Generation of an induced pluripotent stem cell line carrying biallelic deletions (SCTCi019-B) in ALDH7A1 using CRISPR/Cas9.

Biallelic pathogenic variants in ALDH7A1 are associated with pyridoxine-dependent epilepsy (PDE). ALDH7A1 encodes for the third enzyme of the lysine catabolism pathway. In this study a human isogenic ALDH7A1 knock-out iPSC line was created using CRISPR/Cas9 technology. One clone (SCTCi019-B) with biallelic deletions in ALDH7A1 was obtained and fully characterized, showing expression of pluripotency markers, a normal karyotype and no off-targets. Human-based models derived from this iPSC line will contribute to gain insights in the molecular mechanism of disease underlying PDE.

Generation of an induced pluripotent stem cell line carrying a biallelic deletion (SCTCi019-A) in GCDH using CRISPR/Cas9.

GCDH encodes for the enzyme catalyzing the sixth step of the lysine catabolism pathway. Biallelic pathogenic variants in GCDH have been associated with glutaric aciduria type 1 (GA1). In this study CRISPR/Cas9 technology was used to create an isogenic GCDH knock-out human iPSC line. One clone with a biallelic deletion (SCTCi019-A) in GCDH was obtained and fully characterized, revealing a normal karyotype, no off-targets detected and expression of pluripotency markers. This iPSC line can contribute to gain insights in the molecular mechanism of disease.

Repurposing of triamterene as a histone deacetylase inhibitor to overcome cisplatin resistance in lung cancer treatment.

PURPOSE: Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect. METHODS: A few clinically approved drugs were identified by a computational drug repurposing tool called "DRUGSURV" and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient. RESULTS: Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo. CONCLUSION: The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.

Causes infectieuses de décompensation du diabète: « un prédateur infectieux se cache chez tout diabétique en Afrique¼ / Infectious causes of diabetes decompensation: "an infectious predator hides in any diabetic in Africa"

Introduction : Les infections survenant chez les sujets diabétiques ont été longtemps considérées comme une des causes de l'accroissement de la morbidité et de la mortalité. Elles représentent un motif de plus en plus fréquent d'admission dans le service de médecine interne du Centre Hospitalier Régional et Universitaire de Thiès. Les mécanismes sont plus ou moins élucidés par l'influence de l'hyperglycémie sur les fonctions des polynucléaires neutrophiles. Le but de cette étude est de déterminer les particularités épidémiologiques des infections chez les diabétiques. Patients et Méthode : Il s'agissait d'une étude rétrospective avec recueil de données réalisée sur 24 mois (1er janvier 2016 au 31 décembre 2018) au service de Médecine Interne du Centre Hospitalier Régional et Universitaire de Thiès. Cette étude incluait tous les patients diabétiques quel que soit le genre et le type de diabète, âgés de 15 ans et plus, présentant une infection comme facteur principal de décompensation. Résultats : Durant la période d'étude 2350 patients ont été hospitalisés dans le service de médecine interne dont 390 diabétiques. Parmi eux, 138 patients ont répondu à nos critères d'inclusion soit une prévalence de 35,38%. La moyenne d'âge de nos malades était de 53,49 ans ± 15,65 ans avec un sex-ratio H/F était de 0,70 en faveur des femmes (81 femmes contre 57 hommes). Les infections responsables de la décompensation étaient à localisation cutanéo-muqueuse (30,4%), pulmonaire (22,4%), uro-génitale (18,11%), buccodentaire (10,11%), ORL (1,44%), phanérienne (0,72%). Ailleurs, une infection aux pieds était retrouvée chez 43 patients soit 31,15% des cas. Plusieurs infections pouvaient être présentes chez un même malade. Le diabète était déséquilibré dans 86,2 % (n=94) des cas avec une HbA1c moyenne à 10, 5 % à l'admission Nous n'avons pas noté de corrélation entre l'infection et l'ancienneté du diabète (p =0, 60), l'infection et le type de diabète (p = 0,50) et paradoxalement entre l'infection et le déséquilibre du diabète (p=0,70). Conclusion : Le dépistage des infections chez le diabétique en déséquilibre chronique ou diabétique de novo doit être systématique car généralement ces infections peuvent être asymptomatiques.

Introduction: Infections in people with diabetes have long been considered one of the causes of increased morbidity and mortality. They represent an increasingly frequent reason for admission to the Department of Internal Medicine of the Regional and University Hospital of Thies. The mechanisms are more or less elucidated by the influence of hyperglycemia on neutrophil polynuclear functions. The purpose of this study is to determine the epidemiological characteristics of infections in diabetics. Method: This was a retrospective study with data collected over 24 months (1 January 2016 to 31 December 2018) at the Internal Medicine Department of the Regional and University Hospital of Thies. This study included all diabetic patients, regardless of gender and type of diabetes, aged 15 years and older, with an infection as the primary decompensation factor. Result: During the study period 2,350 patients were hospitalized in the Internal Medicine Department, 390 of whom were diabetic. Of these, 138 patients met our inclusion criteria, a prevalence of 35.38%. The average age of our patients was 53.49 years 15.65 years with a sex-ratio H/F was 0.70 in favor of women (81 Women versus 57 Men). The infections responsible for decompensation were dermal localization (30.4%), pulmonary (22.4%), urogenital (18.11%), oral (10.11%), ENT (1.44%), phanerian (0.72%). Elsewhere, a foot infection was found in 43 patients or 31.15% of cases. Several infections could be present in the same patient. Diabetes was unbalanced in 86.2% (n=94) of cases with an average HbA1c of 10.5% at admission We did not find a correlation between the infection and the age of diabetes (p =0, 60), the infection and the type of diabetes (p = 0.50), and paradoxically between the infection and the imbalance of diabetes (p = 0.70). Conclusion: The detection of infections in diabetics in chronic imbalance or de novo diabetics must be systematic because generally these infections can be asymptomatic.

Cerebral venous thrombosis in a sub-saharan African country: A preliminary monocentric study of a 70 case series at the neurology department of Fann teaching hospital in Dakar - Senegal.

INTRODUCTION: Cerebral venous thrombosis (CVT) are underdiagnosed in sub-saharan Africa where publications are uncommon. Our study aim was to describe the CVT diagnostic and therapeutic features through a senegalese case series. PATIENTS AND METHOD: A monocentric retrospective and prospective study was conducted at the adult Neurology department of Fann Teaching Hospital in Dakar (Senegal), between January 01, 2013 and April 30, 2020. It had included all CVT cases diagnosed by neurovascular imaging. RESULTS: Seventy CVT cases were collected including 48 women (68.6%). The average age of the patients was 35.2±14 years. The main neurological signs were headache (92.8%) and motor deficit (41.4%), with subacute onset in 67.2% of cases. The superior sagittal sinus (54.3%) and the transverse sinus (38.6%) were the most affected with multiple involvements in 27 patients (38.6%). Thirty patients (42.8%) had indirect parenchymal signs such as venous infarction (15.7%), cerebral edema (11.4%) or intracerebral hemorrhage (12.8%). The etiological factors were mostly infectious (41.4%) with meningoencephalitis (12.8%) and otorhinolaryngological infection (10%). Gyneco-obstetric factors (27%) and Behçet's disease (7%) were the main aseptic factors. In the short-term clinical course, curative anticoagulation (98.6%) had enabled a favourable outcome (mRS 0-1) in half of the patients. CONCLUSION: Our study, the largest series in sub-saharan Africa to this date, confirms that CVT is a young women disease. Infectious etiology is the most frequent at the Fann national teaching hospital (41.4% in Dakar against 6.5% in Germaine Bousser's series) even if the etiological assessment is limited by financial constraints (no coagulopathy/thrombophilia check-up).

[Neuro-Behçet in a Sub-Saharan Africa Country: a Series of Sixteen Patients in Fann Teaching Hospital, Dakar, Senegal]. / Neuro-Behçet dans un pays d'Afrique subsaharienne : une série de 16 patients au centre hospitalier national universitaire de Fann de Dakar, Sénégal.

Neuro-Behçet (NB) African studies are mainly North African, but Sub-Saharan Africa is not to be outdone. Our aim was to describe diagnostic and therapeutic features of NB in a Senegalese series collected in Dakar. This was a descriptive and retrospective study conducted at the Neurology department of Fann Teaching Hospital in Dakar, Senegal. All patients who met the NB's diagnostic criteria were included. Sixteen patients were collected, 14 males and 2 females with an average age of 40 years [18-71]. The main neurological signs were motor deficit (13 cases), headache (10 cases), and language disorders (4 cases). Extra-neurological signs were dermatological (14 cases), ocular (2 cases), and articular (2 cases) with aseptic unilateral gonarthritis. Fever was present in 9 patients. Neurological involvement was mostly isolated parenchymal (8 cases) or mixed (6 cases). The main clinical forms of NB were rhombencephalitis (8 cases) and retrobulbar optic neuritis (4 cases). Seven patients had a cerebral angio-Behçet with cerebral venous thrombosis (3 cases), ischemic stroke (2 cases), and intracerebral hematoma (2 cases). Under prednisone (16 cases) and azathioprine (3 cases), the short-term clinical outcome was mostly favorable (14 cases) with a modified Rankin scale at 2. NB is an under-diagnosed adult male disease in Sub-Saharan Africa and further studies are needed.

Les études africaines sur le neuro-Behçet (NB) sont majoritairement maghrébines, mais l'Afrique noire n'est pas en reste. L'objectif de l'étude était de décrire les particularités diagnostiques et thérapeutiques du NB dans une série sénégalaise colligée à Dakar. Il s'agit d'une étude rétrospective à visée descriptive menée à la clinique de neurologie du centre hospitalier universitaire de Fann de Dakar, au Sénégal. Tous les patients répondant aux critères diagnostiques de NB ont été inclus. Seize patients ont été colligés, 14 hommes et deux femmes avec un âge moyen de 40 ans [18­71]. Les principaux signes neurologiques étaient un déficit moteur (13 cas), des céphalées (10 cas) et un trouble du langage (4 cas). Les signes extraneurologiques étaient dermatologiques (14 cas), oculaires (2 cas) et articulaires (2 cas) à type de gonarthrite unilatérale aseptique. Une fièvre était présente chez neuf patients. L'atteinte neurologique était majoritairement parenchymateuse isolée (8 cas) ou mixte (6 cas). Les principales formes cliniques de NB étaient la rhombencéphalite (8 cas) et la névrite optique rétrobulbaire (4 cas). Sept patients avaient un angio-Behçet cérébral à type de thromboses veineuses cérébrales (3 cas), d'infarctus cérébraux (2 cas) et d'hématomes intracérébraux (2 cas). Sous prednisone (16 cas) et azathioprine (3 cas), l'évolution clinique à court terme était majoritairement favorable (14 cas) avec un score de Rankin modifié de 2 au moment de l'exeat. Le NB est une maladie de l'homme adulte sous-diagnostiquée en Afrique noire. Des études ultérieures multicentriques nationales et sous-régionales sont souhaitables.

Unfolding and displaying the influencing factors of advance directives from the stakeholder's perspective: A concept mapping approach.

AIMS: To develop a culturally relevant conceptual map to discover perceptions of a statutory form of advance directive (AD) for Hong Kong Chinese. DESIGN: This was the first study on AD using a concept mapping approach with two phases. METHODS: The data collection of the two phases was conducted from February 2016-February 2017. In Phase I, 96 participants were recruited using purposive sampling. In Phase II, multi-dimensional scaling and hierarchical cluster analysis were used to create a concept map based on quantitative data. RESULTS: The map depicted six clusters of factors affecting the acceptance of AD, with their importance rating in decreasing order: Conditional factor, value system, process of AD, physical and illness factor, personal situation factor, and socio-cultural factor. CONCLUSION: The study adopted a comprehensive approach to unfolding the multi-faceted factors affecting the acceptance of ADs by stakeholders. Strategies targeting the clusters could be developed to facilitate the discussion and completion of AD.

Experimental and In Silico Analysis of Cordycepin and its Derivatives as Endometrial Cancer Treatment.

The aim of this study was to investigate the inhibition effects of cordycepin and its derivatives on endometrial cancer cell growth. Cytotoxicity MTT assays, clonogenic assays, and flow cytometry were used to observe the effects on apoptosis and regulation of the cell cycle of Ishikawa cells under various concentrations of cordycepin, cisplatin, and combinations of the two. Validated in silico docking simulations were performed on 31 cordycepin derivatives against adenosine deaminase (ADA) to predict their binding affinities and hence their potential tendency to be metabolized by ADA. Cordycepin has a significant dose-dependent inhibitory effect on cell proliferation. The combination of cordycepin and cisplatin produced greater inhibition effects than did cordycepin alone. Apoptosis investigations confirmed the ability of cordycepin to induce the apoptosis of Ishikawa cells. The in silico results indicate that compound MRS5698 is least metabolized by ADA and has acceptable drug likeness and safety profiles. This is the first study to confirm the cytotoxic effects of cordycepin on endometrial cancer cells. This study also identified cordycepin derivatives with promising pharmacological and pharmacokinetic properties for further investigation in the development of new treatments for endometrial cancer.

The Microtubule-Modulating Drug Epothilone D Alters Dendritic Spine Morphology in a Mouse Model of Mild Traumatic Brain Injury.

Microtubule dynamics underpin a plethora of roles involved in the intricate development, structure, function, and maintenance of the central nervous system. Within the injured brain, microtubules are vulnerable to misalignment and dissolution in neurons and have been implicated in injury-induced glial responses and adaptive neuroplasticity in the aftermath of injury. Unfortunately, there is a current lack of therapeutic options for treating traumatic brain injury (TBI). Thus, using a clinically relevant model of mild TBI, lateral fluid percussion injury (FPI) in adult male Thy1-YFPH mice, we investigated the potential therapeutic effects of the brain-penetrant microtubule-stabilizing agent, epothilone D. At 7 days following a single mild lateral FPI the ipsilateral hemisphere was characterized by mild astroglial activation and a stereotypical and widespread pattern of axonal damage in the internal and external capsule white matter tracts. These alterations occurred in the absence of other overt signs of trauma: there were no alterations in cortical thickness or in the number of cortical projection neurons, axons or dendrites expressing YFP. Interestingly, a single low dose of epothilone D administered immediately following FPI (and sham-operation) caused significant alterations in the dendritic spines of layer 5 cortical projection neurons, while the astroglial response and axonal pathology were unaffected. Specifically, spine length was significantly decreased, whereas the density of mushroom spines was significantly increased following epothilone D treatment. Together, these findings have implications for the use of microtubule stabilizing agents in manipulating injury-induced synaptic plasticity and indicate that further study into the viability of microtubule stabilization as a therapeutic strategy in combating TBI is warranted.

Aerobic sludge granulation for simultaneous anaerobic decolorization and aerobic aromatic amines mineralization for azo dye wastewater treatment.

In this study, the capability of using aerobic granules to undergo simultaneous anaerobic decolorization and aerobic aromatic amines degradation was demonstrated for azo dye wastewater treatment. An integrated acclimation-granulation process was devised, with Mordant Orange 1 as the model pollutant. Performance tests were carried out in a batch column reactor to evaluate the effect of various operating parameters. The optimal condition was to use 1.0-1.7 mm (1.51 ± 0.33 mm) granules, 5 g/L biomass, and 4000 mg/L organics as nutrient; and supplement the wastewater with 1  mg/L dissolved oxygen. This led to a dye mineralization of 61 ± 2%, an anaerobic dye removal of 88 ± 1%, and an aerobic aromatic amines removal of 70 ± 3% within 48 h. This study showed that simultaneous anaerobic/aerobic process by aerobic granules could be a possible alternative to the conventional activated sludge process.

Differences Between Access to Follow-Up Care and Inappropriate Shocks Based on Insurance Status of Implantable Cardioverter Defibrillator Recipients.

Differences in implantable cardioverter defibrillator (ICD) utilization based on insurance status have been described, but little is known about postimplant follow-up patterns associated with insurance status and outcomes. We collected demographic, clinical, and device data from 119 consecutive patients presenting with ICD shocks. Insurance status was classified as uninsured/Medicaid (uninsured) or private/Health Maintenance Organization /Medicare (insured). Shock frequencies were analyzed before and after a uniform follow-up pattern was implemented regardless of insurance profile. Uninsured patients were more likely to present with an inappropriate shock (63% vs 40%, p = 0.01), and they were more likely to present with atrial fibrillation (AF) as the shock trigger (37% vs 19%, p = 0.04). Uninsured patients had a longer interval between previous physician contact and index ICD shock (147 ± 167 vs 83 ± 124 days, p = 0.04). Patients were followed for a mean of 521 ± 458 days after being enrolled in a uniform follow-up protocol, and there were no differences in the rate of recurrent shocks based on insurance status. In conclusion, among patients presenting with an ICD shock, underinsured/uninsured patients had significantly longer intervals since previous physician contact and were more likely to present with inappropriate shocks and AF, compared to those with private/Medicare coverage. After the index shock, both groups were followed uniformly, and the differences in rates of inappropriate shocks were mitigated. This observation confirms the importance of regular postimplant follow-up as part of the overall ICD management standard.

An intact helical domain is required for Gα14 to stimulate phospholipase Cß.

BACKGROUND: Stimulation of phospholipase Cß (PLCß) by the activated α-subunit of Gq (Gαq) constitutes a major signaling pathway for cellular regulation, and structural studies have recently revealed the molecular interactions between PLCß and Gαq. Yet, most of the PLCß-interacting residues identified on Gαq are not unique to members of the Gαq family. Molecular modeling predicts that the core PLCß-interacting residues located on the switch regions of Gαq are similarly positioned in Gαz which does not stimulate PLCß. Using wild-type and constitutively active chimeras constructed between Gαz and Gα14, a member of the Gαq family, we examined if the PLCß-interacting residues identified in Gαq are indeed essential. RESULTS: Four chimeras with the core PLCß-interacting residues composed of Gαz sequences were capable of binding PLCß2 and stimulating the formation of inositol trisphosphate. Surprisingly, all chimeras with a Gαz N-terminal half failed to functionally associate with PLCß2, despite the fact that many of them contained the core PLCß-interacting residues from Gα14. Further analyses revealed that the non-PLCß2 interacting chimeras were capable of interacting with other effector molecules such as adenylyl cyclase and tetratricopeptide repeat 1, indicating that they could adopt a GTP-bound active conformation. CONCLUSION: Collectively, our study suggests that the previously identified PLCß-interacting residues are insufficient to ensure productive interaction of Gα14 with PLCß, while an intact N-terminal half of Gα14 is apparently required for PLCß interaction.

Ebola virus disease epidemic in West Africa: lessons learned and issues arising from West African countries.

The current Ebola virus disease (EVD) outbreak ravaging three nations in West Africa has affected more than 14,000 persons and killed over 5,000. It is the longest and most widely spread Ebola epidemic ever seen. At the time of this overview (written November 2014), having affected eight different nations, Nigeria and Senegal were able to control and eliminate the virus within a record time. Ghana has successfully, to date, kept the virus away from the country, despite economic and social relationships with affected nations. What lessons can we learn from Nigeria, Senegal and Ghana in the current epidemic? How can the world improve the health systems in low- and middle-income countries to effectively manage future outbreaks? Recently, the Royal College of Physicians launched a new partnership with the West African College of Physicians to curtail the effects of HIV/AIDS, malaria and tuberculosis in the region. We believe that strengthened health systems, skilled human resources for health and national ownership of problems are key to effective management of outbreaks such as EVD.

Bronchial inflammation in seasonal allergic rhinitis with or without asthma in relation to natural exposure to pollen allergens

BACKGROUND: Nasal inflammation in allergic rhinitis enhances bronchial Th2 driven inflammation and development of asthma. We assessed bronchial inflammation induced by natural allergen exposure during pollen season in patients with pollinosis with or without asthma to show the intensity of inflammation in asthma and rhinitis and possible persistence of inflammation in periods without allergen exposure. METHODS: Sputum was induced in 52 patients with seasonal allergic rhinitis without asthma, 38 patients with seasonal allergic rhinitis and seasonal asthma and 23 healthy volunteers. Sampling was performed 6---8 weeks before the expected beginning of symptoms, during symptomatic period and 6---8 weeks after the end of symptoms. Sputum ECP was measured by means of chemiluminiscent immunometric assay and sputum cell counts were assessed by classical staining and immunocytochemistry. RESULTS: Sputum eosinophils were on the whole higher in both asthma and rhinitis compared to controls (p < 0.001, p = 0.003). The rise of eosinophils during pollen season compared with values out of pollen season was significant in asthma (classical staining) (p = 0.014) and slightlyapparent in rhinitis (immunocytochemistry) (p = 0.073). The seasonal rise of sputum ECP was observed only in rhinitis (p = 0.006). CONCLUSIONS: Inflammation of the lower airway in patients with allergic rhinitis with and without asthma has been confirmed by means of both sputum eosinophil count and sputum ECP level.Persistent inflammation of lower airway in periods without allergen exposure was proven in seasonal asthma. This may have implications for the therapy of seasonal allergic rhinitis with and without asthma in terms of promoting long-term anti-inflammatory treatment

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[Systems biology and the project "Encode"].

The goal of this review is to give an incipient knowledge on the background of system biology, the premises to its assignment as a new branch of biology, its principles, methodology and its great achievements in identification of functional elements of human genome and regulation of their concordant and differential activity. The short characteristics of functional elements including the protein-coding sequences and those coding noncoding RNAs, the DNAse 1 hypersensitivity sites and methylated CpG islets, modified histones and specific 3D structure of chromatin, are represented. The topology of transcription factors network with its main motifs, hierarchy, combination and association of transcription factors and their allelic specificity are highlighted.

[Role of enterosorbents in treatment of complicated varicose disease].

Results of treatment of 43 patients, suffering varicose disease, complicated by trophic disorders, were analyzed. To the patients a complex was prescribed, including sorpents, angioprotectors, locally - ointments. There were operated 14 patients.

[Tuberculoid leprosy revealed by active ulcerative colitis: a case report]. / Une rectocolite hémorragique révélant une lèpre tuberculoïde.

Leprosy is endemic in Senegal. In 2011, there were 73 new cases reported in Dakar. The circumstances of discovery are often dermatologic or neurologic. Few case reports describe an association with chronic inflammatory colitis, probably fortuitous. We report the case of a 30-year-old woman who had a tuberculoid leprosy revealed by active ulcerative colitis. Treatment according to the WHO protocol of leprosy, combined with corticosteroids and then methotrexate, resulted in healing of the leprosy and remission of the colitis.

[Clinical and genetic features of APC- and MYH-mutation-negative patients with multiple polyposis of large bowel that tested by conventional methods].

The genealogic analysis, molecular and clinical investigations has been carried out in 19 probands with multiple colorectal adenomas (approximately 100 or more). Twelve of these patients (63.1%) were APC and MYH mutation-negative. Three (25%) probands have positive family history. The median of the disease manifestation age in APC-negative patients was intermediate between the median of the disease manifestation age in APC- and MYH-positive patients. Extraintestinal manifestations in the APC-negative probands are more rare than in APC-positive patients. A half of APC- and MYH-negative probands with multiple polyposis had colorectal cancer. APC- and MYH-negative patients formed a genetically heterogenous group.

[Rehabilitation features in the prevention of asthma exacerbations in patients with different body weight].

Bronchial asthma patients with excessive body weight compared to persons with normal weight had more severe course of the disease, associating with more pronounced inflammation (increased level of the proinflammatory interleukin-6, interferon-gamma, tumor necrosis factor alpha). After the rehabilitation treatment including speleotherapy we observed the improvement of clinical manifestation and reduction of the studied immune parameters.