Ferritin heavy chain supports stability and function of the regulatory T cell lineage.

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.

Efficacy of a mephentermine-based product as a vasopressor and a cardiac performance enhancer when given intramuscularly to cattle.

The goal of this study was to confirm the vasopressor and cardiac effects of POTENAY® INJETÁVEL (POT), a mephentermine-based product, given to cattle with induced vascular/cardiac depression. Ten healthy Holstein cattle (206 ± 13 kg) followed a randomized-complete-block design (RCBD) utilizing crossover study design. Each animal randomly received (1 ml/25 kg, IM) of either POT (n = 10) or volume-matched placebo control (0.9%NaCl, CP, n = 10). A subset of animals (n = 5) received POT first (day 0) while the remaining (n = 5) received CP; after a six-day washout period, cattle received the opposite compound. Animals were anesthetized and catheterized for systemic/left ventricular hemodynamic monitoring. Myocardial dysfunction/hypotension was induced by increasing the end-tidal isoflurane concentration until arterial blood pressure was 20% lower than at baseline and remained stable. Once the animal was determined to be hypotensive and hemodynamically stable, steady-state hypotensive baseline data (BL2) were acquired, and treatment with either POT or CP was given. Data were acquired post-treatment at every 15 min for 90 min. POT improved cardiac output (+68 L/min, ±14%, p < 0.05), MAP (+14 mmHg, ±4%, p < 0.05), HR (+22 bpm, ±8%, p < 0.05), and peak rates of ventricular pressure change during both systole (dP/dtmax : +37 mmHg/s ±13%, p < 0.05) and diastole (dP/dtmin : +31 mmHg/s, ±7%, p < 0.05). No improvements were noted following placebo-control administration. Results indicate that POT improves cardiac performance and systemic hemodynamics in cattle with induced cardiovascular depression when given as single intramuscular injection.

Gender verification of female athletes.

The International Olympic Committee (IOC) officially mandated gender verification for female athletes beginning in 1968 and continuing through 1998. The rationale was to prevent masquerading males and women with "unfair, male-like" physical advantage from competing in female-only events. Visual observation and gynecological examination had been tried on a trial basis for two years at some competitions leading up to the 1968 Olympic Games, but these invasive and demeaning processes were jettisoned in favor of laboratory-based genetic tests. Sex chromatin and more recently DNA analyses for Y-specific male material were then required of all female athletes immediately preceding IOC-sanctioned sporting events, and many other international and national competitions following the IOC model. On-site gender verification has since been found to be highly discriminatory, and the cause of emotional trauma and social stigmatization for many females with problems of intersex who have been screened out from competition. Despite compelling evidence for the lack of scientific merit for chromosome-based screening for gender, as well as its functional and ethical inconsistencies, the IOC persisted in its policy for 30 years. The coauthors of this manuscript have worked with some success to rescind this policy through educating athletes and sports governors regarding the psychological and physical nature of sexual differentiation, and the inequities of genetic sex testing. In 1990, the International Amateur Athletics Federation (IAAF) called for abandonment of required genetic screening of women athletes, and by 1992 had adopted a fairer, medically justifiable model for preventing only male "impostors" in international track and field. At the recent recommendation of the IOC Athletes Commission, the Executive Board of the IOC has finally recognized the medical and functional inconsistencies and undue costs of chromosome-based methods. In 1999, the IOC ratified the abandonment of on-site genetic screening of females at the next Olympic Games in Australia. This article reviews the history and rationales for fairness in female-only sports that have led to the rise and fall of on-site, chromosome-based gender verification at international sporting events.

Suprarenal vena caval filter placement: follow-up of four filter types in 22 patients.

PURPOSE: To determine if suprarenal placement of inferior vena cava (IVC) filters is associated with renal dysfunction or other complications. MATERIALS AND METHODS: Case files of all patients with suprarenal vena caval filter placement since 1985 were reviewed for clinical and biochemical evidence of renal dysfunction and renal vein thrombosis. The occurrence of associated complications, including IVC occlusion, filter fracture, device migration, and recurrence of pulmonary embolism was also recorded. RESULTS: Twenty-two (2.9%) of 764 IVC filters were implanted above the renal veins: titanium Greenfield filter modified hook (TGF-MH) (n = 16), LGM type I (n = 2), LGM type II (n = 2), and Bird's Nest (BN) type I (n = 2). Reasons for suprarenal filter placement included thrombus to the level of the renal veins (n = 9), failure or poor position of the infrarenal filter (n = 6), pregnancy or intent of pregnancy (n = 4), and the malpositioning of BN filters above the renal veins (n = 2). A single patient demonstrated evidence of transient renal dysfunction. Pulmonary embolus was found at autopsy in one patient. Abdominal radiographs were obtained at follow-up of 18 patients and demonstrated a 2 cm or more migration of the filter in five patients (27.7%). This rate of migration was significantly different from the 3% migration rate reported by the authors' institution in the follow-up of 320 infrarenal IVC filters. There was one filter fracture (5.5%.) and penetration of the IVC occurred in one patient (5.5%). CONCLUSION: Follow-up indicates suprarenal IVC filter placement is safe, and no evidence of permanent renal dysfunction after placement was found. Filter migration was the most frequent complication, but no clinical sequelae were noted with these patients.

Extended evaluation of the titanium Greenfield vena caval filter.

PURPOSE: The purpose of this study was to evaluate the long-term safety and efficacy of the titanium Greenfield filter-modified hook for prevention of pulmonary embolism. METHODS: We conducted a prospective study in 173 patients from four institutions who underwent clinical examination, abdominal radiography, and duplex ultrasound examinations of the vena cava and lower extremities. If indicated by protocol or clinical presentation, computed tomography scans, pulmonary angiograms, or venacavograms were obtained. RESULTS: The most common procedural event was filter limb asymmetry (10%), which had no clinical significance. A variety of other minor procedural events occurred in another 10% of cases. Early follow-up (< 6 months) was completed in 149 patients, and long-term evaluation was completed in 113 (> 12 months). Deaths in 24 patients were from nonembolic causes in all but one. There were four suspected or confirmed recurrent pulmonary emboli, for an incidence of 3.5% (four of 113), with one death (0.9%). Four patients had inferior vena cava occlusion at early follow-up and at long-term evaluation, only one remained occluded (1%). Insertion site venous thrombosis was seen in only two patients (2%). CONCLUSION: The titanium Greenfield filter provides protection comparable to the standard stainless steel Greenfield filter after 1 year with a low incidence of recurrent pulmonary embolism (3.5%) and a high caval patency rate (99%).

Gender verification in competitive sports.

The possibility that men might masquerade as women and be unfair competitors in women's sports is accepted as outrageous by athletes and the public alike. Since the 1930s, media reports have fuelled claims that individuals who once competed as female athletes subsequently appeared to be men. In most of these cases there was probably ambiguity of the external genitalia, possibly as a result of male pseudohermaphroditism. Nonetheless, beginning at the Rome Olympic Games in 1960, the International Amateur Athletics Federation (IAAF) began establishing rules of eligibility for women athletes. Initially, physical examination was used as a method for gender verification, but this plan was widely resented. Thus, sex chromatin testing (buccal smear) was introduced at the Mexico City Olympic Games in 1968. The principle was that genetic females (46,XX) show a single X-chromatic mass, whereas males (46,XY) do not. Unfortunately, sex chromatin analysis fell out of common diagnostic use by geneticists shortly after the International Olympic Committee (IOC) began its implementation for gender verification. The lack of laboratories routinely performing the test aggravated the problem of errors in interpretation by inexperienced workers, yielding false-positive and false-negative results. However, an even greater problem is that there exist phenotypic females with male sex chromatin patterns (e.g. androgen insensitivity, XY gonadal dysgenesis). These individuals have no athletic advantage as a result of their congenital abnormality and reasonably should not be excluded from competition. That is, only the chromosomal (genetic) sex is analysed by sex chromatin testing, not the anatomical or psychosocial status. For all the above reasons sex chromatin testing unfairly excludes many athletes. Although the IOC offered follow-up physical examinations that could have restored eligibility for those 'failing' sex chromatin tests, most affected athletes seemed to prefer to 'retire'. All these problems remain with the current laboratory based gender verification test, polymerase chain reaction based testing of the SRY gene, the main candidate for male sex determination. Thus, this 'advance' in fact still fails to address the fundamental inequities of laboratory based gender verification tests. The IAAF considered the issue in 1991 and 1992, and concluded that gender verification testing was not needed. This was thought to be especially true because of the current use of urine testing to exclude doping: voiding is observed by an official in order to verify that a sample from a given athlete has actually come from his or her urethra. That males could masquerade as females in these circumstances seems extraordinarily unlikely. Screening for gender is no longer undertaken at IAAF competitions.

Percutaneous inferior vena caval filters: follow-up of seven designs in 320 patients.

Three hundred twenty-four percutaneous inferior vena caval (IVC) filters of different designs were placed in 320 patients from April 1985 through June 1992. No acute mortality or substantial morbidity was attributed to filter placement. Radiologic or pathologic follow-up data were obtained in 227 (71%) patients (230 filters); clinical follow-up data only were obtained in 50 (16%) patients (50 filters). One hundred twenty (43%) patients died; post-filter-placement pulmonary emboli (PE) were related to the cause of death in eight. At IVC filter imaging studies, 26 of 137 (19%) filters demonstrated caval thrombus; 12 of 132 (9%) filters had delayed penetration through the IVC wall of greater than 3 mm; 13 of 230 (6%) filters migrated more than 1 cm; and five of 230 (2%) filters had fracture of a strut or leg. Deep venous thrombosis (DVT) at the insertion puncture site or in the lower extremity was noted in 26 of 117 (22%) cases of filter placement. Among patients without imaging studies, clinical suspicion of complications included PE in four patients, IVC thrombus in 14 patients, and lower-extremity DVT in 10 patients. Long-term clinical and radiologic follow-up of all IVC filters is indicated due to the relatively high prevalence of some complications.

Thromboembolism in patients undergoing thoracotomy.

To determine the incidence of thromboembolism in relation to thoracotomy, 77 patients undergoing pulmonary resection were prospectively studied up to 30 days postoperatively for deep venous thrombosis and pulmonary embolism. Overall, 20 of 77 patients (26%) had thromboembolic events during their hospitalization. Four deep venous thromboses and 1 pulmonary embolism were detected in 5 of 77 patients preoperatively for an incidence of 6%. Postoperative thromboembolism was detected in 15 of 77 (19%): deep venous thrombosis in 11 (14%) and pulmonary embolism in 4 (5%). No postoperative thromboembolisms occurred in the 17 patients receiving preoperative aspirin or ibuprofen, whereas they did occur in 25% of the remainder (15/60). Thromboembolism after pulmonary resection was more frequent with bronchogenic carcinoma than with metastatic cancer or benign disease (15/59 [25%] versus 0/18 [0%]; p < 0.01), adenocarcinoma compared with other types of carcinoma (11/25 [44%] versus 4/34 [12%]; p < 0.0004), large primary lung cancer (> 3 cm in diameter) compared with smaller lesions (9/19 [47%] versus 6/40 [15%]; p < 0.0001), stage II compared with stage I (7/14 [50%] versus 7/34 [21%]; p < 0.04), and pneumonectomy or lobectomy compared with segmentectomy and wedge resection (14/49 [29%] versus 1/28 [4%]; p < 0.005). Three of 4 patients with thromboembolism detected preoperatively had operation within the previous year. Postoperative pulmonary embolism was fatal in 1 of 4 (25%) and accounted for the one death. These results suggest patients undergoing thoracotomy for lung cancer, especially adenocarcinoma, should be considered for thromboembolic prophylaxis.

George W. Holmes Lecture. Deep venous thrombosis and pulmonary embolism: correlative evaluation and therapeutic implications.

Deep venous thrombosis and pulmonary embolism are significant causes of morbidity and mortality in the United States; estimates range from 120,000 to 150,000 deaths annually. Although usually symptomatic, deep venous thrombosis can be clinically occult, in part due to incomplete obstruction or in part related to duplication, triplication, and fenestration anomalies, primarily of the superficial femoral or popliteal vein. Additionally, pulmonary emboli caused by deep venous thrombosis may be clinically silent. Because of therapeutic implications, especially indications for insertion of inferior vena caval filters, comprehensive assessments of both the disease process (i.e., deep venous thrombosis) and the complication (i.e., pulmonary emboli) are important. Thus, when a pulmonary embolus is the presenting process, correlative assessment of deep venous thrombosis, even in the absence of symptoms or signs in the lower extremity, may be of therapeutic significance. Conversely, when deep venous thrombosis of the lower extremities involving the popliteal or superficial femoral vein is the presenting process, correlative assessment of the pulmonary circulation, even when no pulmonary symptoms or signs are present, may be of therapeutic significance. Relative to the diagnosis of pulmonary embolism, the roles of assays of D-dimer, ventilation-perfusion lung scans, and segmental occlusion studies of the pulmonary circulation are discussed. Finally, the indications for insertion of inferior vena caval filters above the renal veins are presented and examples are shown.

Long-term effects of superficial femoral vein ligation: thirteen-year follow-up.

This study examines the late clinical, hemodynamic, and anatomic results of superficial femoral vein ligation performed in 35 extremities that were followed an average of 13 1/2 years (range, 5 to 22 years). Indications for interruption were to prevent recurrent embolization from distal deep venous thrombosis (14 cases), to prevent emboli in patients with contraindication to anticoagulants (eight cases), to prevent distal reflux in selected patients undergoing iliofemoral thrombectomy (11 cases), and to control reflux in failed venous reconstruction (two cases). Ligation was effective in the prevention of pulmonary emboli as indicated by no significant clinical events and 15 negative postligation ventilation-perfusion scans. Long-term clinical follow-up showed normal (class 0) or near-normal (class 1) extremities in 83%. Fourteen percent developed mild to moderate symptoms of pain or swelling but without ulceration (class 2), and only one case (3%) had ulcerative sequelae (class 3). The only two findings that correlated with worse clinical outcome were the presence of an incompetent profunda femoris or an obstructed greater saphenous vein. Profunda femoris reflux was found in 60% (3/5) of patients with class 2 or 3 sequelae, which was significantly higher than the 14% (3/22) found in those patients with class 0 or 1 results (p < 0.05). Obstruction of the greater saphenous vein was found in 50% of those patients with class 2 or 3 results as opposed to 9% with class 0 or 1 results (p = 0.05). A large collateral vessel between the profunda femoris and the distal superficial femoral or popliteal vein was associated with poor long-term results.(ABSTRACT TRUNCATED AT 250 WORDS)

Is anticoagulation indicated for asymptomatic postoperative calf vein thrombosis?

The purpose of this study was to determine the effect of anticoagulation on the incidence of thrombotic propagation and pulmonary embolism in patients with calf vein thrombosis after total hip or total knee arthroplasty. Patients undergoing arthroplasties had prospective surveillance for postoperative deep vein thrombosis by both bilateral contrast venography and venous duplex scanning. Calf vein thrombosis was documented by venography in 42 patients (50 limbs), including 29 of 253 patients undergoing total hip arthroplasty (11.4%) and 13 of 99 patients undergoing total knee arthroplasty (13%). Of patients on whom follow-up duplex scans were performed, heparin followed by warfarin anticoagulation was used in 11 (13 limbs) and withheld in 21 (25 limbs). Propagation of thrombosis to the popliteal or superficial femoral vein or both was detected by serial duplex scanning in 3 of 13 treated limbs (23%) and 2 of 25 untreated limbs (8%), (p = 0.43). All thrombus propagations were detected within 2 weeks of the operative procedure. There were no pulmonary emboli or deaths. Propagation of asymptomatic calf vein thrombosis after arthroplasty was not influenced by anticoagulation, suggesting that postoperative calf vein thrombosis need not be routinely treated. Serial venous duplex scanning is useful to identify the occasional patient in whom thrombotic propagation requiring anticoagulation develops.