Central nervous system actions of atrial natriuretic factor

The recently discovered cardiac peptides, called atrial natriuretic factors (ANF), act peripherally as hormones which control fluid and electrolyte homeostasis. Their renal, adrenal and vascular effects are complemented by central nervous system (CNS) actions to inhibit vasopressin secretion, salt preference, and water intake, and to inhibit the CNS component of the hypothalamo-pituitary-adrenal axis. These central actions of ANF are thought to mirror physiological roles played by endogenous, neuronally derived ANF within the brain. ANF immunoreactivity and binding sites in the anterior pituitary gland and median eminence suggest, as well, neuroendocrine actions of the peptide. We have failed to observe direct pituitary effects of ANF on basal or stimulated pituitary hormone secretion, however, specific hypothalamic actions have been discovered. ANF infusions (IV or cerebroventricular) inhibit luteinizing hormone (LH) secretion via, at least in part, an opioid mechanism since naloxone pretreatment blocks the effect. Additionally ANF inhibits catecholamine stimulation of the release of LH-releasing factor in the median eminence. Direct effects of ANF on tuberoinfundibular dopamine neurons are suggested by the observation that the prolactin-inhibiting action of ANF is prevented by domperidone treatment and is absent following alpha methyl-p-tyrosine inhibition of tyrosine hydroxlyase activity. These recent results imply neuromodulatory actions of ANF within the CNS that are expressed via interaction with brain peptide and catecholamine systems.     

Clinicopathologic significance of histologic vascular invasion in papillary and follicular thyroid carcinomas

BACKGROUND: The association of angioinvasion with tumor aggressiveness in follicular and papillary thyroid carcinoma remains unclear. This study addresses this problem focusing on clinicopathologic relevance of angioinvasion in the treatment of papillary thyroid carcinoma and follicular thyroid carcinoma. METHODS: From a university hospital database, 358 patients with papillary thyroid carcinoma or follicular thyroid carcinoma were randomly selected. Their charts were retrospectively analyzed and divided into papillary thyroid carcinoma and follicular thyroid carcinoma groups. Each group was subdivided into angioinvasive and nonangioinvasive tumor subgroups. All data were analyzed using Student's t-test, Mann-Whitney rank sum test, chi-square test, and Fisher's exact test. RESULTS: There were 289 women and 69 men, ages 18 to 89 years. Papillary thyroid carcinoma (86%) was more frequent than follicular thyroid carcinoma. Most patients had nonangioinvasive tumor (90.2%). After a mean followup of 43.6 months, there were no significant differences between papillary thyroid carcinoma subgroups for local recurrence (p = 0.69), persistent elevated serum thyroglobulin (p = 0.568), and distant metastasis rates (p = 0.422). No death related to the cancer was observed in both papillary thyroid carcinoma subgroups (p = 1), except for one death resulting from a concomitant nasopharyngeal cancer. The longterm prognosis was less favorable for angioinvasive papillary thyroid carcinoma based on AJCC (American Joint Committee on Cancer staging), AMES (age, distant metastasis, tumor extent, and size), and MACIS (distant metastasis, age, completeness of primary tumor resection, local invasion, and tumor size), but the angioinvasive papillary thyroid carcinoma were larger than nonangioinvasive papillary thyroid carcinomas. The short-term clinical outcomes in both follicular thyroid carcinoma, after a mean followup of 72.3 months, were comparable in terms of local recurrence (p = 0.34), persistent elevated serum thyroglobulin (p = 1), and distant metastasis (p = 0.597). There was no death related to cancer in both follicular thyroid carcinoma subgroups (p = 1). There were no significant differences between both follicular thyroid carcinoma subgroups for longterm prognosis. CONCLUSIONS: Our results indicate that angioinvasion does not adversely influence short-term outcomes or longterm prognosis in follicular thyroid carcinoma and short-term outcomes in papillary thyroid carcinoma. Angioinvasion is a postoperative pathologic finding that does not justify an ominous prognosis or drastic therapeutic measures.     

Isolated femoropopliteal bypass graft for limb salvage after failed tibial reconstruction: a viable alternative to amputation

PURPOSE: Femoropopliteal bypass grafting procedures performed to isolated popliteal arteries after failure of a previous tibial reconstruction were studied. The results were compared with those of a study of primary isolated femoropopliteal bypass grafts (IFPBs). METHODS: IFPBs were only constructed if the uninvolved or patent popliteal segment measured at least 7 cm in length and had at least one major collateral supplying the calf. When IFPB was performed for ischemic lesions, these lesions were usually limited to the digits or small portions of the foot. Forty-seven polytetrafluoroethylene grafts and three autogenous reversed saphenous vein grafts were used. RESULTS: Ankle brachial pressure index (ABI) increased after bypass grafting by a mean of 0.46. Three-year primary life table patency and limb-salvage rates for primary IFPBs were 73% and 86%, respectively. All eight IFPBs performed after failed tibial bypass grafts remained patent for 2 to 44 months, with patients having viable, healed feet. CONCLUSION: In the presence of a suitable popliteal artery and limited tissue necrosis, IFPB can have acceptable patency and limb-salvage rates, even when a polytetrafluoroethylene graft is used. Secondary IFPB can be used to achieve limb salvage after failed tibial bypass grafting.     

Bisphenol A replacement chemicals,BPF and BPS,induce protumorigenic changes in human mammary gland organoid morphology and proteome

Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.

Bisphenols, of which the most prevalent is bisphenol A (BPA), are environmental chemicals that are used as plasticizers in a variety of goods, including plastic bottles, children''s toys, eyeglass lenses, food containers, and some types of thermal paper (e.g., cash register receipts). They leach from these products, contaminating humans (and animals) either directly or indirectly via other environmental media, such as household dust. Thus, in most adults, BPA is detected in serum, tissues, and urine (1, 2). Children (ages 6 to 11) have the highest concentrations of urinary BPA (3, 4). This chemical has structural similarities to estrogen (17-β-estradiol [E2]) and as a result, weakly mimics its activity (5). Hormones and growth factors play an important role in controlling prenatal mammary gland development and later on, the morphologic and functional alterations that occur during puberty, pregnancy, and eventually, menopause. Due to this plasticity, the mammary gland is particularly susceptible to the actions of endocrine-disrupting chemicals (EDCs), such as BPA (6–8). In vivo and in vitro studies have consistently shown that exposures to BPA at crucial developmental stages impair mammary gland development and increase neoplastic transformation (9–12). Treating rats with BPA results in mammary epithelial hyperplasia and enhances proliferation (13), common features of precancerous lesions. Additionally, BPA induces cell cycle progression and increases proliferation of human breast cancer cells in vitro via the up-regulated expression of estrogen-dependent genes (14).Based on these and other data, BPA has been removed from many commercial products. Most commonly, this chemical of concern is replaced by bisphenol S (BPS) and bisphenol F (BPF) compounds that share close structural similarities with BPA. However, little is known about their endocrine effects and more broadly, their biological activities. Marketing a product as “BPA free” suggests to the consumer that a product is safer, but research shows that replacement bisphenols have adverse effects similar to, or even greater than, BPA. For example, studies in zebrafish, rodents, and human cell culture models show that BPS and BPF have endocrine-disrupting activities. In zebrafish, despite species-specific differences in estrogen receptor (ER) affinity and specificity, BPF and BPS have estrogenic activities similar to BPA (15–17). In rats, exposure to BPF induces uterine growth, which suggests estrogenic effects (18). BPA, BPF, and BPS promote estrogen-dependent cell cycle progression, proliferation, and migration of human MCF-7 breast cancer cells along with epigenetic changes (19, 20). BPS exposure of pregnant and lactating mice limits milk production, suggesting alterations in mammary gland composition (21). In addition to estrogen signaling, BPF affects other endocrine pathways; in rats, oral administration of this compound alters thyroid hormone levels (22).Current research on bisphenol actions is mainly focused on endocrine effects. It is less well understood whether these chemicals have additional protumorigenic effects independent of their endocrine-disrupting activity. Moreover, tumor development is a multistep process involving heterogeneous cell types and numerous factors, including the potential roles of a variety of environmental chemicals (23, 24). Recapitulating this complexity in an experimental setup is challenging. In this context, tissue organoids are valuable models for understanding the early steps of carcinogenesis. They can be derived from nonmalignant primary tissues ex vivo. When grown for short periods of time in vitro, they maintain many of the genetic and epigenetic features of their normal cognates. Also, organoids have the added advantage of consisting of multiple cell types that are representative of the complexity of the tissue from which they are derived (25, 26).In this study, we exploited the strengths of the human mammary gland organoid culture system to understand the impact of the BPA replacements, BPF and BPS. Organoids established from nonmalignant human mammary gland tissues were exposed to one of the bisphenols, E2, or the vehicle control. The results showed that BPA replacements, in particular BPS, disrupted organoid architecture, enhanced branching, and caused compound-specific proteomic alterations—effects that were mostly E2 independent. Together, these observations suggested that the mammary gland effects of BPA substitutes should be equally or more concerning than those of the compound they are replacing.     

Sexually transmitted infections among female sex workers in Kupang,Indonesia: searching for a screening algorithm to detect cervical gonococcal and chlamydial infections

BACKGROUND AND GOAL: Notifications of HIV infection in Indonesia are increasing, but there are few data on other sexually transmitted infections (STIs), especially in the eastern islands of Indonesia. We aimed to measure the prevalence of STIs among female sex workers (FSWs) in Kupang, West Timor, and to develop screening algorithms to detect cervical infections with Neisseria gonorrhoeae and/or Chlamydia trachomatis (NG/CT). STUDY DESIGN: During 6 months in 1999, we recruited all the FSWs at Kupang's only brothel complex and a smaller number of independent FSWs. The women were examined at dedicated clinics and most laboratory tests were performed at provincial laboratories. Algorithms based on the strongest associations of variables with NG/CT were compared with the laboratory diagnoses. RESULTS: We recruited 288 women. The prevalence of N gonorrhoeae infection was 31%, that of C trachomatis infection was 24%, that of Trichomonas vaginalis infection was 5%, and that of syphilis was 13%. No case of HIV infection was detected. Few women had symptoms of STI. The only variables significantly associated with NG/CT after logistic regression analysis were the presence of cervical discharge (either yellow or clear) and a high count of polymorphonuclear leukocytes on gram-stained endocervical smear. Several algorithms to screen for NG/CT achieved high (>80%) sensitivity, but the highest specificity among these was only 50%. CONCLUSIONS: Although several of the generated algorithms may be useful in the absence of simple, accurate, affordable diagnostic tests, the high rates of STIs in this population could justify a more aggressive strategy incorporating periodic presumptive treatment to rapidly reduce prevalence.     

Effects of treatment on the histopathology of leprosy.

AIMS--To identify the histological changes in leprosy skin lesions over the first few weeks after the start of leprosy treatment and to examine their relationship to reversal reaction. METHODS--Sequential skin biopsy during treatment with multiple drug therapy. In this study, a series of 28 patients was studied, from whom two or more biopsies were taken at two week intervals. Fourteen patients had paucibacillary leprosy (PBL) and 14 had multibacillary leprosy (MBL). RESULTS--In most cases, granuloma fraction and bacterial index fell during treatment, the bacterial index being less sensitive than the granuloma fraction. Since the biopsies were fixed in buffered formalin and processed through to paraffin wax, little immunohistochemistry was feasible. However, there was strong evidence of immune activation, with increased expression of HLA-DR in the granulomas of MBL and PBL cases: the epidermis also expressed HLA-DR in several patients. Such changes may reflect gamma IFN production from granuloma lymphocytes. Patients with reversal reaction often showed HLA-DR expression on admission which decreased with corticosteroid treatment. CONCLUSIONS--The results suggest that activation of cell mediated immunity in leprosy lesions occurs during treatment with multiple drug therapy and may not be restricted to those with clinical evidence of reversal reaction.     

The impact of sleep deprivation on visual perspective taking

Total sleep deprivation (TSD) is known to alter cognitive processes. Surprisingly little attention has been paid to its impact on social cognition. Here, we investigated whether TSD alters levels‐1 and ‐2 visual perspective‐taking abilities, i.e. the capacity to infer (a) what can be seen and (b) how it is seen from another person's visual perspective, respectively. Participants completed levels‐1 and ‐2 visual perspective‐taking tasks after a night of sleep and after a night of TSD. In these tasks, participants had to take their own (self trials) or someone else's (other trials) visual perspective in trials where both perspectives were either the same (consistent trials) or different (inconsistent trials). An instruction preceding each trial indicated the perspective to take (i.e. the relevant perspective). Results show that TSD globally deteriorates social performance. In the level‐1 task, TSD affects the selection of relevant over irrelevant perspectives. In the level‐2 task, the effect of TSD cannot be unequivocally explained. This implies that visual perspective taking should be viewed as partially state‐dependent, rather than a wholly static trait‐like characteristic.     

Functional-task exercise versus resistance strength exercise to improve daily function in older women: a randomized, controlled trial

OBJECTIVES: To determine whether a functional-task exercise program and a resistance exercise program have different effects on the ability of community-living older people to perform daily tasks. DESIGN: A randomized, controlled, single-blind trial. SETTING: Community leisure center in Utrecht, the Netherlands. PARTICIPANTS: Ninety-eight healthy women aged 70 and older were randomly assigned to the functional-task exercise program (function group, n=33), a resistance exercise program (resistance group, n=34), or a control group (n=31). Participants attended exercise classes three times a week for 12 weeks. MEASUREMENTS: Functional task performance (Assessment of Daily Activity Performance (ADAP)), isometric knee extensor strength (IKES), handgrip strength, isometric elbow flexor strength (IEFS), and leg extension power were measured at baseline, at the end of training (at 3 months), and 6 months after the end of training (at 9 months). RESULTS: The ADAP total score of the function group (mean change 6.8, 95% confidence interval (CI)=5.2-8.4) increased significantly more than that of the resistance group (3.2, 95% CI=1.3-5.0; P=.007) or the control group (0.3, 95% CI=-1.3-1.9; P<.001). Moreover, the ADAP total score of the resistance group did not change significantly compared with that of the control group. In contrast, IKES and IEFS increased significantly in the resistance group (12.5%, 95% CI=3.8-21.3 and 8.6%, 95% CI=3.1-14.1, respectively) compared with the function group (-2.1%, 95% CI=-5.4-1.3; P=.003 and 0.3%, 95% CI=-3.6-4.2; P=.03, respectively) and the control group (-2.7%, 95% CI=-8.6-3.2, P=.003 and 0.6%, 95% CI=-3.4-4.6; P=.04, respectively). Six months after the end of training, the increase in ADAP scores was sustained in the function group (P=.002). CONCLUSION: Functional-task exercises are more effective than resistance exercises at improving functional task performance in healthy elderly women and may have an important role in helping them maintain an independent lifestyle.