COVID-19 and IL-6: Why vitamin D (probably) helps but tocilizumab might not.

Interleukin 6 (IL-6), which is involved in the cytokine storm phenomenon, is a therapeutic target in COVID-19, but monoclonal receptor antibody therapeutic agents such as tocilizumab have demonstrated mixed results. Could Vitamin D, which modulates IL-6, be more effective than currently deployed IL-6 antagonists, including tocilizumab, thereby presenting a useful therapeutic option in COVID-19? A narrative review of published trials examining the effect of Vitamin D administration in COVID-19 patients was conducted, and the theoretical basis for the use of tocilizumab as an IL-6 antagonist was compared with the immunomodulatory effect of Vitamin D on IL-6 production. Four of the six included studies reported a positive effect of Vitamin D on outcomes. While tocilizumab non-selectively blocks both anti-inflammatory and pro-inflammatory actions of IL-6, Vitamin D lowers immune cell IL-6 production, potentially reducing pro-inflammatory effects, but does not specifically target IL-6 receptors, avoiding any deleterious effect on the anti-inflammatory actions of IL-6. Vitamin D may have advantages over tocilizumab as an IL-6 immunomodulator, and, given that it is safe if administered under clinical supervision, there is a strong rationale for its use.

Correlation between premorbid IL-6 levels and COVID-19 mortality: Potential role for Vitamin D.

There is recent evidence that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19, but it is also possible that this cytokine may have a far more important role in the pathogenesis of viral infection. IL-6 is known to be modulated by Vitamin D, and there is preliminary evidence that deficiency of this vitamin is linked to poorer outcomes. To identify whether IL-6 levels prior to infection might predict outcome, early data on COVID-19 mortality from Italy and the UK were compared with previously published results of mean IL-6 levels from these countries as well as from the USA. There was a highly significant correlation (r = 0.9883; p = 0.00025) between age-stratified mortality rates and IL-6 levels from previously published data on healthy individuals. To determine whether Vitamin D may be beneficial at lowering IL-6 levels in patients, a limited analysis of trials examining the relationship between these entities published since 2015 was undertaken. Eight out of 11 studies described a significant lowering effect of Vitamin D on IL-6. Given that IL-6 likely facilitates viral cell entry and replication, levels prior to infection may predict mortality. This provides a rationale for prophylactic and therapeutic measures directed at lowering IL-6, including Vitamin D prescription.

Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19?

There is anecdotal evidence that tocilizumab, an immunosuppressant drug, may be a potential therapeutic option for patients with severe manifestations of coronavirus disease 2019 (COVID-19). Like tocilizumab, Vitamin D appears to modulate the activity of an interleukin (IL-6), which may explain the seasonal variation in prevalence of influenza. While most cases of COVID-19 have, thus far, occurred in the Northern Hemisphere winter, limiting the ability to assess seasonal variation, there remains substantial variation in the severity of this condition that has yet to be explained. A retrospective comparison of Vitamin D levels in previously obtained blood samples between survivors and confirmed fatalities could establish a rationale for implementation of widespread Vitamin D supplementation. This would be far cheaper and simpler than tocilizumab as a therapeutic option to trial.

A Human Sensory Pathway Connecting the Foot to Ipsilateral Face That Partially Bypasses the Spinal Cord.

Human sensory transmission from limbs to brain crosses and ascends through the spinal cord. Yet, descriptions exist of ipsilateral sensory transmission as well as transmission after spinal cord transection. To elucidate a novel ipsilateral cutaneous pathway, we measured facial perfusion following painfully-cold water foot immersion in 10 complete spinal cord-injured patients, 10 healthy humans before and after lower thigh capsaicin C-fiber cutaneous conduction blockade, and 10 warm-immersed healthy participants. As in healthy volunteers, ipsilateral facial perfusion in spinal cord injured patients increased significantly. Capsaicin resulted in contralateral increase in perfusion, but only following cold immersion and not in 2 spinal cord-injured patients who underwent capsaicin administration. Supported by skin biopsy results from a healthy participant, we speculate that the pathway involves peripheral C-fiber cross-talk, partially bypassing the cord. This might also explain referred itch and jogger's migraine and it is possible that it may be amenable to training spinal-injured patients to recognize lower limb sensory stimuli.

Is acupuncture "stimulation" a misnomer? A case for using the term "blockade".

BACKGROUND: The term used most frequently in the literature to describe acupuncture's effects is "stimulation" which may be used to describe either (or both) the direct stimulus applied to a needle as well as putative stimulation of the nervous system, despite little published evidence describing what is actually being stimulated. In contrast, recent published work has suggested that acupuncture may, in fact be inhibitory at a peripheral level, acting by blocking neural transmission. DISCUSSION: The suggestion that acupuncture exerts its effects through peripheral neural blockade is supported by recent evidence explaining related techniques including low level laser and capsaicin at acupoints. It also explains acupuncture's effect on painful and non-painful conditions and both Eastern and Western concepts of acupuncture. There is a need for additional work to elucidate acupuncture's mechanism of action, and the suggestion that it acts through neural blockade should prompt further research in this direction. SUMMARY: If the term "blockade" were applied to acupuncture, this would, likely, be expected to promote this minimally invasive technique, and, potentially, bring it into mainstream clinical practice for pain management as well as other therapeutic applications.

Do acupuncture meridians exist? Correlation with referred itch (mitempfindung) stimulus and referral points.

OBJECTIVE: To describe the relationship between referred itch (mitempfindung) stimulus and referral points and acupuncture meridians, noting that the neuroanatomical mechanism of mitempfindung has never previously been satisfactorily explained. METHODS: Analysis of clinical findings in the author as well as subjects in four previously described studies, comparing proportions in each of five groups. RESULTS: Ninety-two per cent (range 85-94%) of mitempfindung point pairs (stimulus and referral) aligned to a recognised acupuncture meridian with no statistical difference (p<0.05) between the five data sources. CONCLUSION: While previous authors have speculated on an association between mitempfindung and acupuncture, this is the first description of a relationship between stimulus and referral points and acupuncture meridians. The author suggests that the transmission of mitempfindung along acupuncture meridians may involve a series of C-fibre-Merkel cell relays, with the final referred itch sensation caused by substance P release triggering mast cell degranulation.

Synthesis, structural, and photophysical investigation of diimine triscarbonyl Re(I) tetrazolato complexes.

The synthesis, structural, and photophysical properties of a novel family of neutral fac-[Re(N(∧)N)(CO)(3)(L)] complexes, where N(∧)N is either 2,2'-bipyridine or 1,10-phenanthroline and L is a para functionalized 5-aryltetrazolate [namely, 5-phenyltetrazolate (Tph(-)), 4-(tetrazolate-5-yl)benzaldehyde (Tbdz(-)), 5-(4-acetylphenyl)tetrazolate (Tacy(-)), and methyl 4-(tetrazolate-5-yl)benzoate (Tmeb(-))] are reported. The complexes were prepared by direct addition of the corresponding tetrazolate anion to the acetonitrile solvated fac-[Re(N(∧)N)(CO)(3)](+) precursor. NMR data demonstrate that the coordination of the metal fragment is regiospecific at the N2 atom of the tetrazolate ring. These conclusions are also supported by X-ray structural determinations. Photophysical data were obtained in diluted and deaerated dichloromethane solutions displaying broad and structureless profiles with emission maxima ranging from 566 to 578 nm. The absorption profiles indicate the presence of higher energy intraligand (IL) π-π* transitions and lower energies ligand-to-ligand charge transfer (LLCT) and metal-to-ligand charge transfer (MLCT). As the last two transitions are mixed, they are better described as a metal-ligand-to-ligand charge transfer (MLLCT), a result that is also supported by density functional theory (DFT) calculations. The complexes show excited state lifetime values ranging from 102 to 955 ns, with associated quantum yield between 0.012 and 0.099. Compared to the parent neutral chloro or bromo [Re(N(∧)N)(CO)(3)X], the complexes show a slightly improved performance because of the π accepting nature of the tetrazolato ligand. The metal-to-ligand backbonding is in fact depleting the Re center of electron density, thus widening the HOMO-LUMO gap and reducing the non-radiative decay mechanism in accordance with the energy gap law. Finally, the electron-withdrawing or donating nature of the substituent on the phenyltetrazolato ligand allows the fine-tuning of the photophysical properties.

The cutaneous intrinsic visceral afferent nervous system: a new model for acupuncture analgesia.

The mechanism of acupuncture, whilst not known with certainty, has previously been considered to be stimulatory. A novel hypothesis is presented here in which C fiber tactile afferent axons bifurcate at acupuncture points and then diverge, running along acupuncture meridians, to subsequently communicate with Merkel cells. It is proposed that acupuncture disrupts the bifurcation of these axons, preventing neural transmission between Merkel cells as well as central communication with the spinal cord. Making use of the known phenomenon that acupuncture points have lower electrical resistance than adjacent skin, this hypothesis was tested using an electrical circuit model and successfully predicted the observed 10(3) reduction in skin resistance at acupuncture points. In addition to explaining acupuncture and the roles of both Merkel cells and C fiber tactile afferents, the model has greater implications for neuroscience, through the postulation of a new division of the autonomic nervous system.

Synthetic and structural comparisons of bismuth(III) carboxylates synthesised under solvent-free and reflux conditions.

Two synthetic approaches to the formation of bismuth(III) carboxylates have been explored and compared. Ph(3)Bi was reacted with a series of carboxylic acids (RCO(2)H) of varying pK(a) and functionality (R = PhCH[double bond, length as m-dash]CH, o-MeOC(6)H(4), m-MeOC(6)H(4), o-H(2)NC(6)H, o-O(2)NC(6)H(4), p-O(2)NC(6)H(4), 2-(C(5)H(4)N)) under reflux conditions in toluene and solvent-free. The thermochemical profiles of the solvent-free reactions were also studied by DSC-TGA. All reactions produced the tri-substituted bismuth carboxylates in comparable yields and purity with the exceptions of picolinic acid and p-nitrobenzoic acid. 2-Picolinic acid exclusively formed the di-substituted complex, [PhBi(2-(C(5)H(4)N)CO(2))(2)](4), by both methods, while p-nitrobenzoic acid gave the tri-substituted complex through reflux and the di-substituted complex under solvent-free conditions. Two of the complexes were structurally authenticated by single crystal X-ray diffraction: [PhBi(2-(C(5)H(4)N)CO(2))(2)](4) is tetrameric formed through five membered chelate rings involving the pyridyl N and O(-C) rather than the less stable carboxylate (-CO(2)) chelates, while [Bi(o-MeOC(6)H(4)CO(2))(3)](infinity), is a polymer in which dimeric units, constructed around two chelating and one unsymmetrical bridging carboxylate on each Bi centre, are then joined together through longer intermolecular Bi-O bridging bonds.

Gelation of La(III) cations promoted by 5-(2-pyridyl)tetrazolate and water.

Addition of water to the product formed when LaCl3 and 1H-5-(2-pyridyl)tetrazole (LH) were treated with an excess of triethylamine in ethanol, resulted in the reversible formation of a hydrogel, which when further treated with EtOH-iPrOH produced crystals of [LaL3(H2O)3].(H2O)4, as determined by X-ray crystallography.

Sonographic and MRI evaluation of the plantar plate: A prospective study.

The purpose of this study was to establish the accuracy of ultrasound in the examination of the plantar plate by comparing it with MRI, or if available, surgical findings. The lesser metatarsophalangeal joint plantar plates of 40 symptomatic and 40 asymptomatic feet (160 asymptomatic and 160 symptomatic plantar plates) were examined with ultrasound and MRI. Patients treated with surgery were chosen on a clinical basis and provided surgical correlation for the imaging techniques. Symptomatic patients with metatatarsalgia and suspected metatarsophalangeal joint instability were referred by an orthopedic foot specialist; asymptomatic feet were obtained either through examination of the contralateral foot of the symptomatic patients or volunteers. Ultrasound detected 75/160 and 139/160 plantar plates torn in the asymptomatic and symptomatic groups, respectively. MRI detected 56/160 and 142/160 tears in the symptomatic and asymptomatic groups, respectively. The sensitivity of MRI and ultrasound with surgical correlation was calculated to be 87 and 96%, respectively, with poor specificity. Ultrasound correlates moderately with MRI in the evaluation of the plantar plate. Surgical correlations, although limited (n = 10), indicate ultrasound is superior to MRI with more accurate detection of tears.

Sonography of plantar plates in cadavers: correlation with MRI and histology.

OBJECTIVE: The purpose of our study was to describe the sonographic appearance of the lesser metatarsal plantar plates in cadavers and to correlate these findings with MRI and histology. MATERIALS AND METHODS: Six soft-embalmed cadaveric feet (74-92 years old; two male, one female) were imaged with sonography and MRI. Tear dimensions of the plantar plate were recorded in the long and short axes. Orthopedic surgeons directly inspected the plantar plates before removing samples for histologic correlation. One young fresh cadaver was imaged with sonography before histologic assessment. RESULTS: The normal plantar plate appearance on sonography was a slightly echoic, homogeneous, curved structure. At direct inspection, a tear was present in 23 (96%) of 24 of the lesser plantar plates in the soft-embalmed feet. This direct inspection correlated with sonography detecting 23 tears correctly and MRI, 22 tears. Both sonography and MRI falsely reported one tear, but MRI also failed to detect one tear. Histologically, the abnormal plantar plate showed loss of the normal dense regular tissue and replacement with vessels, hydropic tissue, and a mixture of loose connective tissue and dense irregular connective tissue. CONCLUSION: Sonography, being noninvasive, shows promise as an imaging tool of the plantar plate. With ongoing research in this area we hope to determine the reliability and significance of such a technique in the evaluation of the plantar plate.

Identification of a by-product of nitric oxide synthase activity in human acute brain injury with in vivo proton magnetic resonance spectroscopy.

BACKGROUND AND PURPOSE: Laboratory studies have been used to identify nitric oxide as a notable mediator in neuronal death after acute brain injury. To our knowledge, this has not previously been confirmed with in vivo study in humans. Our purpose was to seek in vivo evidence for the induction of nitric oxide synthase (NOS) in human acute brain injury by using proton MR spectroscopy. METHODS: In vitro proton MR spectra were obtained in neural extracts from 30 human cadavers, and in vivo spectra were obtained in 20 patients with acute brain injury and in a similar number of control subjects. RESULTS: We identified a unique peak at 3.15 ppm by using in vivo proton MR spectroscopy in eight of 20 patients with acute brain injury but not in 20 healthy volunteers (P <.002). On the basis of in vitro data, we have tentatively assigned this peak to citrulline, a NOS by-product. CONCLUSION: To our knowledge, our findings suggest, for the first time, that excitotoxicity may occur in human acute brain injury. Confirmation with the acquisition of spectra in very early acute cerebral injury would provide a rationale for the use of neuroprotective agents in these conditions, as well as a new noninvasive method for quantification.