Review

Authors: Esteban Jodar, Claudia Campusano, Renate T de Jongh...

BACKGROUND

In addition to the role of vitamin D in bone mineralization, calcium and phosphate homeostasis, and skeletal health, evidence suggests an association between vitamin D deficiency and a wide range of chronic conditions. This is of clinical concern given the substantial global prevalence of vitamin D deficiency. Vitamin D deficiency has traditionally been treated with vitamin D (cholecalciferol) or vitamin D (ergocalciferol). Calcifediol (25-hydroxyvitamin D) has recently become available more widely.

METHODS

By means of targeted literature searches of PubMed, this narrative review overviews the physiological functions and metabolic pathways of vitamin D, examines the differences between calcifediol and vitamin D, and highlights clinical trials conducted with calcifediol in patients with bone disease or other conditions.

RESULTS

For supplemental use in the healthy population, calcifediol can be used at doses of up to 10 µg per day for children ≥ 11 years and adults and up to 5 µg/day in children 3-10 years. For therapeutic use of calcifediol under medical supervision, the dose, frequency and duration of treatment is determined according to serum 25(OH)D concentrations, condition, type of patient and comorbidities. Calcifediol differs pharmacokinetically from vitamin D in several ways. It is independent of hepatic 25-hydroxylation and thus is one step closer in the metabolic pathway to active vitamin D. At comparable doses to vitamin D, calcifediol achieves target serum 25(OH)D concentrations more rapidly and in contrast to vitamin D, it has a predictable and linear dose-response curve irrespective of baseline serum 25(OH)D concentrations. The intestinal absorption of calcifediol is relatively preserved in patients with fat malabsorption and it is more hydrophilic than vitamin D and thus is less prone to sequestration in adipose tissue.

CONCLUSION

Calcifediol is suitable for use in all patients with vitamin D deficiency and may be preferable to vitamin D for patients with obesity, liver disease, malabsorption and those who require a rapid increase in 25(OH)D concentrations.

Topics: Adult; Child; Humans; Calcifediol; Dietary Supplements; Vitamin D; Vitamins; Cholecalciferol; Vitamin D Deficiency

PubMed: 36862209
DOI: 10.1007/s00394-023-03103-1

Review

Authors: Hannah Tharmalingham, Peter Hoskin

The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials.

Topics: Animals; Cell Hypoxia; Female; Humans; Male; Misonidazole; Neoplasms; Niacinamide; Oxygen Consumption; Radiation-Sensitizing Agents; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Treatment Outcome; Tumor Hypoxia

PubMed: 29979089
DOI: 10.1259/bjr.20170966

Authors: S Ramaraju, S Reichert, Y Wang...

OBJECTIVE

To quantify the effect of inhaled 5% carbon-dioxide/95% oxygen on EEG recordings from patients in non-convulsive status epilepticus (NCSE).

METHODS

Five children of mixed aetiology in NCSE were given high flow of inhaled carbogen (5% carbon dioxide/95% oxygen) using a face mask for maximum 120s. EEG was recorded concurrently in all patients. The effects of inhaled carbogen on patient EEG recordings were investigated using band-power, functional connectivity and graph theory measures. Carbogen effect was quantified by measuring effect size (Cohen's d) between "before", "during" and "after" carbogen delivery states.

RESULTS

Carbogen's apparent effect on EEG band-power and network metrics across all patients for "before-during" and "before-after" inhalation comparisons was inconsistent across the five patients.

CONCLUSION

The changes in different measures suggest a potentially non-homogeneous effect of carbogen on the patients' EEG. Different aetiology and duration of the inhalation may underlie these non-homogeneous effects. Tuning the carbogen parameters (such as ratio between CO2 and O2, duration of inhalation) on a personalised basis may improve seizure suppression in future.

Topics: Adolescent; Carbon Dioxide; Child; Child, Preschool; Electroencephalography; Female; Humans; Inhalation; Male; Oxygen; Respiration; Status Epilepticus

PubMed: 33534850
DOI: 10.1371/journal.pone.0240507

Review

Authors: Nuria Vilaplana-Lopera, Maxym Besh, Eui Jung Moon...

Tumour hypoxia is significantly correlated with patient survival and treatment outcomes. At the molecular level, hypoxia is a major driving factor for tumour progression and aggressiveness. Despite the accumulative scientific and clinical efforts to target hypoxia, there is still a need to find specific treatments for tumour hypoxia. In this review, we discuss a variety of approaches to alter the low oxygen tumour microenvironment or hypoxia pathways including carbogen breathing, hyperthermia, hypoxia-activated prodrugs, tumour metabolism and hypoxia-inducible factor (HIF) inhibitors. The recent advances in technology and biological understanding reveal the importance of revisiting old therapeutic regimens and repurposing their uses clinically.

Topics: Humans; Neoplasms; Tumor Microenvironment; Prodrugs; Animals; Tumor Hypoxia; Antineoplastic Agents; Hyperthermia, Induced; Hypoxia

PubMed: 34827602
DOI: 10.3390/biom11111604

Authors: Michael F Holick

It is remarkable how an invisible, inanimate particle-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19)-that is hell-bent on reproducing itself was able to bring our modern civilization to its knees [...].

Topics: COVID-19; Humans; SARS-CoV-2

PubMed: 35267938
DOI: 10.3390/nu14050963

Authors: Avigeet Gupta, Sina Koochakzadeh, Shaun A Nguyen...

OBJECTIVE

This study aims to explore and determine the effectiveness of current pharmacologic agents for the prevention of noise-induced hearing loss (NIHL) via a systematic review.

DATABASES REVIEWED

The PubMed, Scopus, ClinicalTrials.gov, and Cochrane Library databases were searched from inception through February 6, 2020.

METHODS

Full-text, English-language articles detailing prospective randomized and nonrandomized clinical trials with pharmacological interventions administered to prevent NIHL were included in accordance with PRISMA guidelines. The detailed search terms are included in the Appendix, http://links.lww.com/MAO/B67.

RESULTS

Eleven articles were included in this review with 701 patients receiving a pharmacologic prevention for various noise exposures. Various regimens included administration of alpha-lipoic acid, ambient oxygen, beta-carotene, carbogen, ebselen, Mg-aspartate, N-acetylcysteine, and vitamins C, E, and B12. A number of studies demonstrated statistically significant amelioration of NIHL with pharmacologic intervention. Two studies demonstrated significantly better hearing outcomes for pharmacological prophylaxis with carbogen or ebselen as compared with placebo for the 4 kHz frequency, where the noise-notch is most likely to be encountered. Given the considerable heterogeneity in agents and methodologies, however, it was not possible to conduct a meta-analysis.

CONCLUSIONS

While several heterogenous articles demonstrated promising results for Mg-aspartate, carbogen, vitamin B12, and alpha-lipoic acid, the clinical significance of these pharmaceuticals remains unclear. Initial data from this study alongside future clinical trials might potentially contribute to the generation of clinical practice guidelines to prevent NIHL.

LEVEL OF EVIDENCE

2.

Topics: Hearing; Hearing Loss, Noise-Induced; Humans; Noise; Prospective Studies

PubMed: 33229875
DOI: 10.1097/MAO.0000000000002858

Authors: Umman Menendi, Gürdal Nusran, Burak Kaymaz...

BACKGROUND

Bone fractures and fracture healing are one of the most common problems among orthopedic surgeons. In this study, we investigated the effects of hyperbaric oxygen (HBO) and carbogen (C) treatment on fracture healing in the experimental animal model.

METHODS

Twenty-four male Wistar-Albino rats were randomly divided into three groups as Group 1 (C inhalation therapy), Group 2 (HBO inhalation therapy), and Group 3 (control group), with eight rats in each group. HBO and C treatment were given to the rats in Group 1 and Group 2 1 week before the surgical procedure and 3 weeks after the surgical procedure. Following the surgical procedure, all rats were killed at the end of the 3rd week and the healing tissue in the fracture line was evaluated clinically, radiologically, and histopathologically.

RESULTS

Although there were higher histopathological, radiological, and clinical scores in the HBO and C groups in terms of frac-ture healing compared to the control group, there was no statistically significant difference between the groups.

CONCLUSION

There are many studies in the literature that examine the systemic and local effects of HBO and C treatments and show that they increase tissue oxygenation. Our study showed that HBO and C groups had no beneficial or harmful effects on fracture healing compared to the control group.

Topics: Animals; Carbon Dioxide; Fracture Healing; Hyperbaric Oxygenation; Male; Oxygen; Rats; Rats, Wistar

PubMed: 35485502
DOI: 10.14744/tjtes.2021.02575

Review

Authors: Nipith Charoenngam, Aryan Nasr, Arash Shirvani...

Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.

Topics: Humans; Bone Diseases, Metabolic; Rare Diseases

PubMed: 36292765
DOI: 10.3390/genes13101880

Authors: Pieter T Deckers, Alex A Bhogal, Mathijs Bj Dijsselhof...

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO or O does not affect CMRO. We evaluated the null hypothesis that two common hypercapnic stimuli, 'CO in air' and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO were calculated for room-air, 'CO in air' and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for 'CO in air' and carbogen, respectively). CMRO decreased for 'CO in air' (-13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO during carbogen did not significantly change. Our findings indicate that 'CO in air' is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Topics: Adult; Brain; Carbon Dioxide; Cerebrovascular Circulation; Hemodynamics; Humans; Hypercapnia; Hyperoxia; Magnetic Resonance Imaging; Oxygen; Oxygen Consumption

PubMed: 34851757
DOI: 10.1177/0271678X211064572

Authors: Lisa A Feldman, Marie-Sophie Fabre, Carole Grasso...

BACKGROUND

Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy.

AIM

To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2).

RESULTS

PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone.

CONCLUSION

IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors.

Topics: Animals; Brain Neoplasms; Carbon Dioxide; Disease Models, Animal; Dose-Response Relationship, Drug; Emulsions; Fluorocarbons; Glioma; Mice, Inbred C57BL; Oxygen; Radiation-Sensitizing Agents; Survival Analysis; Tumor Hypoxia

PubMed: 28873460
DOI: 10.1371/journal.pone.0184250