Effect of digital ocular massage on intraocular pressure and Schlemm's canal dimensions.

Digital ocular massage has been reported to temporarily lower intraocular pressure (IOP). This could be related to an enhanced aqueous humor outflow; however, the mechanism is not clearly understood. Using anterior segment optical coherence tomography, the Schlemm's canal (SC) and trabecular meshwork (TM) can be imaged and measured. Here, 66 healthy adults underwent digital ocular massage for 10 min in their right eyes. The IOP and dimensions of the SC and TM were measured before and after ocular massage. All subjects demonstrated IOP reduction from 15.7 ± 2.5 mmHg at baseline to 9.6 ± 2.2 mmHg immediately after, and median of 11.6 mmHg 5-min after ocular massage (Friedman's test, p < 0.001). There was significant change in SC area (median 10,063.5 µm2 at baseline to median 10,151.0 µm2 after ocular massage, Wilcoxon test, p = 0.02), and TM thickness (median 149.8 µm at baseline to 144.6 ± 25.3 µm after ocular massage, Wilcoxon test, p = 0.036). One-third of the subjects demonstrated collapse of the SC area (-2 to -52%), while two-thirds showed expansion of the SC area (2 to 168%). There were no significant changes in SC diameter (270.4 ± 84.1 µm vs. 276.5 ± 68.7 µm, paired t-test, p = 0.499), and TM width (733.3 ± 110.1 µm vs. 733.5 ± 111.6 µm, paired t-test, p = 0.988). Eyes with a higher baseline IOP demonstrated a greater IOP reduction (Pearson correlation coefficient r = -0.521, p < 0.001). Eyes with smaller SC area at baseline showed greater SC area expansion (Pearson correlation coefficient = -0.389, p < 0.001). Greater IOP reduction appeared in eyes with greater SC area expansion (Pearson correlation coefficient r = -0.306, p = 0.01). Association between change in IOP and change in TM thickness was not significant (Spearman's ρ = 0.015, p = 0.902). Simple digital ocular massage is an effective method to lower IOP values, and change in the SC area was significantly associated with IOP changes.

[Severe small bowel involvement and chronic intestinal pseudo-obstruction in systemic sclerosis (scleroderma): Pathophysiological, diagnostic and therapeutic basis, including parenteral nutrition]. / Atteinte sévère de l'intestin grêle et pseudo-obstruction intestinale chronique au cours de la sclérodermie systémique : bases physiopathologiques, diagnostiques et thérapeutiques, dont la nutrition parentérale.

Gastrointestinal involvement in systemic sclerosis can be severe, reaching the critical point of chronic intestinal pseudo-obstruction, secondary to major disorders of small bowel motility. It is associated with some clinical and biological characteristics, in particular the positivity of anti-fibrillarin/U3RNP antibodies. Chronic intestinal pseudo-obstruction (CIPO) is complicated by a small intestinal bacterial overgrowth that requires cyclic antibiotic therapy. CIPO leads to a reduction of the food intake, due to painful symptoms, nausea and vomiting caused by meals, and ultimately to severe malnutrition. Meal splitting is often transiently effective and patients require exogenous nutritional support, mostly parenteral. Systemic sclerosis is not an obstacle to initiation and long-term continuation of parenteral nutrition and central venous catheter implantation is not associated with an increased risk of cutaneous or infectious complications. However, continuation of long-term parenteral nutrition requires monitoring in an expert nutrition center in order to adapt nutritional volumes and intakes and to limit potentially fatal cardiac and hepatobiliary complications. In addition to nutrition, prokinetic treatments, whose side effects must be known, can be associated. Invasive procedures, whose risk-benefit ratio must be carefully assessed, can also be used to treat symptoms exclusively.

Discontinuation of Car Seat Tolerance Screening and Postdischarge Adverse Outcomes in Infants Born Preterm.

OBJECTIVE: To study the association between discontinuing predischarge car seat tolerance screening (CSTS) with 30-day postdischarge adverse outcomes in infants born preterm. STUDY DESIGN: Retrospective cohort study involving all infants born preterm from 2010 through 2021 who survived to discharge to home in a 14-hospital integrated health care system. The exposure was discontinuation of CSTS. The primary outcome was a composite rate of death, 911 call-triggered transports, or readmissions associated with diagnostic codes of respiratory disorders, apnea, apparent life-threatening event, or brief resolved unexplained events within 30 days of discharge. Outcomes of infants born in the periods of CSTS and after discontinuation were compared. RESULTS: Twelve of 14 hospitals initially utilized CSTS and contributed patients to the CSTS period; 71.4% of neonatal intensive care unit (NICU) patients and 26.9% of non-NICU infants were screened. All hospitals participated in the discontinuation period; 0.1% was screened. Rates of the unadjusted primary outcome were 1.02% in infants in the CSTS period (n = 21 122) and 1.06% after discontinuation (n = 20 142) (P = .76). The aOR (95% CI) was 0.95 (0.75, 1.19). Statistically insignificant differences between periods were observed in components of the primary outcome, gestational age strata, NICU admission status groups, and other secondary analyses. CONCLUSIONS: Discontinuation of CSTS in a large integrated health care network was not associated with a change in 30-day postdischarge adverse outcomes. CSTS's value as a standard predischarge assessment deserves further evaluation.

Bromelain and acetylcysteine (BromAc®): a novel approach to the treatment of mucinous tumours.

Mucins are a significant extracellular component of neoplastic entities such as pseudomyxoma peritonei and several gastrointestinal adenocarcinomas. Mucinous tumours present a challenge for systemic treatments due to poor drug penetrance and increased resistance. Therefore, the development of an effective mucolytic therapy has significant therapeutic implications for these tumour types. BromAc® is a novel mucolytic agent consisting of bromelain and acetylcysteine. It has demonstrated significant mucolysis and antitumour effects in vitro and in vivo for several mucinous tumours. It has also exhibited a synergistic potentiation of the effect of several cytotoxic agents on mucinous tumours in preclinical studies. Furthermore, it demonstrates locoregional safety and efficacy in animal and clinical studies. This literature review will summarise the history of BromAc® for mucinous tumours, including its conception, preclinical development in vitro and in vivo, and clinical evidence. The implications of current data and directions for future research are then discussed.

Nrf2 transcriptional derepression from Keap1 by dietary polyphenols.

The liver expresses batteries of cytoprotective genes that confer cellular resistance to oxidative stress and xenobiotic toxins, and protection against cancer and other stress-related diseases. These genes are mainly regulated by Nrf2, making this transcription factor a target for small molecule discovery to treat such diseases. In this report, we identified dietary polyphenolic antioxidants that not only activated these genes but also relieved Nrf2 repression by Keap1, a Cul3-dependent ubiquitin ligase adaptor protein that mediates its degradation. Analysis of postprandial liver RNA revealed a marked activation of both genes by all test polyphenols compared with controls. Nrf2 inhibition by RNA interference reduced polyphenol effects on its target gene expression. Our data suggest that polyphenols may induce cellular defense genes by derepressing Nrf2 inhibition by Keap1. We posit that this ability to derepress Nrf2 and reactivate its target genes may underlie the protection conferred by polyphenols against oxidative stress-related diseases.

Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption.

Hepcidin is a liver-derived antimicrobial peptide that regulates iron absorption and is also an integral part of the acute phase response. In a previous report, we found evidence that this peptide could also be induced by toxic heavy metals and xenobiotics, thus broadening its teleological role as a defensin. However it remained unclear how its sensing of disparate biotic and abiotic stressors might be integrated at the transcriptional level. We hypothesized that its function in cytoprotection may be regulated by NFE2-related factor 2 (Nrf2), the master transcriptional controller of cellular stress defenses. In this report, we show that hepcidin regulation is inextricably linked to the acute stress response through Nrf2 signaling. Nrf2 regulates hepcidin expression from a prototypical antioxidant response element in its promoter, and by synergizing with other basic leucine-zipper transcription factors. We also show that polyphenolic small molecules or phytoestrogens commonly found in fruits and vegetables including the red wine constituent resveratrol can induce hepcidin expression in vitro and post-prandially, with concomitant reductions in circulating iron levels and transferrin saturation by one such polyphenol quercetin. Furthermore, these molecules derepress hepcidin promoter activity when its transcription by Nrf2 is repressed by Keap1. Taken together, the data show that hepcidin is a prototypical antioxidant response or cytoprotective gene within the Nrf2 transcriptional circuitry. The ability of phytoestrogens to modulate hepcidin expression in vivo suggests a novel mechanism by which diet may impact iron homeostasis.

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.

Isotopic biomarker discovery and application in translational medicine.

Rational drug discovery relies on pathognomonic molecular reporters of disease or biomarkers. Therefore biomarkers contain relational or contextual information about disease pathophysiology. Two broad pathways can be taken to identify biomarkers: a 'top-down', holistic approach that makes no assumptions about biomarker type, or the 'bottom-up' approach, which is hypothesis driven and relies on a priori information. Both approaches involve parallel or sequential methods that include genomic and proteomic profiling. Biomarker discovery and translational medicine owe much to isotopic techniques because these provide near-real-time information about disease status as diagnostics, in drug delivery and for monitoring treatment. Here, we provide an overview of recent developments and some insight into the future role of isotopes in biomarker discovery and disease therapy.

Enhanced long-term stability for single ion channel recordings using suspended poly(lipid) bilayers.

Black lipid membranes (BLMs) are widely used for recording the activity of incorporated ion channel proteins. However, BLMs are inherently unstable structures that typically rupture within a few hours after formation. Here, stabilized BLMs were formed using the polymerizable lipid bis-dienoyl phosphatidylcholine (bis-DenPC) on glass pipettes of approximately 10 microm (I.D.). After polymerization, these BLMs maintained steady conductance values for several weeks, as compared to a few hours for unpolymerized membranes. The activity of an ion channel, alpha-hemolysin, incorporated into bis-DenPC BLMs prior to polymerization, was maintained for 1 week after BLM formation and polymerization. These lifetimes are a substantial improvement over those achievable with conventional BLM technologies. Polymerized BLMs containing functional ion channels may represent an enabling technology for development of robust biosensors and drug screening devices.

Successful blood conservation during craniosynostotic correction with dual therapy using procrit and cell saver.

BACKGROUND: Craniosynostotic correction typically performed around infant physiologic nadir of hemoglobin (approximately 3-6 months of age) is associated with high transfusion rates of packed red blood cells and other blood products. As a blood conserving strategy, we studied the use of 1) recombinant human erythropoietin or Procrit (to optimize preoperative hematocrit) and 2) Cell Saver (to recycle the slow, constant ooze of blood during the prolonged case). METHODS: UCLA Patients with craniosynostosis from 2003-2005 were divided into 1) the study group (Procrit and Cell Saver) or 2) the control group (n = 79). The study group 1) received recombinant human erythropoietin at 3 weeks, 2 weeks, and 1 week preoperatively and 2) used Cell Saver intraoperatively. Outcomes were based on morbidities and transfusion rate comparisons. RESULTS: The 2 groups were comparable with regards to age (5.66 and 5.71 months), and operative times (3.11 vs 2.59 hours). In the study group there was a marked increase in preoperative hematocrit (56.2%). The study group had significantly lower transfusions rates (5% vs 100% control group) and lower volumes transfused than in the control group (0.05 pediatric units vs 1.74 pediatric units). Additionally, of the 80% of patients in the study group who received Cell Saver blood at the end of the case, approximately 31% would have needed a transfusion if the recycled blood were unavailable. CONCLUSION: Our data showed that for elective craniosynostotic correction, successful blood conserving dual therapy with Procrit and Cell Saver might be used to decrease transfusion rates and the need for any blood products.

A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells.

It was previously demonstrated that Menta-FX, a mixture of Panax quinquefolius L. (PQE), Ginkgo biloba (GBE), and Hypericum perforatum extracts (HPE), enhances retinal ganglion cell survival after axotomy. However, the mechanisms of neuroprotection remain unknown. The aim of this study is to elucidate the neuroprotective mechanisms of Menta-FX. Since PQE, GBE and HPE have all been observed to display anti-oxidative property, the involvement of anti-oxidation in Menta-FX's neuroprotective effect was investigated. Menta-FX lowered nitric oxide (NO) content in axotomized retinas without affecting nitric oxide synthase activity, suggesting that Menta-FX possibly exhibited a NO scavenging property. In addition, the effect of Menta-FX on the frequency of axotomy-induced nuclear fragmentation and caspase-3 activation was investigated. Menta-FX treatment significantly reduced nuclear fragmentation in axotomized retinas. Surprisingly, Menta-FX had no effect on caspase-3 activation, but selectively lowered caspase-3-independent nuclear fragmentation in axotomized retinal ganglion cells. In addition, inhibition of PI3K activity by intravitreal injection of wortmannin, a phosphoinositide-3 kinase (PI3K) inhibitor, completely abolished the neuroprotective effect of Menta-FX, indicating that Menta-FX's neuroprotective effect was PI3K-dependent. Data here suggest that Menta-FX displayed a PI3K-dependent, selective inhibition on a caspase-3-independent apoptotic pathway in axotomized RGCs, thus, highlighting the potential use of herbal remedies as neuroprotective agents for other neurodegenerative diseases.

Bexarotene and narrowband ultraviolet B phototherapy combination treatment for mycosis fungoides.

Combination therapy for mycosis fungoides (MF) has the potential to be synergistic, improve therapeutic efficacy and reduce toxicities. We present a patient with MF who improved on combination therapy with bexarotene and narrowband ultraviolet B (NB-UVB) therapy. The patient is an 81-year-old Caucasian male who initially presented with stage IB MF. After temporary improvement with NB-UVB phototherapy, he progressed to develop plaques and tumors. Psoralen and ultraviolet A therapy was contraindicated because of ophthalmologic disease. Addition of bexarotene 300 mg daily led to rapid clinical improvement in combination with NB-UVB. Interruption of NB-UVB during a prolonged hospitalization led to a clinical flare of lesions, despite continued treatment with bexarotene. Reinitiating NB-UVB was associated with clinical improvement. This report demonstrates that combination treatment with oral bexarotene and NB-UVB therapy may represent a safe alternative for the treatment of plaque-stage MF.

Narrow-band UVB induces apoptosis in human keratinocytes.

Narrow-band ultraviolet (NB-UVB) phototherapy emits mostly 311/312 nm light and is commonly used in the treatment of inflammatory skin disorders. As a source of UVB irradiation, NB-UVB causes apoptosis in T lymphocytes but its effects on keratinocytes are unknown. Herein, we have investigated the ability of NB-UVB to induce apoptosis in keratinocytes. Two types of human keratinocytes, primary and immortalized, were exposed to NB-UVB and broad-band UVB (BB-UVB; 315-280 nm) and tested for apoptosis. Both UVB light sources induced apoptosis in keratinocytes as determined by the presence of DNA ladders, although NB-UVB required approximately ten fold higher doses; NB-UVB (1000 mJ/cm2) and BB-UVB (125 mJ/cm2). By comparison, lower doses of NB-UVB (750 mJ/cm2) induced apoptosis in T lymphocytes, suggesting cell type specificity for NB-UVB induced apoptosis. Approximately, 50% or more of the cells underwent apoptosis when exposed to NB-UVB or BB-UVB as revealed by TUNEL assay. Electron micrographs showed that NB-UVB irradiated keratinocytes contained marked chromatin condensation, extensive cytoplasmic vacuolization and fragmentation of the nuclear envelope. Furthermore, Western blot analysis confirmed the presence of activated products of caspase 3 in keratinocytes that received apoptotic doses of NB-UVB. This study defines conditions by which NB-UVB irradiation causes apoptosis in keratinocytes.

Enhanced survival and regeneration of axotomized retinal ganglion cells by a mixture of herbal extracts.

The aim of this study is to investigate the effects of Panax quinquefolius L. extract (PQE), Ginkgo biloba extract (GBE), and Hypericum perforatum extract (HPE), in combination or alone, on the survival and regeneration of axotomized retinal ganglion cells (RGCs) in an optic nerve transection model in adult hamsters. Unilateral transection of the optic nerve was performed to evaluate the effects of herbal extracts on the survival of axotomized RGCs. Effects of the herbal extracts on axonal regeneration of axotomized RGCs, on the other hand, were studied by attaching a peripheral nerve graft onto the transected ocular stump to induce regeneration. Operated animals received daily oral administration of vehicle or herbal extracts (PQE, GBE, and HPE), alone or in combination, for 7 and 21 days, respectively, in the survival and regeneration experiments. Surviving and regenerating RGCs were retrogradely labeled with Fluoro-Gold. The eyes were then enucleated and the retinas were flat-mounted for the counting of the labeled RGCs. Treatment with PQE, GBE and HPE alone failed to offer neuroprotection to injured RGCs. However, treatment with Menta-FX, a mixture of PQE, GBE, and HPE, significantly augmented RGC survival 7 days postaxotomy. Treatment with Menta-FX also induced a significant (87%) increase in the number of regenerating RGCs 21 days after optic nerve transection. This study demonstrates that herbs can act as a potential neuroprotective agent for damaged RGCs. It also suggests that the therapeutic value of herbal remedies can be maximized by the use of mixtures of appropriate herbs.

Cochlear nerve acoustic envelope response detection is improved by the addition of random-phased tonal stimuli.

We test Lowenstein's dc bias hypothesis as an alternative mechanism for the phenomenon sometimes called 'stochastic resonance'. Probe stimuli consisting of paired phase-locked tones at frequencies f(1) and f(2) (where f(2)-f(1)=800 Hz, f(1)>4.5 kHz) and at equal intensity were used to generate synchronous 800 Hz cochlear nerve activity (envelope responses). When a background tone of the same intensity, with a frequency halfway between f(1) and f(2), is presented simultaneously with the probe stimulus, the envelope response amplitude typically decreases. Consistent with Lowenstein's hypothesis, however, when the intensities of the probe and background tone are near the detection threshold of the envelope response (approximately 0-20 dB sound pressure level), the simultaneous presence of the background tone often increases the amplitude of the envelope response. At these same intensity levels, when the background tone precedes the probe stimulus, it decreases the amplitude of the response to the probe stimulus. The effects of simultaneous presentation of the probe and the background tone are frequency-dependent, becoming less pronounced or reversing as the frequency of the background tone departs from those of the probe stimuli.

The effects of shiatsu on lower back pain.

Shiatsu, a specific type of massage, was used as an intervention in this study of 66 individuals complaining of lower back pain. Each individual was measured on state/trait anxiety and pain level before and after four shiatsu treatments. Each subject was then called 2 days following each treatment and asked to quantify the level of pain. Both pain and anxiety decreased significantly over time. Extraneous variables such as gender, age, gender of therapist, length of history with lower back pain, and medications taken for lower back pain did not alter the significant results. These subjects would recommend shiatsu massage for others suffering from lower back pain and indicated the treatments decreased the major inconveniences they experienced with their lower back pain.

Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity.

Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.

Noise improves transfer of near-threshold, phase-locked activity of the cochlear nerve: evidence for stochastic resonance?

Stochastic resonance can be described as improved detection of weak periodic stimuli by a dynamic nonlinear system, resulting from the simultaneous presentation of a restricted dynamic range of low-intensity noise. This property has been reported in simple physical and biological activities. The present study describes data consistent with the interpretation that stochastic resonance can be observed in the response of cochlear neurons. These experiments utilized low levels (-5 to 25 dB SPL) of stimuli and noise (5 to 30 dB SPL). Stimuli consisted of simultaneously presented 8 kHz (F1) and 8.8 kHz (F2) tone bursts, which generated an 800 Hz F2-F1 cochlear nerve envelope ensemble response in the gerbil. The mean response threshold was approximately -3 dB SPL. Simultaneous presentation of a low-intensity wideband noise increased the amplitude of this response. This was observed with tonal stimuli having intensities of 0-5 dB SPL; responses to stimulus levels > 10 dB were attenuated by noise. Response amplitude was increased by noise levels of 10-15 dB; the amplitude was unaffected by lower levels of noise, and decreased in the presence of higher noise levels. These properties are compatible with those of stochastic resonance.