effect on His-Purkinje conduction. The drug must be used judiciously in patients with a diseased His- Purkinje system because it may cause atrioventricular block distal to His at fast heart rates. Sotalol had no effect on macrore-entry utilising bundle branches.
Review : Restoring Sinus Rhythm in Patients with Atrial Flutter and Fibrillation: Pharmacologic or Electrical Cardioversion?
Authors: Gallik Donna , Altamirano Jaime , Singh Bramah N.
Published: November 2007

Atrial fibrillation and atrial flutter, the most frequently encountered tachyarrhythmias requir ing treatment, have become a major focus for clinical and basic research in recent years. Restoration and maintenance of sinus rhythm, having been shown to improve exercise capac ity, alleviate symptoms, and reduce the incidence of thromboembolic events, may be the opti mal management strategy. Identification of the safest, most efficacious and cost-effective means of restoring sinus rhythm is necessary prior to the institution of optimal antiarrhyth mic therapy to maintain sinus rhythm. Potential advantages of pharmacologic compared with electrical cardioversion include lack of need for general anesthesia and likely lower cost. Pharmacologic conversion has been accomplished with drugs that prolong atrial refractori ness, including class Ia (quinidine, procainamide, disopyramide), class Ic (flecainide, propafenone), and class III (sotalol, amiodarone) compounds. The so-called pure class III agents were created to overcome the blocker side effects of sotalol and the complex pharma codynamic profile of amiodarone. Two such agents are dofetilide, which selectively blocks the rapid component of the delayed rectifier current (Ikr) and ibutilide, which augments the slow inward sodium current, with a smaller component of action mediated by the block of Ikr. Reported overall conversion rates for recent onset atrial fibrillation and atrial flutter were 31 % and 54% for dofetilide, respectively, and 29-31 % and 38-63%, respectively, for ibu tilide. Proarrhythmia, manifested as polymorphic ventricular tachycardia requiring cardiover sion, was a significant early side effect of both agents. Data from clinical trials with these new agents, combined with increasing knowledge of the electrophysiologic substrate for these arrhythmias, has renewed interest in the development of safer, more efficacious class III drugs for atrial fibrillation and atrial flutter conversion.
Angiotensin II Receptor Regulates Ionic Currents in Guinea Pig Ventricular Myocytes
Authors: Yang Xiang-jun , Jiang Wen-ping
Published: November 2007

Background: Previous studies have shown that angiotensin II (Ang II) receptors are preset in a wide variety of target tissues and that Ang II regulates the target tissue functions through Ang II receptors. However, the action of Ang II receptors on transsarcolemmal currents in ventricular myocytes has not been elucidated.

Methods and Results: We performed whole-cell voltage clamp and patch clamp experi ments to determine the effects of Ang II-receptor agonists and antagonists on ionic currents in single isolated guinea pig ventricular myocytes. We found that extracellular perfusion of Ang II (30 nM) increased the L-type Ca2+ current from 581 ± 27 to 837 ± 42 pA (n = 5, P < .01). Ang II also prolonged the Ca2+ current activation and inactivation time constants. These were reversible by losartan (100 nM), a type 1 Ang II receptor (AT,) blockade. On the other hand, perfusion of 30 nM Ang II decreased K+ current (IK) from 1543 ± 28 to 1194 ± 50 pA (n = 5, P < .05) and K+ tail current (IK-tail ) from 275 ± 24 to 206 ± 29 pA (n = 5, P < .05). These effects were also abolished by perfusion of losartan. However, perfusion of Ang II resulted in an increase of inward rectified K+ current (IK1) in whole-cell recordings. Single- channel recordings showed that the increase in IK1 was attributed to a burst opening current with a larger unit of amplitude. These effects were reversed by saralasin but not losartan, indicating possible type 2 Ang II receptor (AT2) involvement.

Conclusions : Our results provide evidence that Ang II receptors regulate the transsar colemmal currents in single guinea pig ventricular myocytes. Therefore, Ang II regulation of ionic currents is mediated through the different subtypes of Ang II receptors.
Prolonged Captopril Therapy in Murine Viral Myocarditis
Authors: Reyes Milagros P. , Khatib Riad , Khatib Ghada , Ho K.L. , Smith Frederic , Kloner Robert A.
Published: November 2007

Background: Acute myocarditis can progress to chronic heart muscle disease and cardiomyop athy. In the coxsackievirus B 3 (CB3) mouse model of myocarditis, early administration of cap topril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated histopathological changes in inflammation, necrosis, and calcification and reduced heart weight. Late administra tion of captopril reduced heart weight but did not affect the histological findings. In this study, we investigated the effects of prolonged captopril treatment in the chronic phase of this model.

Methods and Results: Three-week-old male CD1 mice were infected with CB3 and then randomized to receive placebo or captopril starting on day 7 of infection. Captopril, 2 g/L, was given as the drinking water daily for up to 6 months. Autopsies were performed at 6 and 10 months. Heart-to-body weight ratios were obtained, and deaths were tallied. Myocardial fibrosis was graded according to a score system. In addition, picrosirius red stain (PSR) also was used for assessment of collagen deposition. Mean heart weights were similar in both groups. Mean body weight was significantly lower in captopril-treated mice (40.7 g) than in the untreated group (43.6 g) at 6 months ( P = .0155), and mortality was higher (8.7 vs 0.87%; P = .009). At 6 months, the mean myocardial fibrosis score in treated mice (0.12) was significantly less than in untreated animals (0.35; P = .035). With PSR, the mean myo cardial fibrosis score in the captopril group (1.20) was also significantly less than in the untreated group (1.58; P = .045). At 10 months, fibrosis scores were similar in both groups.

Conclusions: Chronic captopril treatment in CB3 myocarditis reduces myocardial fibrosis.
Infarct Size Reduction by Ischemic Preconditioning is a Monophasic, Short-Lived Phenomenon in Anesthetized Pigs
Authors: Schwarz Ernst R. , Fleischhauer Jan , Montino Holger , Chakupurakal Raj , Foresti Mike , Schuetz Thorsten , Sack Stefan , Mohri Masahiro , Arras Margarete , Schaper Wolfgang , Hanrath Peter
Published: November 2007

Background: Controversy exists concerning the duration of infarct size reduction with ischemic preconditioning in different species. In the present study, we (a) evaluated the time course of protection with preconditioning and (b) sought to determine whether late protec tion (the "second window") after 24 hours is manifest in the open-chest pig model.

Methods and Results: Six groups of pentobarbital-anesthetized pigs underwent 1 hour of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Group 1 served as control, and pigs in group 2 received two 10-minute episodes of preconditioning ischemia followed by 30 minutes of reperfusion before the sustained 1-hour occlusion. In groups 3-6, the period of intervening reperfusion between the preconditioning stimulus and the index ischemia was extended to 60, 90, and 300 minutes and 24 hours, respectively. The area at risk was determined by fluorescein dye injection, and infarct size was measured by incubation in p-nitrobluetetrazolium and expressed as percent of the risk area. Infarct size in preconditioned pigs (group 2) was significantly reduced compared with controls (25.6 ± 3.9% v 71.3 ± 5.9%, P < .001). Extension of the intervening reperfusion to 60, 90, and 300 minutes and 24 hours resulted in infarct sizes of 64.5 ± 5.5%, 67.2 ± 8%, 62.6 ± 6.1%, and 75.3 ± 7%, respectively ( P = NS v control).

Conclusions: The infarct size-limiting effects of ischemic preconditioning last less than 1 hour in the pig model. Moreover, in contrast to other species, a late protection at 24 hours after the preconditioning stimulus was not detected. These results indicate that precondi tioning-induced reduction of infarct size is monophasic in anesthetized pigs.
The Effect of Atorvastatin on the Human Lens After 52 Weeks of Treatment
Authors: Reid Leon , Bakker-Arkema Rebecca , Black Donald
Published: November 2007

Background: The effect of atorvastatin calcium (Lipitor, Parke-Davis, Morris Plains, NJ) on the crystalline lenses of hypercholesterolemic patients was evaluated and compared with that of lovastatin after 52 weeks of treatment to reduce cholesterol levels.

Methods and Results: Six hundred ninety-six atorvastatin-treated and 235 lovastatin- treated patients completed a large safety study that included an ophthalmologic examina tion. Efficacy was evaluated as mean percent change from baseline in low-density lipopro tein (LDL) cholesterol. Patients received atorvastatin, 10 or 20 mg, or lovastatin, 20 or 40 mg, once daily for either 36 or 52 weeks. Patients were evaluated by slit-lamp examination, and a standardized format was used to describe the findings. Best corrected visual acuity was measured using the Snellen chart. Patients treated with atorvastatin had significantly ( P ≤ .05) greater decreases in LDL cholesterol than those treated with lovastatin (37% vs 29%). Although some patients in both groups experienced various lenticular opacities, none were considered unexpected. In addition, there were no significant ( P ≤ .05) differences in the distribution of cortical opacities and spokes right eye (OD) and left eye (OS) and posterior subcapsular opacity (OS) between the atorvastatin and lovastatin groups. In general, the percent deterioration in best corrected visual acuity was similar in both groups. Overall, there were no clinically significant differences in the development of lenticular opacity between patients treated with atorvastatin and those treated with lovastatin.

Conclusions: Treatment with atorvastatin, 10 or 20 mg, significantly reduced LDL-cholesterol ( P < .05) and was not associated with an increased risk of lenticular opacity development compared with lovastatin, a widely prescribed compound in the same class of drugs.
The Effect of Melatonin on Hemodynamics, Blood Flow, and Myocardial Infarct Size in a Rabbit Model of Ischemia-Reperfusion
Authors: Dave Ravi H. , Hale Sharon L. , Kloner Robert A.
Published: November 2007

Background: Melatonin, a hormone, has gained popularity and is being used by millions for a variety of indications. There are few data on its safety or its effects on hemodynamics and coronary blood flow. Also, studies have confirmed that melatonin is a potent antioxidant. Therefore, it may be capable of scavenging free radicals during the reperfusion phase after a heart attack. This study evaluates the safety of melatonin with regard to its cardiovascular effects and tests the hypothesis that melatonin might be protective in the setting of ischemia-reperfusion and reduce myocardial infarct size.

Methods and Results: Anesthetized rabbits were treated with melatonin (n = 8, 10 mg/kg, intravenously) 10 minutes before coronary artery occlusion (CAO) and again 15 minutes before reperfusion. Control rabbits received vehicle (n = 8). All rabbits underwent 30 min utes of occlusion and 3 hour reperfusion. Both before and during CAO, melatonin did not alter heart rate compared with control (185 ± 7 beats/min v 181 ± 7 before; and 179 ± 5 v 181 ± 9 during, respectively, P = NS) or blood pressure (70 ± 4 mmHg v 66 ± 6 before and 59 ± 4 v 58 ± 5 during, respectively, P = NS). Regional myocardial blood flow (RMBF) was similar before CAO in the melatonin group (1.18 ± 0.17 mL/min/g) versus the control group (1.15 ± 0.10 mL/min/g). Infarct size, expressed as a fraction of ischemic risk zone, was simi lar in the melatonin (0.29 ± 0.03) and control groups (0.29 ± 0.06, P = NS). At a higher dose of 50 mg/kg in treated (n = 7) versus control (n = 7) rabbits, melatonin treatment did not alter heart rate (204 ± 14 in melatonin group v 181 ± 5 in controls, P = NS) or blood pressure (80 ± 11 in melatonin v 66 ± 7 in controls, P = NS) when compared with control. Melatonin at this dose also did not affect infarct size, 0.38 ± 0.06, when compared with con trol, 0.34 ± 0.07, P = NS.

Conclusion: Melatonin's effects on hemodynamics and coronary blood flow were neutral, and it did not exacerbate myocardial ischemia or necrosis in this model. Melatonin appears to be a safe drug with no apparent effects on the cardiovascular system in this model.
State-of-the-Art-Review : Essential Thrombocythemia in Young Adults: Major Thrombotic Complications and Complications During Pregnancy—A Follow-up Study in 68 Patients
Authors: Randi Maria Luigia , Rossi Carla , Fabris Fabrizio , Girolami Antonio
Published: November 2007

Objectives: Although essential thrombocythemia (ET) is usually primarily considered a disorder of middle age, it has been observed in children and young adults. However, the real risk for thrombosis in these patients has not been clearly established. Design: Prospective analysis of consecu tive patients younger than 40 at the time of the diagnosis of ET and followed in our department between 1980 and 1998. Sub jects : Sixty-eight patients (28 males and 40 females, median follow-up 99.14 months) affected by ET diagnosed in agree ment with the Polycythemia Vera Study Group criteria. Inter ventions : Asymptomatic ET patients were not treated. In con trast, patients with associated atherosclerotic risk factors, mi crovascular disturbances, or a previous major arterial thrombosis were given acetyl salicylic acid (ASA 100 mg/day). Only patients with major thrombotic complications and a plate let count >1,000 x 10 9/L received cytoreductive therapy. Out come measures: (1) to evaluate thrombotic complications in young patients with ET, (2) to relate thrombotic risk to the presence of general atherosclerotic risk factors, and (3) to adopt treatment, and (4) to report the outcome of the pregnancies monitored in our population. Results: Fifteen patients had ma jor thrombosis, 11 of which were the presenting features of ET. No rethrombosis has been observed. Only one patient with thrombotic complications was under efficient treatment. Ath erosclerotic risk factors are more common in patients with ma jor arterial thrombosis than in asymptomatic subjects. Thirteen normal babies were delivered out of 16 pregnancies, 6 of the pregnant women were on ASA therapy. Conclusions: Most thrombosis in young ET patients occurred at the time of the diagnosis, and venous thrombotic events represent one-third of total thrombosis. Cardiovascular risk factors seem to be con current stimuli for arterial thrombosis in ET. The thrombotic complication rate was 2.6/100 patients/year ASA reduces mi crovascular disturbances, thrombosis, and rethrombosis and possibly reduces obstetric complications in women with ET.
Recurrent Miscarriage Syndrome due to Blood Coagulation Protein/Platelet Defects: Prevalence, Treatment and Outcome Results
Authors: Bick Rodger L.
Published: November 2007

Although first-time miscarriages are usually caused by chromosomal defects, about 55% of recurrent miscarriages are caused by procoagulant defects that induce thrombosis and infarction of placental vessels. Of recurrent miscarriages, about 7% are caused by chromosome defects, 15% to hormonal de fects, and 10% to 15% to anatomical defects. Recurrent mis carriage involves more than 500,000 women in the United States each year. During the past 4 years, 179 patients, pre- screened for chromosomal, hormonal, and anatomical defects, and found to harbor none, underwent hemostasis defect evalu ation. A total of 160 of these have been analyzed. A hemostasis defect was found in 150 of 160 women ( n = 94% of screened women). The mean age was 33 years; the mean number of miscarriages before referral was three. All women with a pro coagulant defect (149) were treated with preconception ASA at 81 mg/d, and unfractionated porcine heparin at 5000 U every 12 hours was added immediately postconception; both agents were used to term delivery. Only two of 149 patients failed therapy. The defects found were as follows: antiphospholipid syndrome, 67%; sticky platelet syndrome, 21 %; tissue plasmin ogen activator (TPA) deficiency, 9%; factor V Leiden, 7%; high PAI-1, 6%; protein S, 5%; high LP(a), 3%; AT, 2%; protein C, 1%. Thirty-eight patients had more than one defect. In the group with antiphospholipid syndrome, 24% only had a subgroup antibody (antiphosphatidyl-serine, -inositol, -ethanol amine, -choline, -glycerol) or antiphosphatidic acid antibody, in the absence of anticardiolipin antibody or lupus anticoagulant. This finding is similar to that recently reported in early age ischemic stroke patients (<50 years old).

In summary, about 55% of patients with recurrent miscar riage harbor a procoagulant defect to account for placental vascular occlusion. More than 98% will have a normal term delivery with preconception aspirin (ASA) and addition of postconception heparin to term. Patients should be screened by an obstetrician or by reproductive specialists for hormonal and anatomic defects before initiating a procoagulant evaluation; if such prescreening is done, the yield of a defect is high and appropriate therapy leads to an excellent outcome.
Rapid Genetic Diagnosis in Neonatal Pulmonary Artery Thrombosis Caused by Homozygous Antithrombin Budapest 3
Authors: Brown Simon A. , Mitchell Mike , Cutler Jacky A. , Moore Gary , Smith Mark P. , Savidge Geoffrey F.
Published: November 2007

We report a case of spontaneous left pulmonary artery thrombosis in a 3-day-old male neonate. The presenta tion of heparin resistance and thrombosis raised the possibility of a type II heparin binding site antithrombin deficiency. A continuous infusion of antithrombin concentrate was used suc cessfully, following failure of plasma, to correct the heparin resistance. Rapid genetic analysis allowed sequencing of the antithrombin gene within 5 working days. This showed the infant to be homozygous for the substitution of C to T at nucleotide 2759. This base change causes mutation of the na tive leucine at codon 99 to a phenylalanine. This antithrombin variant has been previously reported (antithrombin Budapest 3) and results in reduced binding of heparin to antithrombin. Such a molecular diagnostic approach is feasible and warranted in such cases of neonatal thrombosis because of the diagnostic difficulties encountered.
Differential Effects of Unfractionated Heparin and Low-Molecular-Weight Heparins on Tissue Thromboplastin Inhibition Test
Authors: Gerbutavicius Rolandas , Iqbal Omer , Messmore Harry , Hoppensteadt Debra A. , Demir Muzaffer , Khan Erum , Bacher Peter , Fareed Jawed
Published: November 2007

Circulating anticoagulants are endogenously pro duced substances that interfere with in vitro tests of coagulation like activated partial thromboplastin time (APTT), and cause prolongation of the clotting times. Evaluation of the abnormal APTT involving various factor assays and mixing studies may provide inconclusive and ambiguous results. Tissue thrombo plastin inhibition test (TTIT) is one of the screening assays for detection of circulating anticoagulants. However, this test is influenced by the presence of unfractionated heparin (UFH) from concentrations 0.2 U/mL and higher. Since low- molecular-weight heparins (LMWHs) are increasingly used for the prevention of thrombotic disorders and may replace UFH in the future, in this study the authors studied the influence of LMWHs on the performance of TTIT and compared the results with UFH. UFH and LMWHs showed a prolongation of TTIT in the concentration range of 0.25-1.0 U/mL. The marked pro longation of the TTIT with UFH and different LMWHs is in decreasing order of UFH > ardeparin > tinzaparin > dalteparin > enoxaparin. Patients with circulating anticoagulants who are given LMWHs may have false-positive results of TTIT and this influence should be kept in mind during patient management.
Changes of Hemostatic Molecular Markers After Gynecological Surgery
Authors: Noda Kazuhiko , Wada Hideo , Yamada Norikazu , Noda Naomi , Gabazza Esteban C. , Kumeda Kouzou , Okugawa Toshiharu , Yanoh Kenji , Ito Masazumi , Nakano Takeshi , Shiku Hiroshi , Nobori Tsutomu , Kato Hisao , Toyoda Nagayasu
Published: November 2007

The authors evaluated the hemostatic abnormalities occurring in the postoperative period of eight patients with malignant tumors and compared them with those occurring in the postoperative period of eight patients with benign tumors. Two of the patients with malignant tumor presented pulmonary embolism after operation. Plasma fibrinogen and fibrin degra dation product levels in patients with malignant tumors were already high before operation and further increased signifi cantly after operation. The plasma levels of D-dimer, thrombi n-antithrombin complex, and free-tissue factor pathway inhibi tor were increased in both groups after operation, but they were higher in patients with malignant tumors than in patients with benign tumors. The plasma levels of protein C and antithrom bin were significantly decreased in both groups after operation, but they were significantly lower in patients with malignant tumors than in those with benign tumors. The decreased activ ity of protein C or antithrombin may be not only a risk factor of thrombotic disease, such as pulmonary embolism, but also the cause of thrombosis. In patients with malignant tumors, the operation time was significantly longer than that in patients with benign tumors. This long operative period might cause vascular endothelial cell injury which is reflected by the plasma levels of free-tissue factor pathway inhibitor, antithrombin, and protein C.
Lung Scintigraphy and Helical Computed Tomography for the Diagnosis of Pulmonary Embolism: A Meta-Analysis
Authors: van Beek Edwin J. R. , Brouwers Elise M. J. , Bing Song  , Bongaerts Alfons H. H. , Oudkerk Matthijs
Published: November 2007

To assess the diagnostic value of lung scintigraphy and helical computed tomography (hCT) in patients with suspected pulmonary embolism (PE), all English-language articles that described lung scintigraphy and hCT in patients with suspected PE were retrieved. Articles were assessed for strength of methodology, based on nine a priori-defined criteria. Parameters of diagnostic accuracy and results of management studies were calculated and evaluated. Lung scintigraphy is diagnostic in approximately 50% of patients with suspected PE. A normal perfusion scan has a chance of recurrent PE in two of 693 patients (0.3%; 95% CI: 0.2-0.4%; fatal in 0.15%). A high-probability lung scan is corrected with angiographically proven PE in 308 of 350 patients (88%; 95% CI: 84-91%). Pulmonary embolism was proven in 385 of 1529 patients (25%; 95% CI: 24-28%) with a nondiagnostic lung scan. Helical CT studies were compared with angiography and lung scintigraphy in 1171 patients, with a prevalence of PE of 39%. The sensitivity and specificity of hCT was 283/320 (88%; 95% CI: 83-91%) and 374/408 (92%; 95% CI:89-94%), respectively. Only one prospective management study using hCT was available. In patients in whom anticoagulants were withheld based on a normal hCT study, recurrent thromboembolic events occurred in six of 109 patients (5.5%; 95% CI: 2-12%), with one fatality (1%; 95% CI: 0.02-4.3%). Lung scintigraphy is evaluated extensively and yields a diagnostic result in 50% of patients. Helical CT has similar positive predictive value to a high-probability lung scan. However, the exact role of hCT in the management of patients with suspected PE needs to be determiined in prospective studies.
Acquired von Willebrand Syndrome Type 1 in Hypothyroidism: Reversal After Treatment With Thyroxine
Authors: Michiels Jan Jacques , Schroyens Wilfried , Bememan Zwi , van der Planken Marc
Published: November 2007

In 16 cases, acquired von Willebrand syndrome (AvWS) and hypothyroidism have been described that occur with each other: 15 women and one man, at a mean age of 32 years, range, 13 to 82 years of age. Activated partial thromboplastin time (APTT) was normal in six patients, and five patients had factor VIII concentration (factor VIIIc) levels in excess of 60%. The bleeding time was prolonged in nine of 13 evaluable patients. Activated partial thromboplastin time was prolonged in seven patients, and five of these had factor VIIIc levels between 18 and 45%, with two patients having levels in excess of 60%. A deficiency of other coagulation factors, including factor VII, V. IX, and X, caused by a generalized diminution in protein synthesis in hypothyroidism, may have contributed to the prolongation of the APTT. The AvWS was very likely type 1 in all cases because of a normal von Willebrand factor antigen/ristocetin cofactor (vWF Ag/RCF) ratio. Acquired von Willebrand syndrome was documented via cross immunoelectrophoresis in three patients and via multimeric analysis of vWF in six patients. A definite diagnosis of AvWS type I has to be confirmed by a normal response to 1-desamino-8-D-arginine vasopressin (DDAVP). Treatment of hypothyroidism with thyroxine was associated with the disappearance of the AvWS and the bleeding diathesis. Decreased factor VIIIc, vWF Ag ,and vWF RCF levels (50%, 33%, and 36% respectively) before thyroxine treatment increased to normal values (97%, 93%, and 107% respectively) after treatment. The absence of bleeding, or mild bleeding, symptoms, in relation to those more commonly recognized with hypothyroidism, has led to the complication of acquired vWF deficiency being under-diagnosed. Acquired von Willebrand syndrome type I should be considered whenever hypothyroidism is diagnosed and thyroid biopsy or surgery is contemplated. The complete relief of AvWS via treatment of hypothyroidism with thyroxine is the final proof of this association and causal relationship.
Spontaneous Cervical Epidural Hematoma Associated With Oral Anticoagulant Therapy
Authors: Vayá Amparo , Resurección Manuel , Ma Ricart José , Ortufio Carmen , Ripoll Francisco , Mira Yolanda , Aznar Justo
Published: November 2007

A 54-year-old woman who was on anticoagulant treatment with acenocoumarol for a mitral prothesis developed a cervical spinal epidural hematoma, probably triggered by coughing fits together with supratherapeutic anticoagulation. Because of the subacute evolution of the hematoma, it was not diagnosed until the patient was admitted to the hospital with profuse hemorrhages. Given the subacute nature of the hematoma, along with the favorable evolution, conservative treatment with dexamethasone was decided upon, and it was resolved with almost no sequelae. This unusual clinical entity definitely should be suspected in patients on anticoagulants who comptain of severe localized neck pain, most often with radicular irradiation.
Urinary Prostanoid Metabolites and Serum Thromboxane Following Recovery from Cyclooxygenase Inhibition with Aspirin
Authors: Vial Janet Helen , Narkowicz Christian
Published: November 2007

A previous study that measured urinary nary 11-dehydro-TXB2, 114.4 ± 13.8%, and urinary thromboxane B2 (TXB2) and 6-keto-PGF1α after with- TXB2, 106.0 ± 12% (all not significant compared with drawal of aspirin found evidence of a rebound in urinary control). The urinary 6-keto-PGF1α level 14 days after prostanoid excretion above control levels 14 days after aspirin withdrawal was 96.9 ± 17.8% of control (NS). aspirin administration ceased. This study aimed to con- Twenty-one days after aspirin withdrawal, TXB2 metab firm these findings using a wider range of prostanoid me- olites as a percentage of control were, respectively, se tabolites. The subjects were 17 young, healthy volunteers rum TXB2, 154 ± 39%; urinary TXB2, 114 ± 11% (both who had taken 100 mg of enteric-coated aspirin daily for NS compared with control; and urinary 11-dehydro- 7 days followed by 650 mg of enteric-coated aspirin for a TXB2, 127.2 ± 11.9% (p = 0.037 compared with control). further 7 days as part of another study. They showed Urinary 6-keto-PGF 1α 21 days after aspirin withdrawal signs of the expected inhibition of TXB2 metabolites at was 159.9 ± 46.2% of control (NS). Overall there would the end of aspirin treatment. After 650 mg aspirin, serum appear to be a trend to increased production of prostanoid generation of TXB 2 by clotting blood was 0.77 ± 0.2% of metabolites 14 and 21 days after aspirin withdrawal, but it control (p < 0.0001), urinary 11-dehydro-TXB 2 was 21.8 reached statistical significance only for 11-dehydro-TXB 2 ± 2.8% of control (p < 0.0001), and urinary TXB2 was at 21 days' withdrawal. As platelets are the major source 33.7 ± 4.2% of control (p < 0.0001). Fourteen days after of this metabolite, this finding would suggest that in- aspirin withdrawal, TXB2 metabolites as a percentage of creased platelet generation of TXB2 plays a part.