Premature birth and disruption of the normal maturation process leave the immature ductus arteriosus unable to respond to postnatal cues for closure. Recent strategies that advocate conservative management of the patent ductus arteriosus (PDA) in premature infants are dependent on identification of the symptomatic PDA and understanding the risk factors that predispose to PDA. Exposure of premature infants to unintended vasodilatory stimuli may be one of the risk factors for PDA that is under-recognized. In this paper, we summarize the clinical factors that are associated with PDA and review commonly used neonatal drugs for their vasodilatory properties. Data demonstrating relaxation of the ductus arteriosus by gentamicin and other aminoglycoside antibiotics, by cimetidine and other H2 receptor antagonists, and by heparin are provided as examples of neonatal therapies that have unanticipated effects that may promote PDA.

SummaryBackground An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. Aim To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. Methodology We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. Results The median (range) tumour size in group 1 and group 2 was 4Á8 cm (1Á7-22) and 3Á0 cm (1Á7-5) respectively (P < 0Á001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). Conclusions Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade. Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants.

Vitamin K (VK) has an established biological function in blood coagulation and hemostasis and maintains general health and bone wellbeing. VK supplements have been promoted to treat and prevent many diseases, particularly for decreasing fracture risk in osteoporosis, a chronic condition described by weak bone tissue, and a high fracture risk following minor trauma. It affects older people from different races and ethnicity, mainly postmenopausal women. Many kinds of research emphasize the role of VK in improving bone health and preventing osteoporotic bone fracture, but the findings are mostly inconclusive. In this literature review, PubMed and Google Scholar databases were used as the primary sources to select the relevant studies and review the association between VK and bone health and also, to explore the impact of VK supplementation in osteoporosis management. A majority of studies reported that VK has an essential role in promoting bone health. Although some studies revealed that VK might increase bone mineral density and reduce fracture risk in people with osteoporosis, VK supplements' potential benefits were not sufficiently supported. Thus, more clinical studies are needed to determine the positive effects of VK supplementation in osteoporosis prevention and treatment.

Rheumatoid arthritis and systemic lupus erythematosus (SLE) are autoimmune diseases that are commonly seen in the female population. Rheumatoid arthritis mainly consists of distal symmetrical deforming polyarthritis. SLE patients have immune complexes that damage the organs and systems of the body, and this can present with one or more symptoms including the characteristic malar rash, serositis, lupus nephritis, photosensitivity, and arthritis of large joints. The onset and progression of the diseases are affected by physiological processes that occur in the body such as menopause and aging. The studies used as evidence were found in the PubMed, ScienceDirect, ProQuest, Taylor & Francis Online, Wiley Online Library, Ovid, and Oxford Academic databases. By analyzing these studies, the effects of aging and menopause on rheumatoid arthritis and SLE were revealed. In relation to menopause and aging, it was found that there was a progression of disease in women who had rheumatoid arthritis. However, aging and menopause caused the progression of SLE to decrease in women. An earlier age of onset of menopause was correlated with an increased chance of developing rheumatoid arthritis and SLE. Furthermore, while some studies showed that a later onset of SLE caused an increase in the progression of the disease, other studies showed that a later onset of SLE led to a decrease in the progression of the disease. Due to the prevalence of rheumatoid arthritis and SLE in females, we believe that the effects of menopause, age, and other factors on these two diseases should be examined in future studies.

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.

18Occupational noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large 19 social and personal burden. Some genetic variants in the mitochondrial oxidative stress response correlate 20 strongly with susceptibility to NIHL in both humans and mice. Here we test the hypothesis that SIRT3, a 21 regulator of the mitochondrial oxidative stress response, is required in mice for endogenous recovery of 22 auditory thresholds after a sub-traumatic noise exposure. We expose homozygous Sirt3-KO mice and their 23 wild-type littermates to a noise dose that confers a temporary threshold shift, but is not sufficient to 24 permanently reduce cochlear function, compromise cell survival, or damage synaptic structures. We find no 25 difference in hearing function after recovery from noise exposure between the two genotypes, when measured 26 by either auditory brainstem response (ABR) or distortion product otoacoustic emissions (DPOAE). We show 27 that SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner 28 hair cells, and faintly within inner hair cells. Nonetheless, outer hair cells and auditory synapses show no 29 increase in loss after noise exposure in the homozygous Sirt3-KO mouse. These data show that SIRT3-30 dependent processes are not necessary for endogenous hearing recovery after a single, sub-traumatic noise 31 exposure. They demonstrate the existence of cellular mechanisms of cochlear homeostasis in addition to the 32 mitochondrial oxidative stress response. We also present a novel statistical analysis for identifying differences 33 between peak 1 amplitude progressions in ABR waveforms. 34

No abstract