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Abstract Background Cold hypersensitivity in the hands and feet (CHHF) is a common symptom in Korea and patients with CHHF complain of coldness in the hands and feet in an environment that is not considered cold by unaffected people. In traditional East Asian medicine, CHHF is believed to be accompanied by various diseases and symptoms, and is considered a symptom that needs active treatment. CHHF is used for pattern identification in the cold pattern, yang deficiency, and constitution. This study aimed to examine the differences in frequencies of chronic diseases with respect to the presence of CHHF. Methods Disease history, CHHF, body measurements, and blood test survey data from 6149 patients collected by 25 medical institutes in Korea were obtained from the Korean Medicine Data Center. The participants were divided into CHHF (n = 1909) and non-CHHF groups (n = 3017) according to the CHHF survey. The differences in frequencies of 18 diseases were analysed using chi-square tests, and the odds ratios (ORs) for each disease according to CHHF status were examined via logistic regression with adjustment for age, sex, and body mass index (BMI). Results Based on chi-square test results, the CHHF group showed a higher frequency of the following diseases: anaemia, hypotension, chronic gastritis, reflux oesophagitis, chronic rhinitis, dysmenorrhoea, and gastroduodenal ulcer. Diseases found in lower frequencies were as follows: hypertension, diabetes mellitus, impaired fasting glucose, dyslipidaemia, stroke, fatty liver, and angina pectoris. In addition, from the logistic regression with adjustment for age, sex, and BMI, the CHHF group showed a lower OR in diabetes mellitus and dyslipidaemia than the non-CHHF group, but a higher OR in degenerative arthritis, chronic gastritis, gastroduodenal ulcer, reflux oesophagitis, and chronic rhinitis. Conclusions This study showed that CHHF is associated with chronic disease. Further large-scale prospective studies are needed to validate these associations.

Verbal communication is one of the most sophisticated human motor skills reflecting both—the mental and physical health of an individual. Voice parameters and quality changes are usually secondary towards functional and/or structural laryngological alterations under specific systemic processes, syndrome and pathologies. These include but are not restricted to dry mouth and Sicca syndromes, body dehydration, hormonal alterations linked to pubertal, menopausal, and andropausal status, respiratory disorders, gastrointestinal reflux, autoimmune diseases, endocrinologic disorders, underweight versus overweight and obesity, and diabetes mellitus. On the other hand, it is well-established that stress overload is a significant risk factor of cascading pathologies, including but not restricted to neurodegenerative and psychiatric disorders, diabetes mellitus, cardiovascular disease, stroke, and cancers. Our current study revealed voice perturbations under the stress overload as a potentially useful biomarker to identify individuals in suboptimal health conditions who might be strongly predisposed to associated pathologies. Contextually, extended surveys applied in the population might be useful to identify, for example, persons at high risk for respiratory complications under pandemic conditions such as COVID-19. Symptoms of dry mouth syndrome, disturbed microcirculation, altered sense regulation, shifted circadian rhythm, and low BMI were positively associated with voice perturbations under the stress overload. Their functional interrelationships and relevance for cascading associated pathologies are presented in the article. Automated analysis of voice recordings via artificial intelligence (AI) has a potential to derive digital biomarkers. Further, predictive machine learning models should be developed that allows for detecting a suboptimal health condition based on voice recordings, ideally in an automated manner using derived digital biomarkers. Follow-up stratification and monitoring of individuals in suboptimal health conditions are recommended using disease-specific cell-free nucleic acids (ccfDNA, ctDNA, mtDNA, miRNA) combined with metabolic patterns detected in body fluids. Application of the cost-effective targeted prevention within the phase of reversible health damage is recommended based on the individualised patient profiling. [ABSTRACT FROM AUTHOR]

Background: Flammer syndrome (FS) occurs from well-described signs and symptoms. The syndrome itself is not a disease, but it may be a directive marker for advancing therapeutic approaches by predictive and preventive measures as well as for personalization of treatments. The syndrome is related to many diseases, but FS has been rarely studied in multiple sclerosis (MS). The study aimed to determine whether FS signs and symptoms occur more often in people with MS than in healthy controls, and in order to personalize the treatment, we investigated the possible effect of current therapies on FS signs and symptoms. Methods: Two hundred twenty-two MS patients and 203 healthy controls answered the questionnaire consisting of 15 signs and symptoms of FS. Results: MS patients had significantly more complaints in 9 items of FS signs and symptoms (cold hands or/and feet, the reduced feeling of thirst, dizziness, drug side effects, other headaches (tension-type, medication overuse), weight loss, feeling cold, long sleep-onset time, and skin blotches) compared to healthy controls. Six items (low blood pressure, tinnitus, increased odor sensitivity, low pain threshold, and perfectionism) were similar between the two groups. The treatment agents currently used did not have any effect on the signs and symptoms of FS. Conclusion: This study showed that FS might be associated with MS. Injectable or oral agents are not related to the signs and symptoms of FS. Further studies are needed to validate this association. Relevance of the article for predictive, preventive, and personalized medicine: FS is common among MS patients. Being aware of this incidence that might impair the life quality of MS patients is useful to predict the comorbidity and develop preventive strategies and applying personalized treatment options and procedures. [ABSTRACT FROM AUTHOR]

Background: Cold hypersensitivity in the hands and feet (CHHF) is a common symptom in Korea and patients with CHHF complain of coldness in the hands and feet in an environment that is not considered cold by unaffected people. In traditional East Asian medicine, CHHF is believed to be accompanied by various diseases and symptoms, and is considered a symptom that needs active treatment. CHHF is used for pattern identification in the cold pattern, yang deficiency, and constitution. This study aimed to examine the differences in frequencies of chronic diseases with respect to the presence of CHHF. Methods: Disease history, CHHF, body measurements, and blood test survey data from 6149 patients collected by 25 medical institutes in Korea were obtained from the Korean Medicine Data Center. The participants were divided into CHHF (n = 1909) and non-CHHF groups (n = 3017) according to the CHHF survey. The differences in frequencies of 18 diseases were analysed using chi-square tests, and the odds ratios (ORs) for each disease according to CHHF status were examined via logistic regression with adjustment for age, sex, and body mass index (BMI). Results: Based on chi-square test results, the CHHF group showed a higher frequency of the following diseases: anaemia, hypotension, chronic gastritis, reflux oesophagitis, chronic rhinitis, dysmenorrhoea, and gastroduodenal ulcer. Diseases found in lower frequencies were as follows: hypertension, diabetes mellitus, impaired fasting glucose, dyslipidaemia, stroke, fatty liver, and angina pectoris. In addition, from the logistic regression with adjustment for age, sex, and BMI, the CHHF group showed a lower OR in diabetes mellitus and dyslipidaemia than the non-CHHF group, but a higher OR in degenerative arthritis, chronic gastritis, gastroduodenal ulcer, reflux oesophagitis, and chronic rhinitis. Conclusions: This study showed that CHHF is associated with chronic disease. Further large-scale prospective studies are needed to validate these associations. [ABSTRACT FROM AUTHOR]

Flammer syndrome (FS) is a prevalent and mostly benign condition. Subjects with FS seem to have a good life expectancy. Nevertheless, FS subjects are at increased risk for certain diseases, mainly when they are challenged by psychological stress or other stimuli such as coldness. FS is related to ocular diseases, such as normal-tension glaucoma, retinitis pigmentosa, central serous chorioretinopathy, optic nerve compartment syndrome, Leber's hereditary optic neuropathy, arterial or venous occlusions in the retina, and choroid and optic nerve head, despite the absence of classical vascular risk factors. FS is also related to some non-ocular diseases, such as multiple sclerosis, breast cancer, and altitude sickness. The role of FS in other diseases such as tinnitus, sudden hearing loss, Ménière's disease, anorexia nervosa, and thyroid dysfunction is currently under investigation. The exact relationship of FS to related diseases however still needs to be established. This may hopefully lead to more targeted diagnostics and personalized treatments. [ABSTRACT FROM AUTHOR]

This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to-beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber's optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment. [ABSTRACT FROM AUTHOR]

Background: Besides intraocular pressure, vascular factors play a role in the pathogenesis of glaucomatous optic neuropathy. One of these potential vascular factors is Flammer syndrome. The purpose of the present study was to determine in a Korean population whether signs and symptoms of Flammer syndrome occur more often in normal tension glaucoma patients than in control subjects. Methods: Two hundred forty-six normal tension glaucoma patients and 1116 control subjects responded to a multiple-choice questionnaire asking about 15 signs and symptoms of Flammer syndrome. Results: Seven of the 15 signs and symptoms of Flammer syndrome (increased drug sensitivity, good smell perception, reversible skin blotches, tinnitus, long sleep onset time, tendency to perfectionism, and cold hands/feet) were significantly more often positive in normal tension glaucoma patients than in controls. Six additional signs and symptoms (migraines, low blood pressure, headaches, dizziness, increased pain sensation, and feeling cold) also occurred more often, but did not reach statistical significance. Only two items (low body weight and reduced feeling of thirst) were more frequently (not significant) positive in the controls. Conclusion: There is an association between normal tension glaucoma and Flammer syndrome. If future studies confirm this relationship, treatment of Flammer syndrome may help to prevent normal tension glaucoma or to slow down its progression. [ABSTRACT FROM AUTHOR]

The endothelium has increasingly been recognized as a smart barrier and a key regulator of blood flow in micro- and macrovascular beds. Endothelial dysfunction marks a stage of atherosclerosis and is an important prognostic marker for cardiovascular disease. Yet, some people who tend to be slim and physically active and with rather low blood pressure show a propensity to respond to certain stimuli such as emotional stress with endothelial-mediated vascular dysregulation (Flammer syndrome). This leads to characteristic vascular symptoms such as cold hands but also a risk for vascular-mediated diseases such as normal-tension glaucoma. It is the aim of this review to delineate the differences between Flammer syndrome and its 'counterpart' endothelial dysfunction in the context of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: We present a long term follow-up of a young female patient with choroidal infarction, primary open angle glaucoma and Flammer syndrome. The patient had no classical risk factors for vascular occlusions, except for the presence of Flammer syndrome. The essential feature of this syndrome is primary vascular dysregulation, sometimes including vasospasm. The vessels of affected people respond more intensely to a number of stimuli, such as coldness or emotional stress. Any organ can be involved, including parts of the eye. The dense autonomic innervation of the choroidal vessels predisposes them particularly to vasospasms.Case Presentation: The patient was originally referred to our centre because of a deep unilateral paracentral scotoma with the presumptive diagnosis of a normal tension glaucoma. The discrepancy between the visual field defect and the optic nerve head morphology, however, led us to a vascular evaluation by a simultaneous fluorescein/indocyanine green angiography. This revealed an antecedent choroidal infarction that explained the visual field scotoma and the retinal nerve fibre layer defect in the corresponding area. During the follow-up period of 11 years, the patient also developed bilateral glaucomatous optic neuropathy despite a well-controlled intraocular pressure.Conclusions: We hypothesise that in the patient presented here, the Flammer syndrome contributed to both the acute unilateral choroidal infarction and to the chronic development of bilateral glaucomatous optic neuropathy. [ABSTRACT FROM AUTHOR]

Purpose: Primary vascular dysregulation (PVD) is a condition in which the response to cold temperature or external stimuli is abnormal. We investigated whether triflusal use results in amelioration of PVD symptoms and improvement of several related parameters compared with aspirin. Materials and Methods: Eighty-eight PVD patients (54% female, 56±8 years) were randomly selected to receive either triflusal (300 mg, b.i.d.) or aspirin (150 mg, b.i.d.) for a period of 6 weeks followed by crossover. PVD was defined as both red-blood-cell standstill in video-assisted microscopic capillaroscopy during cold stimulation using carbon dioxide gas and a score of more than 7 points in a validated questionnaire. Efficacy of treatment was assessed by 1) cold intolerance symptom severity (CISS) score, 2) finger Doppler indices, and 3) indocyanine green perfusion imaging. Results: The use of triflusal resulted in a greater improvement in CISS score (44.5±18.4 vs. 51.9±16.2; p<0.001) and in mean radial peak systolic velocity (69.8±17.2 vs. 66.1±16.4; p=0.011) compared to aspirin. Furthermore, significant differences were also observed in perfusion rates on indocyanine green perfusion imaging between triflusal and aspirin (45.6±25.8 vs. 51.6±26.9; p=0.020). Conclusion: Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin. [ABSTRACT FROM AUTHOR]

The treatment of normal tension glaucoma can be difficult. Some normal tension glaucoma patients show progression of glaucomatous optic neuropathy despite an intraocular pressure in the normal range, and sometimes even with an intraocular pressure in the low teens. The question therefore arises as to whether there are other therapeutic options besides lowering the intraocular pressure. One treatment modality discussed in the literature is calcium channel blockers. We suspect that calcium channel blockers are particularly useful in glaucoma patients having a primary vascular dysregulation. [ABSTRACT FROM AUTHOR]

Purpose: Primary vascular dysregulation (PVD) is a condition in which the response to cold temperature or external stimuli is abnormal. We investigated whether triflusal use results in amelioration of PVD symptoms and improvement of several related parameters compared with aspirin., Materials and Methods: Eighty-eight PVD patients (54% female, 56±8 years) were randomly selected to receive either triflusal (300 mg, b.i.d.) or aspirin (150 mg, b.i.d.) for a period of 6 weeks followed by crossover. PVD was defined as both red-blood-cell standstill in video-assisted microscopic capillaroscopy during cold stimulation using carbon dioxide gas and a score of more than 7 points in a validated questionnaire. Efficacy of treatment was assessed by 1) cold intolerance symptom severity (CISS) score, 2) finger Doppler indices, and 3) indocyanine green perfusion imaging., Results: The use of triflusal resulted in a greater improvement in CISS score (44.5±18.4 vs. 51.9±16.2; p<0.001) and in mean radial peak systolic velocity (69.8±17.2 vs. 66.1±16.4; p=0.011) compared to aspirin. Furthermore, significant differences were also observed in perfusion rates on indocyanine green perfusion imaging between triflusal and aspirin (45.6±25.8 vs. 51.6±26.9; p=0.020)., Conclusion: Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin.