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Purpose of Review: The prevalence and burden of obesity has reached alarming levels. The assessment of human energy expenditure enables the identification of obesity-prone and obesity-resistant individuals and helps to explain the short and long-term success of weight loss treatments. In this review, we describe the state-of-the-art methods used in the assessment of human energy expenditure and the impact of dietary intake on the interpretation of the data., Recent Findings: The reference techniques to assess energy expenditure in humans have not significantly changed during the last century. Today, indirect calorimetry, either using a metabolic chamber or a metabolic cart, is the favored method to assess human energy expenditure and is the only method enabling the assessment of macronutrient oxidation. The doubly labeled water method however provides accurate assessment of human energy expenditure under free living conditions., Summary: Although energy expenditure and macronutrient oxidation can be assessed by simple calculations from oxygen consumption and carbon dioxide production, these calculations can provide erroneous results or require corrections and/or more complex interpretation when several biochemical pathways are simultaneously engaged. Such physiological mechanisms are often elicited by dietary interventions including, among other, gluconeogenesis, lipogenesis, ketogenesis, alcohol oxidation and under or overfeeding.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF)., Methods and Results: FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14-1.48; P<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction, P=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02-1.60; P=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro-B-type natriuretic peptide (C-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%; P<0.001)., Conclusions: FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities., (© 2015 American Heart Association, Inc.)

Background: Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF., Methods and Results: Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001)., Conclusions: vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients., (© 2014 American Heart Association, Inc.)

Gamma-aminobutyric acid (GABA)ρ receptors are selectively targeted to the axon terminals of the retinal bipolar neurons. The traffic of a green fluorescent protein-tagged GABAρ2 was examined in retinal bipolar neurons and cerebellar astrocytes. In bipolar neurons, time-lapse laser confocal microscopy revealed that the fluorescence emitted by GABAρ2-green fluorescent protein accumulates first, in clusters, in the soma and is then distributed along the axon in at least two populations: one that remains relatively immobile and a second population of smaller clusters that moved constantly to and from the axon end. In astrocytes, the fluorescent clusters were relatively immobile and located mainly in the soma.

The cartilage of the lower limb joints is exposed to high levels of mechanical stress and therefore is a frequent site of degenerative and traumatic lesions. Magnetic resonance imaging (MRI) is the modality of choice for the assessment of these cartilage lesions. To date, clinically available sequences have focused on morphological defects and cartilage loss. Efforts have been made in recent years to depict cartilage lesions at an earlier stage, with new quantitative sequences focusing on the biochemical assessment of tissue.After a brief review of the hyaline cartilage structure, we review the current morphological imaging methods and the biochemical MRI techniques to assess the cartilage. We then illustrate the application of these MRI sequences for the most common degenerative and traumatic disorders affecting lower limb cartilage.

Objective: The understanding of complex heritable psychiatric disorders such as schizophrenia could be clarified by examining endophenotypes within genetically isolated populations, such as the one found in the Central Valley of Costa Rica. The reduction of familial variability within a sample could allow the relationship between the cognitive and symptomatic manifestations of the illness and the genetic underpinnings to become more observable. This study investigates the neuropsychological test performances of 41 family members from four extended multiplex families within the Spanish origin population of the Central Valley of Costa Rica as potential endophenotypes for genetic studies., Methods: Individuals with a diagnosis of schizophrenia or schizoaffective disorder were compared with unaffected relatives and 15 unrelated controls with no family history of schizophrenia., Results: Although the sample size is small, the results confirm previous reports in the literature of deficits in working memory, executive function, processing speed, and verbal fluency in individuals with schizophrenia compared with controls and intermediate performance in nonpsychotic family members compared with controls. We also found several suggestive quantitative cognitive trait loci with log of the odds greater than 1.75., Conclusion: These findings suggest that the cognitive deficits in schizophrenia are consistent aspects of the illness, although their usefulness as endophenotypes for genetic studies remains unclear.

This work shows a first approximation to the magnitude and characteristics of mortality by homicide in homosexuals in Mexico using the cases registered between the years 1995 and 2000. A statistical analysis was performed of the homicides against homosexuals that were registered through the review of newspaper articles published by the National Press. Sex, age of the victims, kind and number of weapons used, wounds endured, and the situation in which the corpses found were registered. The greater mortality by homicide due to homosexual orientation was recorded in men (95%); it was found that the cases accumulated in the cohort of the third and fourth decades of their age (43%). The homicides were characterized by extreme violence which included the use of various arm types (33%) and wounds (32%). The most frequent situations that occurred were finding the corpses naked and tied (13%). The features of the homicide against homosexuals are associated to the general attributes of the predominant masculinity model; therefore, at a macro social level, some reasons are found in the social construction of homophobia. The degree of violence in these crimes adduces the consideration that they are hate crimes.

Background: Percutaneous transcatheter closure of patent foramen ovale (PFO) is used as an alternative to surgery or long-term anticoagulation for the treatment of patients with paradoxical embolism and PFO., Methods and Results: We report the immediate and long-term clinical and echocardiographic outcome of 110 consecutive patients (58 males, mean age 47+/-14 years) who underwent transcatheter closure of PFO because of paradoxical embolism between 1995 and 2001. Procedural success, defined as successful deployment of the device and effective occlusion (no, or trivial, shunt after device placement), was achieved in all (100%) patients. There was no in-hospital mortality, 1 device migration requiring surgical intervention (0.9%), and 1 episode of cardiac tamponade (0.9%) requiring pericardiocentesis. A progressive increment in full occlusion was observed (44%, 51%, 66%, and 71% at 1 day, 6 months, and 1 and 2 years, respectively, after device placement). At a mean follow-up of 2.3 years, 2 patients experienced recurrent neurological events (1 fatal stroke and 1 transient ischemic attack), representing an annual risk of recurrence of 0.9%. In addition, 4 (3.6%) of the patients required reintervention for device malalignment or significant shunt. Kaplan-Meier analysis showed a freedom from recurrent embolic events and reintervention of 96% and 90% at 1 and 5 years, respectively., Conclusions: Transcatheter closure of PFO is a safe and effective therapy for patients with paradoxical embolism and PFO. It is associated with a high success rate, low incidence of hospital complications, and low frequency of recurrent systemic embolic events.

From July 1974 to December 1984, 24 skinning vulvectomies (17 partial and seven total) were performed in 24 patients with carcinoma in situ of the vulva. The objective for partial skinning vulvectomy was preservation of the cosmetic and functional integrity of the vulva in younger and sexually active patients in whom a steady increase in the incidence of vulvar intraepithelial neoplasia has been observed in the last decade. Two groups selected for partial skinning vulvectomy with skin graft were patients with multicentric vulvar intraepithelial neoplasia with colposcopic evidence of normal skin, and patients with localized but a wide surface area of vulvar intraepithelial neoplasia such that poor cosmetic results would be unavoidable should excision be approximated with primary skin closure. Only patients with involvement of the entire vulva were subjected to total skinning vulvectomy with total skin graft replacement. Recurrence and/or persistence were observed in two patients, both treated with total skinning vulvectomy. At present, all 24 patients remain free of detectable neoplasia on follow-up of six months to 11 years and all have very good cosmetic and functional results.

Thirty-three patients with severe dysplasia and carcinoma in situ had a colposcopically directed cone biopsy in the operating room immediately prior to vaginal hysterectomy. In 3 cases (9%), the hysterectomy specimen showed the same type of residual disease as in the cone biopsy; in the remainder no residual disease was evident in the hysterectomy specimen. If colposcopically directed biopsies were performed, the long-term debate over the use of cone biopsy or hysterectomy for intraepithelial neoplasms would be resolved. Selected patients could be treated adequately by cone biopsy with a small number of patients requiring hysterectomy as indicated by direct examination with the colposcope.

In this study, two different radioactive microspheres were used to measure blood flow of an irradiated segment of small intestine in four dogs before, and 12 days after, irradiation with 2000 rad. The technique and implications are discussed. Using multiple radioactive microspheres, the study demonstrated an increased blood flow in irradiated tissues twelve days after a single dose of 2000 rad. There was also an increase in blood flow to adjoining nonradiated segments of intestine in the same animal. These observations may be of significance in clinical applications of radiation therapy and surgery. A major surgical concern is the impaired healing of irradiated tissue in the immediate postradiation period. The mechanism of this has generally implicated decreases in the perfusion of irradiated tissue. No decrease in blood flow was shown in this study, suggesting that other mechanisms, e.g., stem cell depletion, should be considered. Further studies of this type are recommended to increase understanding of the blood flow in irradiated tissue.

Intraoperative electron beam irradiation is being used for the therapeutic and prophylactic treatment of the paraaortic nodes in cancer of the uterine cervix. A Varian 18 meV accelerator is employed at an electron energy setting of 6--18 meV. Special aluminum and lucite collimators allow visualization of treatment area and keep the uninvolved small bowel out of the treatment beam. A one-time dose of 2000 rads is delivered in 4 minutes. The procedure presents no special surgical problems, is well tolerated, and appears as a promising supplement in cases where abdominal exploration for surgical staging of cervical carcinoma is carried out.

Forty evaluable patients with advanced epithelial cancers of the ovary received chemotherapy. Twenty-seven previously untreated patients underwent a 1:1 randomization between a combination of Cytoxan, Hexamethylmelamine, and Fluorouracil (CHF) versus a single agent, L-phenylalanine mustard (L-pam). Thirteen patients previously treated with other therapies received CHF as a second-line therapy. Eighty-five percent of the patients receiving triple therapy were responders, versus 57% in the single agent group. Fifty percent of the CHF group had a complete response versus 17% in the L-pam group (p = 0.09). All patients with complete resection of less than 2 cm residual disease at primary surgery were responders, regardless of the type of therapy. Response in these patients is defined in terms of disease-free interval. The importance of maximal surgical resection in management of these cancers is discussed. Five of eight patients treated with CHF undergoing second-look operations had no evidence of disease. One of three L-pam treated patients had no evidence of disease at second-look surgery. Six of 13 patients (46%) had partial response to CHF as a second-line drug.

The use of automated stapling instruments in 17 patients requiring intestinal surgery following irradiation therapy for gynecologic malignancies has been reviewed. Fifteen of these patients also had other medical problems thought to inhibit optimal anastomotic healing: malnutrition, persistent intraabdominal cancer, uremia, hypoalbuminemia, and recent antineoplastic chemotherapy. Although these conditions severely test a method of intestinal anastomosis, no patient had a complication involving the intestinal anastomosis. The use of these stapling instruments reduced both the operating time and the contamination of the peritoneal surfaces by bowel content, thereby improving the postoperative recovery of these patients. The favorable results and the secure anastomoses justify the continued use of stapling instruments in gynecologic oncology patients with prior irradiation therapy.

Nineteen patients with invasive cervical cancer were treated with intraoperative radiation and most of the patients subsequently received conventional external radiation therapy and intracavitary applications. The technique, resulting complications, and survival of the patients are discussed.

Eighty-six patients with pelvic malignancies had paraaortic node dissection; 30% had positive paraaortic lymph nodes. At the time of laparotomy, 77 patients had malignancies apparently confined to the pelvis after extensive work-up and histologic examination of tissue biopsies outside the pelvis; 20 (26%) had metastatic cancer in the paraaortic lymph nodes. Thirteen of 49 patients with cancer of the cervix, 5 of 18 with uterine cancer, and 2 of 10 with ovarian cancer had positive paraaortic lymph nodes. The value of paraaortic dissection in patients with pelvic malignancies apparently confined to the pelvis is discussed.