Balneotherapy, a Complementary Non-pharmacological Approach for Non-Inflammatory Complaints in Systemic Lupus Erythematosus: A Pilot Study.

BACKGROUND/AIM: Despite remission or low disease activity non-inflammatory complaints like exhaustion, fatigue, and pain persist in a significant proportion of patients with systemic lupus erythematosus (SLE) and have a considerable impact on health-related quality of life. This study evaluated the effects of balneotherapy on non-inflammatory complaints, quality of life, and work productivity of patients with SLE. PATIENTS AND METHODS: SLE patients in remission/low disease activity in three rheumatology centers were included in this randomized, controlled, follow-up study. In addition to the standard of care (SOC), sixteen out of the thirty patients with SLE received balneotherapy (3-week period, 15 times, for 30 min) and fourteen patients received the SOC only. Pre-validated survey instruments including Lupus Quality of Life (LupusQoL), Short-Form Health Survey (SF-36), Work Productivity, and Activity Impairment-Lupus (WPAI-Lupus) questionnaires were used. RESULTS: Based on the SF-36 questionnaires, several subdomains of physical condition improved significantly after the course; the improvement remained durable (p=0.019). General health improved significantly by the end of the course (p=0.001). According to the LupusQoL questionnaire, physical health and pain showed a tendency of improvement shortly after the spa treatment. Changes in the WPAI-lupus questionnaire indicated a short-term improvement of the daily activity by the end of the observation period. No adverse reactions were observed. CONCLUSION: Thermal water therapy may be an effective, well-tolerated, complementary non-pharmacological approach for non-inflammatory complaints of patients with SLE. Physical condition improved in the short-term, whereas fatigue worsened despite treatment.

Hungarian consensus recommendation on the role of vitamin D in disease prevention and treatment / Magyarországi konszenzusajánlás a D-vitamin szerepérol a betegségek megelozésében és kezelésében

Nine Hungarian medical societies have developed a consensus recommendation on the preferred normal range of vitamin D, the dose of vitamin D supplementation and the method of administration. They summarized the clinical conditions and diseases the development of which may be associated with vitamin D deficiency (VDD). VDD is extremely common in Hungary, especially in late winter. The lower limit of the recommended normal range is 75 nmol/l, although the clinical significance of deficiency is evident mainly at values below 50 nmol/l, but since vitamin D supplementation at the recommended dose is safe, it is worthwhile for everyone to reduce the health risk associated with VDD. The aim of vitamin D supplementation is to prevent deficiency. The recommended normal range is 75­125 nmol/l, above which there is no clear benefit of vitamin D supplementation. To maintain the normal range, a daily intake of 2000 IU in adults is recommended during the UV-B radiation-free period. Vitamin D supplementation is also recommended for children during the same periods and conditions as for adults, but the dose varies with age. In adults, vitamin D3 supplementation at daily, weekly and monthly intervals is equally effective and safe. In severe deficiency, a loading dose is recommended, followed by maintenance supplementation. In addition to the wellknown skeletal, immunological and oncological effects of VDD, more and more data support unfavorable gyneco- logical and obstetric effects. The process of building the consensus has met the requirements of the latest Delphi criteria.

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis.

OBJECTIVE: To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. RESULTS: Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). CONCLUSIONS: These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.

Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents.

The five TNF inhibitors currently approved for the treatment of RA are characterised by differences in their molecular structures, half-lives, administration routes, dosing intervals, immunogenicity, and use in women who wish to become pregnant. TNF inhibitors still represent the first biologic after conventional synthetic DMARD (csDMARD) in the majority of patients according to registry data. This was possibly because they were historically the first biological agents available (biological DMARDS with a different mechanism of action or targeted synthetic DMARDs did not become available until 2006s), and so switching from one to another was frequent in the case of an inadequate response and/or side effects. TNF inhibitors are also efficacious for other inflammatory joint and spine diseases, and have been approved for inflammatory bowel disease, uveitis and psoriasis. In addition, national registries have provided long-term safety data and demonstrated their beneficial effect on cardiovascular morbidity and mortality. However, approximately 30-40% of patients discontinue anti-TNF treatment because of primary failure, secondary loss of response, or intolerance. The options for managing anti-TNF treatment failures include switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action (swapping). The aim of this review is to evaluate the pros and cons of whether it is more appropriate to choose a second anti-TNF biological agents after the failure of the first or swap treatment early.

Hypothalamic dopamine is required for salsolinol-induced prolactin secretion in goats.

The aim of the present study was to clarify the relationship between hypothalamic dopamine (DA) and salsolinol (SAL) for the secretion of prolactin (PRL) in goats. SAL or thyrotropin-releasing hormone (TRH) was intravenously injected into female goats treated with or without the D2 DA receptor antagonist haloperidol (Hal), which crosses the blood-brain barrier, and the PRL-releasing response to SAL was compared with that to TRH. PRL-releasing responses to SAL, Hal, and Hal plus SAL were also examined after a pretreatment to augment central DA using carbidopa (Carbi) and L-dopa. The PRL-releasing response to Hal alone was greater than that to SAL or TRH alone. The PRL-releasing response to Hal plus SAL was similar to that of Hal alone. In contrast, the PRL-releasing response to Hal plus TRH was greater than that to TRH or Hal alone. The treatment with Carbi plus L-dopa inhibited SAL- and Hal-induced PRL secretion. The inhibition of the PRL-releasing response to SAL disappeared when SAL was injected with Hal. These results indicate that the mechanisms underlying the SAL-induced PRL response differ from those of TRH, and suggest that hypothalamic DA and its synthesis is associated in part with SAL-induced PRL secretion in goats.

Effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in male goats.

The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) release in goats. The PRL-releasing response to an intravenous (i.v.) injection of SAL was examined after treatment with augmentation of central DA using carbidopa (carbi) and L-dopa in male goats under 8-h (8 h light, 16 h dark) or 16-h (16 h light, 8 h dark) photoperiod conditions. The carbi and L-dopa treatments reduced basal PRL concentrations in the 16-h photoperiod group (P < 0.05), while a reduction was not observed in the 8-h photoperiod group. The mean basal plasma PRL concentration in the control group for the 8-h photoperiod was lower than that for the 16-h photoperiod (P < 0.05). SAL significantly stimulated the release of PRL promptly after the injection in both the 8- and 16-h photoperiod groups (P < 0.05). PRL-releasing responses for the 16-h photoperiod were greater than those for the 8-h photoperiod (P < 0.05). The carbi and L-dopa treatments blunted SAL-induced PRL release in both the 8- and 16-h photoperiods (P < 0.05). These results indicate that hypothalamic DA blunts the SAL-induced release of PRL in male goats, regardless of the photoperiod, which suggests that both SAL and DA are involved in regulating the secretion of PRL in goats.

Thalamic neuropeptide mediating the effects of nursing on lactation and maternal motivation.

Nursing has important physiological and psychological consequences on mothers during the postpartum period. Tuberoinfundibular peptide of 39 residues (TIP39) may contribute to its effects on prolactin release and maternal motivation. Since TIP39-containing fibers and the receptor for TIP39, the parathyroid hormone 2 receptor (PTH2 receptor) are abundant in the arcuate nucleus and the medial preoptic area, we antagonized TIP39 action locally to reveal its actions. Mediobasal hypothalamic injection of a virus encoding an antagonist of the PTH2 receptor markedly decreased basal serum prolactin levels and the suckling-induced prolactin release. In contrast, injecting this virus into the preoptic area had no effect on prolactin levels, but did dampen maternal motivation, judged by reduced time in a pup-associated cage during a place preference test. In support of an effect of TIP39 on maternal motivation, we observed that TIP39 containing fibers and terminals had the same distribution within the preoptic area as neurons expressing Fos in response to suckling. Furthermore, TIP39 terminals closely apposed the plasma membrane of 82% of Fos-ir neurons. Retrograde tracer injected into the arcuate nucleus and the medial preoptic area labeled TIP39 neurons in the posterior intralaminar complex of the thalamus (PIL), indicating that these cells but not other groups of TIP39 neurons project to these hypothalamic regions. We also found that TIP39 mRNA levels in the PIL markedly increased around parturition and remained elevated throughout the lactation period, demonstrating the availability of the peptide in postpartum mothers. Furthermore, suckling, but not pup exposure without physical contact, increased Fos expression by PIL TIP39 neurons. These results indicate that suckling activates TIP39 neurons in the PIL that affect prolactin release and maternal motivation via projections to the arcuate nucleus and the preoptic area, respectively.

The effect of balneotherapy on antioxidant, inflammatory, and metabolic indices in patients with cardiovascular risk factors (hypertension and obesity)--a randomised, controlled, follow-up study.

INTRODUCTION: The primary objective of our study was to explore the changes of antioxidant, inflammatory, and metabolic parameters in obese and hypertension people patients during balneotherapy and to evaluate the safety of balneotherapy in these participants. METHODS: Following randomisation, 22 obese and 20 hypertensive patients underwent balneotherapy with thermal water of 38°C temperature, in 15 sessions of 30 minutes. An additional 22 obese and 20 hypertensive patients served as controls. Antioxidant, inflammatory, and metabolic parameters were determined at baseline, as well as post-treatment and at the end of follow-up (at 15 weeks). RESULTS: As regards changes observed in hypertensive patients subjected to balneotherapy, differences could be detected between baseline and post-treatment albumin and haemoglobin A(1c) levels only; however, these were no longer significant after 3 months. Although the difference between transferrin levels determined at the end of balneotherapy and 3 months later was significant, it remained within the physiological range, as well as it was accompanied by normal serum iron level and therefore, it was considered irrelevant. C-reactive protein levels of balneotherapy patients decreased significantly after treatment. In obese patients, haemoglobin A(1c) level decreased after balneotherapy, but this difference was not observed either after 3 months. Similarly, both transferrin and C-reactive protein levels changed from baseline, but not between groups. CONCLUSIONS: This study contributes important information regarding the safety of balneotherapy in hypertensive and obese diabetics by showing no alterations of antioxidant, inflammatory, or metabolic indices. The findings of this study confirm that balneotherapy is not contraindicated for hypertensive or obese patients.

Tuberoinfundibular peptide of 39 residues is activated during lactation and participates in the suckling-induced prolactin release in rat.

Tuberoinfundibular peptide of 39 residues (TIP39) and the PTH-2 receptor (PTH2R) constitute a peptide-receptor neuromodulator system. Based on the abundance of TIP39 fibers and axonal terminals as well as PTH2R-containing neurons and their processes in the hypothalamic para- and periventricular and arcuate nuclei TIP39 has been suggested to play a role in neuroendocrine regulation. We showed previously that TIP39 expression decreased dramatically by adulthood. In the present study, using in situ hybridization histochemistry, real-time RT-PCR, and immunohistochemistry, we found that TIP39 mRNA and peptide expression levels are markedly elevated in the posterior intralaminar complex of the thalamus (PIL) of lactating dams, one of the three locations of TIP39-containing cell bodies in the brain. In addition, in mother rats, these TIP39 neurons showed Fos expression in response to pup exposure. Transection of TIP39 fibers originating in the PIL resulted in an ipsilateral disappearance of TIP39 immunoreactivity throughout the mediobasal hypothalamus of mother rats, suggesting that TIP39 fibers there arise from the PIL. To elucidate the function of TIP39 activation in dams, mothers separated from their pups for 4 h on postpartum d 9 received injection of a PTH2R antagonist into the lateral ventricle 5 min before returning the pups. Blood samples were taken seven times during the experimental period through jugular cannulae. The PTH2R antagonist administered in two different concentrations markedly inhibited suckling-induced elevation of plasma prolactin levels in a dose-dependent manner. These results suggest that TIP39 neurons in the PIL may regulate suckling-induced prolactin release in rat dams.

The effect of balneotherapy on C-reactive protein, serum cholesterol, triglyceride, total antioxidant status and HSP-60 levels.

An increasing body of evidence substantiating the effectiveness of balneotherapy has accumulated during recent decades. In the present study, 42 ambulatory patients (23 males and 19 females, mean age 59.5 years) with degenerative musculoskeletal disease were randomised into one of two groups-bathing in tap water or in mineral water at the same temperature-and subjected to 30-min balneotherapy sessions on 15 occasions. Study parameters comprised serum levels of sensitised C-reactive protein (CRP), plasma lipids, heat shock protein (HSP-60) and total antioxidant status (TAS). In both groups, CRP levels followed a decreasing tendency, which still persisted 3 months later. At 3 months after balneotherapy, serum cholesterol levels were still decreasing in patients who had used medicinal water, but exhibited a trend towards an increase in the control group. Triglyceride levels followed a decreasing trend in both patient groups. TAS showed a declining tendency in both groups. No changes of HSP-60 levels were observed in either group. Balneotherapy with the thermal water from Hajdúszoboszló spa had a more pronounced physiological effect compared to that seen in the control group treated with tap water in a 3 month period.

The effect of physical therapy on beta-endorphin levels.

Beta-endorphin (betaE) is an important reliever of pain. Various stressors and certain modalities of physiotherapy are potent inducers of the release of endogenous betaE to the blood stream. Most forms of exercise also increase blood betaE level, especially when exercise intensity involves reaching the anaerobic threshold and is associated with the elevation of serum lactate level. Age, gender, and mental activity during exercise also may influence betaE levels. Publications on the potential stimulating effect of manual therapy and massage on betaE release are controversial. Sauna, mud bath, and thermal water increase betaE levels through conveying heat to the tissues. The majority of the techniques for electrical stimulation have a similar effect, which is exerted both centrally and--to a lesser extent--peripherally. However, the parameters of electrotherapy have not yet been standardised. The efficacy of analgesia and the improvement of general well-being do not necessarily correlate with betaE level. Although in addition to blood, increased brain and cerebrospinal fluid betaE levels are also associated with pain, the majority of studies have concerned blood betaE levels. In general, various modalities of physical therapy might influence endorphin levels in the serum or in the cerebrospinal fluid--this is usually manifested by elevation with potential mitigation of pain. However, a causal relationship between the elevation of blood, cerebrospinal fluid or brain betaE levels and the onset of the analgesic action cannot be demonstrated with certainty.

Physiological role of salsolinol: its hypophysiotrophic function in the regulation of pituitary prolactin secretion.

We have recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) produced by hypothalamic neurons can selectively release prolactin from the anterior lobe (AL) of the pituitary gland. Moreover, high affinity binding sites for SAL have been detected in areas, like median eminence (ME) and the neuro-intermediate lobe (NIL) that are known terminal fields of the tuberoinfundibular DAergic (TIDA) and tuberohypophysial (THDA)/periventricular (PHDA) DAergic systems of the hypothalamus, respectively. However, the in situ biosynthesis and the mechanism of action of SAL are still enigmatic, these observations clearly suggest that sites other than the AL might be targets of SAL action. Based on our recent observations it may be relevant to postulate that an "autosynaptocrine" regulatory mechanism functioning at the level of the DAergic terminals localized in both the ME and NIL, may play a role in the hypophyseotrophic regulation of PRL secretion. Furthermore, SAL may be a key player in these processes. The complete and precise mapping of these intra-terminal mechanisms should help us to understand the tonic DAerg regulation of PRL secretion. Moreover, it may also give insight into the role of pre-synaptic processes that most likely have distinct and significant functional as well as pathological roles in other brain areas using DAergic neurotransmission, like striatonigral and mesolimbic systems.