Clinical Use and Treatment Mechanism of Molecular Hydrogen in the Treatment of Various Kidney Diseases including Diabetic Kidney Disease.

As diabetes rates surge globally, there is a corresponding rise in the number of patients suffering from diabetic kidney disease (DKD), a common complication of diabetes. DKD is a significant contributor to chronic kidney disease, often leading to end-stage renal failure. However, the effectiveness of current medical treatments for DKD leaves much to be desired. Molecular hydrogen (H2) is an antioxidant that selectively reduces hydroxyl radicals, a reactive oxygen species with a very potent oxidative capacity. Recent studies have demonstrated that H2 not only possesses antioxidant properties but also exhibits anti-inflammatory effects, regulates cell lethality, and modulates signal transduction. Consequently, it is now being utilized in clinical applications. Many factors contribute to the onset and progression of DKD, with mitochondrial dysfunction, oxidative stress, and inflammation being strongly implicated. Recent preclinical and clinical trials reported that substances with antioxidant properties may slow the progression of DKD. Hence, we undertook a comprehensive review of the literature focusing on animal models and human clinical trials where H2 demonstrated effectiveness against a variety of renal diseases. The collective evidence from this literature review, along with our previous findings, suggests that H2 may have therapeutic benefits for patients with DKD by enhancing mitochondrial function. To substantiate these findings, future large-scale clinical studies are needed.

The overlooked benefits of hydrogen-producing bacteria.

Intestinal bacteria can be classified into "beneficial bacteria" and "harmful bacteria." However, it is difficult to explain the mechanisms that make "beneficial bacteria" truly beneficial to human health. This issue can be addressed by focusing on hydrogen-producing bacteria in the intestines. Although it is widely known that molecular hydrogen can react with hydroxyl radicals, generated in the mitochondria, to protect cells from oxidative stress, the beneficial effects of hydrogen are not fully pervasive because it is not generally thought to be metabolized in vivo. In recent years, it has become clear that there is a close relationship between the amount of hydrogen produced by intestinal bacteria and various diseases, and this report discusses this relationship.

Guidelines for the selection of hydrogen gas inhalers based on hydrogen explosion accidents.

Despite the fact that we have reported on the dangers of the explosion of hydrogen gas inhalers, hydrogen gas inhalers with explosive hazards are, as a matter of fact, still being sold today. In this study, we investigated past reports of hydrogen gas inhaler explosion accidents to clarify the causes of these explosion incidents. As a result of this investigation, we found that the central cause was the leakage of hydrogen gas inside the hydrogen gas inhaler. Although it is said that the explosive concentration of hydrogen is between 10% and 75%, and that the gas does not explode above 75% due to the lack of oxygen, we confirmed through a series of ignition experiments that explosions can occur even in hydrogen gas inhalers that produce 100% hydrogen gas. Some manufacturers of such highly concentrated hydrogen gas inhalers claim that the high concentration and purity of hydrogen is safe and that there is no risk of explosion. We believe that manufacturing or selling such products that pose a risk of explosion or detonation is a violation of social justice. This paper presents ideas for selecting safe hydrogen gas inhalers based on a survey of past accident cases.

Conventional drug acts as a "rifle gun" while hydrogen as a "machine gun".

Most of the drugs used in modern medical treatments are symptomatic treatments and are far from being a cure for the diseases. The adverse effects are unavoidable in the drugs in modern medical treatments. Molecular hydrogen (H2) has a remarkable therapeutic effect on various diseases, and many clinical studies have reported that H2 has no adverse effects. Therefore, H2 is a novel medical gas that is outside the concept of modern medical treatment. H2, unlike drugs, works on the root of many diseases by scavenging the two kinds of strong reactive oxygen species, hydroxyl radical (·OH) and peroxynitrite (ONOO-). Since the H2 alleviates the root of diseases and can treat many diseases at the same time, the medical application of H2 may be called "machine gun therapy." In this review, we demonstrated that the root of many diseases is based on ·OH-induced oxidative stress in the mitochondria, and at the same time, the root of chronic inflammation is also attributed to ·OH.

Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.

Adjustable Medial Epicanthoplasty Using a Rotational Flap for Epiblepharon Repair.

ABSTRACT: This report aimed to introduce the new adjustable rotational skin flap for epicanthoplasty in combination with traditional epiblepharon repair by the modified Hotz procedure. This retrospective study involved 25 consecutive patients with superficial punctate keratitis secondary to epiblepharon complicated with epicanthal fold who underwent the combined surgery between 2019 and 2020. The mean patient age was 11.4 years in this study with a median follow-up was 8months (range, 3-12months). The rationale of the surgery was to release vertical tension of the eyelids by dissecting dense connective tissue beneath the epicanthal fold and to form a new medial canthus using a rotational skin flap supplied by the redundant the upper and/or lower eyelid skin excised during the epiblepharon repair. Postsurgical resolution ofsuperficial punctate keratitis and patient satisfaction was achieved in all patients. Additionally, there were no complications, and no revisional surgery was required in all patients for a median 8 months follow-up period. Utilizing a rotational skin flap during epiblepharon repair is a useful adjunct during epicanthoplasty surgery. This modification is well tolerated and allows for intraoperative adjustment, whereas minimizing scarring and allowing for improved tissue relaxation.

Impact of habitual swimming on the success of lacrimal surgery.

PURPOSE: To elucidate how factors associated with swimming affect the lacrimal ducts of swimmers. STUDY DESIGN: Prospective, interventional cohort study, METHODS: Five hundred seventy four consecutive epiphora patients were surveyed via a questionnaire regarding details of their swimming-pool usage; i.e., frequency, swim-goggles' wear, and type of pool activity (i.e., swimming vs. waist-depth walking). In this cohort, all the swimmers over 20 years old with anatomical lacrimal duct obstruction underwent surgical reconstruction. The surgical success rates at 12-months postoperative were compared using multivariable logistic regression analyses between swimmer/non-swimmer patients, those with a history of high/low frequency of pool usage, and those with high/low amount of conjunctival contact with the swimming-pool water. RESULTS: Of the patients with anatomical lacrimal duct obstruction, 6.4% were habitual swimmers; nasolacrimal duct obstruction was more common in the swimmers than in the non-swimmers' controls (89.1%/66.7%, P = 0.025). The success rate of lacrimal surgery for the swimmers with anatomical nasolacrimal duct obstruction was lower (60.6%) than of the non-swimmers (83.3%, P = 0.048). A receiver operating characteristic curve analysis of the frequency for the prediction of surgical failure showed that the threshold was 4 days/week. The success rate was statistically lower (26.7%) in the high-frequency swimmers compared to the low-frequency swimmers (88.9%, P = 0.037). However, no statistical difference in the high/low ocular surface contact to the swimming-pool water was observed (71.4%/57.7%, P = 0.56). CONCLUSION: Habitual swimmers have a high risk of nasolacrimal-duct damage retrogradely from the nasal cavity that lowers lacrimal surgery's success rate.

Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression.

While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H2), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H2 has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H2 against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H2 as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.

Molecular Hydrogen as a Novel Protective Agent against Pre-Symptomatic Diseases.

Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (·OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.

Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent.

Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.

Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress.

Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).

Newly Designed Universal Trans-punctal Rigid Lacrimal Microendoscope.

PURPOSE: To report the development and clinical findings of a universal trans-punctal lacrimal microendoscope design. METHODS: In this study, we examined a unique and original "2-bend" (i.e., double-angle) rigid lacrimal microendoscope designed for universal applications for anatomical variations. The shape of endoscope was initially evaluated in 6 lacrimal systems of cadavers (4 Caucasian-cadaver lacrimal systems and 2 Asian-cadaver lacrimal systems). Second, a prospective clinical study involving 45 consecutive cases of nasolacrimal duct obstruction in Japanese patients was conducted to compare the facility and ease of use between the conventional single-bend type and our original 2-bend type trans-punctal lacrimal microendoscope for examination of the lacrimal drainage system. RESULTS: The findings in the cadaver study revealed that original 2-bend lacrimal microendoscope, which was designed double-angled 20°-30° at 10 and 30 mm from the tip of the scope, could more easily used to insert and image all lacrimal systems, while the conventional single-bent lacrimal microendoscope was difficult to insert in subset of patients with a prominent nasal process of the frontal bone. In the clinical trial, our findings showed that 26.7% of lacrimal systems could not be passed using the conventional single-bend design, while using the 2-bend design, all cases could successfully be investigated. CONCLUSIONS: The original 2-bend-design microendoscope was found to be effective and valuable for universal use in examination and evaluation of the lacrimal passage.

Endoscopic Evaluation of Lacrimal Mucosa With Indigo Carmine Stain.

PURPOSE: Histological investigation in the use of indigo carmine for detection of mucosal pathology in lacrimal microendoscopy. To investigate the histopathological correlation of staining found on lacrimal microendoscopy. METHODS: A prospective case series was conducted in patients with a history of nasolacrimal duct obstruction and dacryocystitis requiring treatment with dacryocystorhinostomy or dacryocystectomy. Prior to lacrimal surgery, all patients underwent endolacrimal evaluation using transpunctal lacrimal microendoscopy. Indigo carmine dye (0.2 mg/0.5 ml) was injected into the lacrimal system via the irrigation channel of the endoscope, and after copious irrigation, the differential mucosal staining was recorded. Histopathologic analysis of tissue samples of positively and negatively stained lacrimal sac mucosa collected after surgery was performed to investigate the correlation with the results of each endoscopic evaluation. RESULTS: Four patients underwent dacryocystorhinostomy and 2 patients underwent dacryocystectomy. Histopathology of positive-stained lacrimal sac mucosa corresponded to areas of the advanced fibrous stage of mucosal changes resulting from dacryocystitis, which showed atrophy of epithelium associated with the loss of goblet cells and subepithelium fibrous scarring. In contrast, areas of lacrimal mucosa that did not stain with indigo carmine were still in an active inflammatory stage of dacryocystitis preserving columnar epithelium with goblet cells. CONCLUSIONS: This study suggests that indigo carmine staining is a useful adjunct in lacrimal microendoscopy for accurately detecting areas of highly damaged fibrous lacrimal mucosa, as it allows for direct visualization of lacrimal mucosal pathology and can provide prognostic insight and guidance in regard to treatment options for patients with lacrimal drainage obstruction.Use of indigo carmine dye as an in vivo adjunct in lacrimal microendoscopy is useful for accurately detecting areas of highly damaged lacrimal mucosa.

[A Case of Advanced Gastric Cancer Treated Effectively with Combination Chemotherapy of Paclitaxel plus Ramucirumab].

A 74-year-old man was referred to our hospital because of a gastric tumor. A Borrmann type 2 gastric tumor was found on upper gastrointestinal endoscopy, but tissue biopsy indicated only necrotic tissue and the preoperative diagnosis was difficult. Contrast CT and FDG-PET revealed lymphadenopathy at multiple sites accompanied by high accumulation of FDG in the perigastric lymph nodes, left upper collarbicular fossa, bilateral hilar ganglia, and longitudinal cauda. Because the tumor was strongly suspected to be gastric cancer or malignant lymphoma, distal gastrectomy was performed. The tumor was finally diagnosed as a poorly differentiated adenocarcinoma with multiple lymph node metastasis. S-1 plus cisplatin therapy was administered as first-line chemotherapy, and paclitaxel(PTX)plus ramucirumab(RAM)therapy was administered as secondline chemotherapy. PTX plus RAM therapy was effective, and the patient achieved complete remission(CR), as observed on imaging. However, because adverse events such as numbness in the periphery of the limbs were noted, PTX plus RAM therapy was discontinued per the patient's request. Currently, 13 months since the interruption of treatment, the CR has been maintained, as determined on imaging.

A case of neglected silicone tube in lacrimal duct for 20 years.

PURPOSE: To report a case of prolonged placement of a lacrimal silicone tube for 20 years, with evaluation of the lacrimal duct using lacrimal micro-endoscopy and inspection of deformation of the lacrimal tube. OBSERVATIONS: This study involved a case of dacryocystitis in which a silicone tube had been placed in the patient 20-years previous and that was treated conservatively. Although granulation tissue formation due to dacryocystitis in the lacrimal duct was observed under lacrimal micro-endoscopy, subjective and objective resolution of symptoms, including granulated tissue formation, was achieved after removal of the silicone tube and conservative medical treatment. Follow-up examinations performed over a 12-month period post treatment revealed no recurrence of epiphora or anatomical obstruction. Inspection of the lacrimal tube using the tension test revealed minimal changes in the tube in situ for 20 years. CONCLUSIONS AND IMPORTANCE: The findings in this case suggest both the lacrimal system and the silicone tube are tolerant to prolonged intubation, as long as the tube had been placed properly with careful observation. Our findings may encourage physicians to consider prolonged intubation for select cases of nasolacrimal duct obstruction.

Evaluation of granulation tissue formation in lacrimal duct post silicone intubation and its successful management by injection of prednisolone acetate ointment into the lacrimal duct.

PURPOSE: To evaluate the clinical findings and original treatment method of granulation tissue formation post silicone intubation (SI) for primary acquired lacrimal drainage obstruction (PALDO). METHODS: This retrospective, consecutive, comparative, interventional case series study involved 85 consecutive PALDO patients treated by SI and followed by dacryoendoscopy for 12 months post surgery. Patients in whom complication by granulation tissue formation occurred were treated every 2 weeks until it disappeared with an injection of prednisolone acetate ophthalmic ointment into the lacrimal duct without removing the tube. The frequency of granulation tissue formation post SI, relationship between the locations where the primary obstruction and granulation tissue formation occurred, and impact of the complication on the surgical outcome were evaluated. RESULTS: Granulation tissue formation occurred in 9 of the 85 cases (10.6 %) at 2-8 weeks post surgery, yet disappeared via treatment during that same period. No relationship was found between the location of the primary obstruction and the granulation tissue formation, and no statistical difference was found when comparing the success rate of our surgical treatment in patients with or without the complication (P = 0.46, Fisher's exact test). CONCLUSIONS: Complication by granulation tissue formation occurred in 10.6 % of the patients who underwent SI for PALDO, yet the injection of prednisolone acetate ophthalmic ointment into the lacrimal passage may have successfully treated the complication without removal of the silicone tube.

Effect of rebamipide ophthalmic suspension on the success of lacrimal stent intubation.

PURPOSE: To evaluate the effect of the postoperative administration of rebamipide ophthalmic suspension on the success rate of lacrimal stent intubation (LSI) for the treatment of primary acquired nasolacrimal duct obstruction (PANDO). METHODS: This comparative interventional cohort study investigated 110 consecutive patients with PANDO who were treated with LSI and followed up for 12 months postoperatively at one institution. LSI was performed by one surgeon, and all patients received identical postoperative care. Among the total 110 patients, 71 underwent LSI with postoperative administration of rebamipide ophthalmic suspension, and 39 underwent LSI without administration of the suspension. Data related to patient age, gender, laterality, and postoperative administration of rebamipide ophthalmic suspension were collected and used as independent variables, and logistic regression analyses were performed to compare the anatomical success rate at 12 months postoperatively between patients with and without postoperative administration of the suspension. RESULTS: The anatomical success rate of LSI in patients with and without postoperative administration of rebamipide ophthalmic suspension was 90.1 and 69.2 %, respectively. A comparison of these success rates showed statistical significance, in that the rate of treatment success was higher in PANDO patients who underwent LSI with postoperative administration of the suspension [odds ratio (OR), 3.37; P < 0.05]. CONCLUSIONS: The findings of this study show that postoperative administration of rebamipide ophthalmic suspension increases the rate of anatomical success in patients who undergo LSI for the treatment of PANDO.

Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation.

Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.

A Case of Coats' Disease with Spontaneous Retinal Reattachment after Total Detachment.

PURPOSE: To report a case of Coats' disease in which spontaneous reattachment occurred after total retinal detachment. PATIENT AND METHODS: A young boy (patient age: 4 years and 11 months) presented with leukocoria in the left eye. Slit-lamp examination revealed total retinal detachment with abnormal retinal blood vessels and subretinal exudation just behind the lens. Computed tomography imaging showed no solid mass lesion in the intraocular space. Secondary total retinal detachment as a complication of Coats' disease was diagnosed. No light perception was detected, so we determined that surgical treatment was not indicated. RESULTS: Four months after the initial diagnosis, the retina showed complete reattachment with a large amount of subretinal hard exudate. Visual acuity remained unchanged, with no light perception. CONCLUSIONS: We speculate that the spontaneous retinal reattachment in the present case was caused by the decreased permeability of the abnormal retinal vessels and the good functional effect of the retinal pigment epithelium.