The validity and feasibility of saliva melatonin assessment in the elderly

Recent work in young and middle-aged subjects suggests that melatonin levels in saliva may represent a viable alternative to serum melatonin measurement. We hypothesized that it may be a valid measure of melatonin levels in older adults as well, but features unique to the elderly may limit its utility. To study this, subjects were admitted to an academic medical center where saliva and serum specimens were collected concurrently in dim light conditions during a 14-hr overnight study period and analyzed for melatonin levels with radioimmunoassays (RIAs). Eighty-five subjects over the age of 65 with a broad range of medical conditions participated in the study. Subjects with dementia, depression and anemia were excluded. We found that saliva volume was inadequate for analysis (<200 microL) in 23.6% of specimens, with the majority of inadequate volume specimens occurring after midnight and inadequate specimens occurring more frequently in females than in males. The correlation coefficient for saliva melatonin and serum melatonin was r = 0.659 (Spearman, P < 0.001), and r = 0.466 for saliva dim light melatonin onset (DLMO) and serum DLMO. Saliva melatonin levels were 30.9% of serum melatonin levels, with a wide range of ratios noted between subjects. Overall melatonin levels influenced both the correlation and ratio of saliva melatonin to serum melatonin; higher correlations and lower ratios were noted when melatonin levels were high. Saliva specimens provide an economical and practical method for melatonin assessment, however, in older adults, issues such as hyposalivation and low melatonin levels limit the feasibility and validity, respectively, of saliva melatonin.     

Zinc tetrakis(N-methyl-4'-pyridyl) porphyrinato is an effective inhibitor of stimulant-induced activation of RAW 264.7 cells

One proposed mechanism for the development of silica-induced fibrosis is prolonged pulmonary inflammation and lung damage resulting from the secretion of reactive mediators from alveolar macrophages. Metalloporphyrins have antioxidative and antiinflammatory activities. However, the molecular basis for the antiinflammatory action of zinc tetrakis(N-methyl-4'-pyridyl) porphyrinato (ZnTMPyP) has not been elucidated. The objective of this study was to determine whether ZnTMPyP exhibited the ability to inhibit the production of reactive oxygen species (ROS), the activation of NF-kappaB, or the secretion of IL-1 in RAW 264.7 cells, and whether such inhibitory activity was related to the ROS-scavenging ability of ZnTMPyP. The results indicate that, although ZnTMPyP is not cytotoxic to RAW 264.7 cells, it is a potent inhibitor in ROS production by RAW 264.7 cells in response to various stimulants, such as silica, zymosan, or phorbol myristate acetate. ZnTMPyP is also effective in reducing stimulant-induced DNA-binding activity of NF-kappaB and silica-induced tyrosine phosphorylation of IkappaB-alpha. ZnTMPyP also inhibits LPS-induced IL-1 production. However, ZnTMPyP exhibits relatively weak ability to directly scavenge hyroxyl or superoxide radicals. On the basis of effective concentrations of ZnTMPyP, these results suggest that ZnTMPyP directly acts as an inhibitor of cellular activation in addition to exhibiting an antioxidant effect. Therefore, it is suggested that further studies concerning the effects of ZnTMPyP using in vivo oxidative stress models or its effects on the cytotoxic process of human diseases associated with lung inflammation and injury are warranted. In addition, ZnTMPyP may be a useful tool to investigate the molecular mechanisms involved in stimulant-induced signal pathways.     

Integration of periorbital titanium implants in irradiated bone: case report and histologic evaluation

Extraoral implants are used increasingly frequently in the wake of ablative tumor surgery and adjuvant radiation or chemotherapy for craniofacial rehabilitation with facial prostheses and epitheses. However, high rates of nonintegration and implant loss have been reported for extraoral implants, especially for those in the periorbital region following irradiation. This case report and corresponding histologic evaluation describe the osseointegration pattern in irradiated periorbital bone, based on the example of 3 retrieved, clinically integrated, stable titanium screw implants.     

Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in one family. In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality.     

A pilot study of levonorgestrel concentrations and bleeding patterns in women with epilepsy using a levonorgestrel IUD and treated with antiepileptic drugs

Objectives

We explored levonorgestrel (LNG) concentrations, bleeding patterns and endometrial thickness in women with epilepsy (WWE) initiating an LNG-intrauterine device (IUD) co-administered with antiepileptic drugs (AEDs).

Optimal control of one‐dimensional cellular uptake in tissue engineering

A control problem motivated by tissue engineering is formulated and solved, in which control of the uptake of growth factors (signaling molecules) is necessary to spatially and temporally regulate cellular processes for the desired growth or regeneration of a tissue. Four approaches are compared for determining one‐dimensional optimal boundary control trajectories for a distributed parameter model with reaction, diffusion, and convection: (i) basis function expansion, (ii) method of moments, (iii) internal model control, and (iv) model predictive control (MPC). The proposed method of moments approach is computationally efficient while enforcing a nonnegativity constraint on the control input. Although more computationally expensive than methods (i)–(iii), the MPC formulation significantly reduced the computational cost compared with simultaneous optimization of the entire control trajectory. A comparison of the pros and cons of each of the four approaches suggests that an algorithm that combines multiple approaches is most promising for solving the optimal control problem for multiple spatial dimensions. Copyright © 2012 John Wiley & Sons, Ltd.     

A CO2 greenhouse efficiently warmed the early Earth and decreased seawater 18O/16O before the onset of plate tectonics

The low ¹⁸O/¹⁶O stable isotope ratios (δ¹⁸O) of ancient chemical sediments imply ∼70 °C Archean oceans if the oxygen isotopic composition of seawater (sw) was similar to modern values. Models suggesting lower δ¹⁸O_sw of Archean seawater due to intense continental weathering and/or low degrees of hydrothermal alteration are inconsistent with the triple oxygen isotope composition (Δ’¹⁷O) of Precambrian cherts. We show that high CO₂ sequestration fluxes into the oceanic crust, associated with extensive silicification, lowered the δ¹⁸O_sw of seawater on the early Earth without affecting the Δ’¹⁷O. Hence, the controversial long-term trend of increasing δ¹⁸O in chemical sediments over Earth’s history partly reflects increasing δ¹⁸O_sw due to decreasing atmospheric pCO₂. We suggest that δ¹⁸O_sw increased from about −5‰ at 3.2 Ga to a new steady-state value close to −2‰ at 2.6 Ga, coinciding with a profound drop in pCO₂ that has been suggested for this time interval. Using the moderately low δ¹⁸O_sw values, a warm but not hot climate can be inferred from the δ¹⁸O of the most pristine chemical sediments. Our results are most consistent with a model in which the “faint young Sun” was efficiently counterbalanced by a high-pCO₂ greenhouse atmosphere before 3 Ga.

The amount of carbon that degassed from a solidifying magma ocean on the infant Earth 4.5 Ga ago was probably similar to the amount of CO₂ that is now present in the atmosphere of Venus (pCO₂ ∼90 bar) (1). Subsequently, dynamic carbon cycling between the early Earth’s atmosphere (atmospheric reservoir [R_A]), the ocean (R_O), and the oceanic crust (R_OC) reservoirs stabilized a primordial Earth–atmospheric pCO₂ to about 1.5 bar (2). Decreasing pCO₂ over the Earth’s history reflects the net transfer of large masses of carbon out of the atmosphere-ocean-oceanic crust (R_A+O+OC) system into the mantle and the emerging continental crust reservoir (R_CC), the latter providing a long-term sink for carbon in the form of inorganic carbon (carbonate rocks) and organic material (organic matter–rich shales, coal, oil, and gas) (1, 2).Early carbon-cycle models predicted high Archean pCO₂ to account for the faint young Sun paradox (2, 3), whereas direct pCO₂ estimates from the end of the Archean now imply much lower atmospheric pCO₂ [∼0.01 to 0.1 bar (4)]. However, a compilation of evidence from the sedimentary record implies much higher pCO₂ between 3.2 to 3.0 Ga compared to the 2.9 to 2.7 Ga interval (5). These authors state that even several bars pCO₂ are feasible between 3.2 to 3.0 Ga, which is not in conflict with much lower Neoarchean pCO₂ estimates (Fig. 1) or paleo-atmospheric pressure estimates at 2.7 Ga [<2 bar (6) and <0.5 bar (7)]. A fundamental drop in atmospheric CO₂ mixing ratio is also reflected in the observation that >3 Ga, Archean mafic crust (greenstones) is commonly characterized by very intense carbonatization and silicification that is unparalleled in their modern analogs (8–12). Such observations provide evidence for deep-time paleo-pCO₂ fluctuations with a drastic pCO₂ drop starting around 3 Ga ago (5, 13).Open in a separate windowFig. 1.Constraints on the R_A+O+OC size over time with implications for pCO₂. A illustrates the size of the R_A+O+OC carbon reservoir and its distribution between the oceanic crust (R_OC in gray), ocean water (R_O in dark blue), and the atmosphere (R_A in light blue). Transition of this carbon to the long-term R_CC and the mantle (green) decreases the size of the R_A+O+OC reservoir, which was still large at 3.2 Ga (see SI Appendix) and minimal at the onset of the global glaciations at 2.4 Ga. B shows two recent pH curves over Earth’s history to illustrate how the pH-dependent distribution of carbon between R_A and R_O may translate into pCO₂ at a given time. (C) The panel summarizes pCO₂ estimates [adopted from Catling and Zahnle (4)] and proposed pCO₂ evolution curves illustrated as dashed lines: a (2), b (18), and c (proposed here). Qualitative evidence to construct curve c comes from rare evidence for glaciers (44) and lower degrees of carbonatization of oceanic crust at 3.5 Ga compared to 3.2 Ga (13), suggesting a transient interval of somewhat low pCO₂ in the Paleoarchean. Low pCO₂ is indicated prior to the onset of cold climates later in the rock record. The black bar at 4.5 Ga is derived from carbon-flux arguments and the primordial carbon reservoir (1, 2). The black bar at 3.2 Ga applies the same carbon-flux arguments to translate the high carbonate content observed in the oceanic crust in Pilbara into tentative pCO₂ estimates (SI Appendix), which are most consistent with curve a (2).Today, carbonatization, which is the formation of carbonates during alteration of the oceanic crust, mainly occurs in relatively cool, off-axis hydrothermal systems over the first 20 Mya after crust formation at midocean ridges (14–16). Elevated degrees of carbonatization in oceanic crust from the Cretaceous and Jurassic are assigned to higher dissolved inorganic carbon at the time (14). Hence, higher pCO₂ (i.e., a larger R_A+O+OC) directly translates into higher degrees of carbonatization. While carbonate is mainly observed as vein fillings in the upper 300 m of oceanic crust today (14, 15), it extensively replaces glass and igneous minerals in Archean greenstones down to depths of 2 km below the ancient seafloor (8–10, 17). The amount of CO₂ fixed in 3.2-Ga-old oceanic crust from Pilbara, Australia is estimated at 1.2 × 10⁷ mol ⋅ m⁻² (±10%) (17)—a remarkable figure that is about two orders of magnitude more compared to today (SI Appendix). Much lower degrees of carbonatization in oceanic crust are already observed at 2.6 Ga, suggesting a drastic Mesoarchean drop in pCO₂ (13) (Fig. 1A).The qualitative evidence from the sediment record (5) and from the degree of carbonatization and silicification of oceanic crust (13) has not been included in proposed pCO₂ curves (4, 18) because the quantitative conversions into absolute pCO₂ require some assumptions (SI Appendix). Nevertheless, pCO₂ during the early Archean may have been as high as initially predicted by Kasting (2), followed by a pronounced Mesoarchean drop (13) to levels consistent with available paleo-pCO₂ estimates toward the Neoarchean (4) (stippled line “c” in Fig. 1C). Further decreasing pCO₂ toward modern levels partly reflects increasing ocean pH (Fig. 1) rather than a shrinking R_A+O+OC (SI Appendix). Hence, only small effects of carbonatization on the δ¹⁸O_sw value are expected for post-Archean seawater (16). Here, we focus on the very high carbonatization (8–10, 13) and silicification (11, 12) fluxes before the Mesoarchean pCO₂ drop, and we model the respective effects on ancient δ¹⁸O_sw.