Solving the New Puzzle(s) 2014-2022: Flammer Syndrome Probably Represents a Mild Endophenotype of Raynaud’s Phenomenon Mainly Associated with Ocular Disturbances and Also Due to Latent T. gondii Infection

Abstract

negative effect on quality of life [9]. The study of 334 healthy subjects aged 50 years or elder in Japan showed that proportion of participants with increased sensitivity to cold widely ranged (6.1%-30.8% men, 14.3%-28.3% women) [12].In Eastern Asian populations CHHF occurs in 20%-52% of subjects [13][14][15], and ratio of men to women is 2:3 [16]. In Japan, this condition called "hiesho" is quite common involving over 60% of females, and in the latter stage of pregnancy "hiesho" manifests in about 40% of women, particularly in the advanced maternal age [17,18]. One study comparing Japanese with Brazilians reported that 57% of Brazilian pregnant women were aware of cold sensations [19,20]. CHHF is associated also with RP, gastric disturbances [21], as well as gynecological disorders, such as infertility and dysmenorrhea [22,23]. Nb. T. gondii infection causes ovarian dysfunction and disturbances in sperm motility, viability and concentration values, epididymis weight, and testicle inflammation [24][25][26][27][28].The presence of "hiesho" was found to be risk factor which can also lead to abnormal delivery because of weak labor pains, prolonged labor and atonic bleeding, premature delivery, amnion membrane rupture [17,29,30].In this context, it should be added that traditional Japanese fish dishes sushi and sashimi may, at least in part, play a role in development of these disorders [31], especially that wide distribution of T. gondii amongst sea fish and mammals may affect human health worldwide (e.g. the highest prevalence of the pathogen was found in otter (54.8%), and dolphin, whale and porpoise (30.92%) [32]. B. FS heritability.In Europe, most of FS symptoms appear in puberty and alleviate along with age, in women after menopause begun [33], albeit in the study of 3067 persons aged 65 years or elder 23.6% men and 28.6% women had cold extremities [34]. Importantly, parents of FS subjects also had similar symptoms which may suggest a heritability of this clinical entity [3,4]. Moreover, Konieczka & Erb [4] noted that there is a relationship between FS and RP, and suggested a genetic background of RP [35][36][37][38], but they believed that additional factor(s) may also play a role [4,35]. Nb. genetic factors appeared to be important in the development of RP as has been demonstrated in one familial and twin study [39]. FS often occurs in individuals who are slender, have a low blood pressure, are active, but also have unusually cold extremities, increased pain sensitivity, altered circadian rhythm, and prolonged falling asleep time [40,41]. C. Pathophysiological changes in FS.Individuals with FS have the autonomic nervous system imbalance with sympathetic predominance [4,42], lymphocytes and leukocytes in the eye have altered gene expression, and activated astrocytes in the retina also change their gene expression and morphology [2,[43][44][45], slightly increased plasma endothelin-1 (ET-1) levels, and increased systemic oxidative stress [5,46]. They also have enhanced sensitivity to some drugs, such as for ...