Visual cues added to a virtual environment paradigm do not improve motor arrests in Parkinson's disease.

Objective. Elucidating how cueing alleviates freezing of gait (FOG) in Parkinson's disease (PD) would enable the development of more effective, personalized cueing strategies. Here, we aimed to validate a visual cueing virtual environment (VE) paradigm for future use in e.g. neuroimaging studies and behavioral studies on motor timing and scaling in PD patients with FOG.Approach. We included 20 PD patients with FOG and 16 age-matched healthy control subjects. Supine participants were confronted with a VE displaying either no cues, bars or staircases. They navigated forward using alternate suppression of foot pedals. Motor arrests (as proxy for FOG), and measures of motor timing and scaling were compared across the three VE conditions for both groups.Main results. VE cues (bars and staircases) did not reduce motor arrests in PD patients and healthy control subjects. The VE cues did reduce pedal amplitude in healthy control subjects, without effects on other motor parameters.Conclusion. We could not validate a visual cueing VE paradigm to study FOG. The VE cues possibly failed to convey the necessary spatial and temporal information to support motor timing and scaling. We discuss avenues for future research.

Sparing the hippocampus and the hypothalamic- pituitary region during whole brain radiotherapy: a volumetric modulated arc therapy planning study.

BACKGROUND: Feasibility testing of a simultaneous sparing approach of hippocampus, hypothalamus and pituitary gland in patients undergoing whole-brain radiotherapy (WBRT) with and without a concomitant boost to metastatic sites. INTRODUCTION: Cognitive impairment and hormonal dysfunction are common side effects of cranial radiotherapy. A reduced dose application to the patho-physiologically involved functional brain areas, i.e. hippocampus, hypothalamus and pituitary gland, could reduce these common side effects. While hippocampal sparing is already a common practice to improve cognitive outcome, technical experience of additional combined sparing of the hypothalamus/pituitary gland (HT-P) is insufficient. METHODS: Twenty patients were included in the planning study. In 11 patients, a total dose of 36 Gy of WBRT (2 Gy per fraction) plus a simultaneous integrated boost (SIB) of 9 Gy (0.5 Gy per fraction, total dose: 45 Gy) to the brain metastases was applied. In 9 patients, prophylactic cranial irradiation (PCI) was simulated with a total dose of 30 Gy (2 Gy per fraction). In both patient cohorts, a sparing approach of the hippocampus and the HT-P area was simulated during WBRT. For all treatment plans, volumetric modulated arc therapy (VMAT) was used. Quality assurance included assessment of homogeneity, conformality and target coverage. RESULTS: The mean dose to the hippocampus and HT-P region was limited to less than 50% of the prescribed dose to the planning target volume (PTV) in all treatment plans. Dose homogeneity (HI) of the target volume was satisfying (median HI = 0.16 for WBRT+SIB and 0.1 for PCI) and target coverage (conformation number, CN) was not compromised (median CN = 0.82 for SIB and 0.86 for PCI). CONCLUSION: Simultaneous dose reduction to the hippocampus and the HT-P area did not compromise the PTV coverage in patients undergoing WBRT+SIB or PCI using VMAT. While the feasibility of the presented approach is promising, prospective neurologic, endocrine outcome and safety studies are required.

Are hypothalamic- pituitary (HP) axis deficiencies after whole brain radiotherapy (WBRT) of relevance for adult cancer patients? - a systematic review of the literature.

BACKGROUND: Cranial radiotherapy (cRT) can induce hormonal deficiencies as a consequence of significant doses to the hypothalamic-pituitary (HP) axis. In contrast to profound endocrinological follow-up data from survivors of childhood cancer treated with cRT, little knowledge exists for adult cancer patients. METHODS: A systematic search of the literature was conducted using the PubMed database and the Cochrane library offering the basis for our debate of the relevance of HP axis impairment after cRT in adult cancer patients. Against the background of potential relevance for patients receiving whole brain radiotherapy (WBRT), a particular focus was set on the temporal onset of hypopituitarism and the radiation dose to the HP axis. RESULTS: Twenty-eight original papers with a total of 1728 patients met the inclusion criteria. Radiation doses to the HP area ranged from 4 to 97 Gray (Gy). Hypopituitarism incidences ranged from 20 to 93% for adult patients with nasopharyngeal cancer or non-pituitary brain tumors. No study focused particularly on hypopituitarism after WBRT. The onset of hypopituitarism occurred as early as within the first year following cRT (range: 3 months to 25.6 years). However, since most studies started follow-up evaluation only several years after cRT, early onset of hypopituitarism might have gone unnoticed. CONCLUSION: Hypopituitarism occurs frequently after cRT in adult cancer patients. Despite the general conception that it develops only after several years, onset of endocrine sequelae can occur within the first year after cRT without a clear threshold. This finding is worth debating particularly in respect of treatment options for patients with brain metastases and favorable survival prognoses.

Early neuroendocrine disruption in hypothalamus and hippocampus: developmental effects including female sexual maturation and implications for endocrine disrupting chemical screening.

The timing of puberty has been mainly studied in females for several reasons, including the possible evaluation of a precise timer (i.e. menarcheal age) and concerns with respect to the high prevalence of precocity in females as opposed to males. Human evidence of altered female pubertal timing after exposure to endocrine disrupting chemicals (EDCs) is equivocal. Among the limiting factors, most studies evaluate exposure to single EDCs at the time of puberty and hardly assess the impact of lifelong exposure to mixtures of EDCs. Some rodent and ovine studies indicate a possible role of foetal and neonatal exposure to EDCs, in accordance with the concept of an early origin of health and disease. Such effects possibly involve neuroendocrine mechanisms because the hypothalamus is a site where homeostasis of reproduction, as well as control of energy balance, is programmed and regulated. In our previous studies, pulsatile gonadotrophin-releasing hormone (GnRH) secretion control via oestrogen, glutamate and aryl hydrocarbon receptors was shown to be involved in the mechanism of sexual precocity after early postnatal exposure to the insecticide dichlorodiphenyltrichloroethane. Very recently, we have shown that neonatal exposure to the potent synthetic oestrogen diethylstilbestrol (DES) is followed by early or delayed puberty depending on the dose, with consistent changes in developmental increase of GnRH pulse frequency. Moreover, DES results in reduced leptin stimulation of GnRH secretion in vitro, an effect that is additive with prenatal food restriction. Thus, using puberty as an endpoint of the effects of EDC, it appears necessary to consider pre- and perinatal exposure to low doses and to pay attention to the other conditions of prenatal life, such as energy availability, keeping in mind the possibility that puberty could not only be advanced, but also delayed through neuroendocrine mechanisms.

Perceptions, health care seeking behaviour and implementation of a tuberculosis control programme in Lambaréné, Gabon.

SETTING: Lambaréné, Gabon. OBJECTIVES: To describe patient perceptions of tuberculosis (TB) and to determine factors that influence health care seeking behaviour to gain insight into the management of multidrug-resistant TB. DESIGN: Participant observation, in-depth semi-structured interviews and focus group discussions were conducted with 30 TB patients, 36 relatives, 11 health care providers and 18 traditional/spiritual healers. Recruitment of patients was linked to the PanEpi study and took place at the Albert Schweitzer Hospital, the General Hospital and the TB-HIV (human immunodeficiency virus) clinic. RESULTS: Patients generally described TB as a natural and/or magical disease. The majority of the patients combined treatment at the hospital with (herbal) self-treatment and traditional/spiritual healing. Despite the free availability of anti-tuberculosis treatment in principle, patient adherence was problematic, hindering effective TB control. Most patients delayed or defaulted from treatment due to financial constraints, stigmatisation, ignorance about treatment, change of health care service or use of non-prescribed antibiotics. The situation was occasionally complicated by drug stockouts. CONCLUSION: There is an urgent need to bridge the gap between patients and the hospital by avoiding drug shortages, intensifying culturally sensitive TB health education, embedding TB care into the cultural context and enhancing cooperation between hospitals, patients, traditional healers and communities.

Role of the AMP-activated protein kinase (AMPK) signaling pathway in the orexigenic effects of endogenous ghrelin.

Ghrelin, released from the stomach, stimulates food intake through activation of the ghrelin receptor (GHS-R) located on neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the hypothalamus. A role for the energy sensor AMP-activated protein kinase (AMPK) and its downstream effector uncoupling protein 2 (UCP2) in the stimulatory effect of exogenous ghrelin on NPY/AgRP expression and food intake has been suggested. This study aimed to investigate whether a rise in endogenous ghrelin levels is able to influence hypothalamic AMPK activity, pACC, UCP2 and NPY/AgRP expression through activation of GHS-R. An increase in endogenous ghrelin levels was established by fasting (24h) or by induction of streptozotocin(STZ)-diabetes (15 days) in GHS-R(+/+) and GHS-R(-/-) mice. GHS-R(+/+) mice showed a significant increase in AgRP and NPY mRNA expression after fasting, which was not observed in GHS-R(-/-) mice. Fasting did not affect AMPK activity nor ACC phosphorylation in both genotypes and increased UCP2 mRNA expression. The hyperghrelinemia associated with STZ-induced diabetes was accompanied by an increased NPY and AgRP expression in GHS-R(+/+) but not in GHS-R(-/-) mice. AMPK activity and UCP2 expression in GHS-R(+/+) mice after induction of diabetes were decreased to a similar extent in both genotypes. Exogenous ghrelin administration tended to decrease hypothalamic AMPK activity. In conclusion, an increase in endogenous ghrelin levels triggered by fasting or STZ-induced diabetes stimulates the expression of AgRP and NPY via interaction with the GHS-R. The changes in AMPK activity, pACC and UCP2 occur independently from GHS-R suggesting that they do not play a major role in the orexigenic effect of endogenous ghrelin.

Decreased intracellular GABA levels contribute to spinal cord stimulation-induced analgesia in rats suffering from painful peripheral neuropathy: the role of KCC2 and GABA(A) receptor-mediated inhibition.

Elevated spinal extracellular γ-aminobutyric acid (GABA) levels have been described during spinal cord stimulation (SCS)-induced analgesia in experimental chronic peripheral neuropathy. Interestingly, these increased GABA levels strongly exceeded the time frame of SCS-induced analgesia. In line with the former, pharmacologically-enhanced extracellular GABA levels by GABA(B) receptor agonists in combination with SCS in non-responders to SCS solely could convert these non-responders into responders. However, similar treatment with GABA(A) receptor agonists and SCS is known to be less efficient. Since K⁺ Cl⁻ cotransporter 2 (KCC2) functionality strongly determines proper GABA(A) receptor-mediated inhibition, both decreased numbers of GABA(A) receptors as well as reduced KCC2 protein expression might play a pivotal role in this loss of GABA(A) receptor-mediated inhibition in non-responders. Here, we explored the mechanisms underlying both changes in extracellular GABA levels and impaired GABA(A) receptor-mediated inhibition after 30 min of SCS in rats suffering from partial sciatic nerve ligation (PSNL). Immediately after cessation of SCS, a decreased spinal intracellular dorsal horn GABA-immunoreactivity was observed in responders when compared to non-responders or sham SCS rats. One hour later however, GABA-immunoreactivity was already increased to similar levels as those observed in non-responder or sham SCS rats. These changes did not coincide with alterations in the number of GABA-immunoreactive cells. C-Fos/GABA double-fluorescence clearly confirmed a SCS-induced activation of GABA-immunoreactive cells in responders immediately after SCS. Differences in spinal dorsal horn GABA(A) receptor-immunoreactivity and KCC2 protein levels were absent between all SCS groups. However, KCC2 protein levels were significantly decreased compared to sham PSNL animals. In conclusion, reduced intracellular GABA levels are only present during the time frame of SCS in responders and strongly point to a SCS-mediated on/off GABAergic release mechanism. Furthermore, a KCC2-dependent impaired GABA(A) receptor-mediated inhibition seems to be present both in responders and non-responders to SCS due to similar KCC2 and GABA(A) receptor levels.

Successful pain relief in non-responders to spinal cord stimulation: the combined use of ketamine and spinal cord stimulation.

Although spinal cord stimulation (SCS) is an established therapy for chronic neuropathic pain, still 30% of patients do not respond adequately to trial stimulation. These so called "non-responders" do not receive a permanent implantation for pain relief. The induction and maintenance of central sensitization plays a pivotal role in (chronic) neuropathic pain and is thought to be the resultant of the activation of the N-methyl-d-aspartate (NMDA) receptor in the dorsal horn. Blocking the NMDA receptor through the use of the non-competitive blocker ketamine has shown to attenuate neuropathic pain, although the undesirable side effects limit its use. The present study was performed to examine whether the combination of SCS with an individually determined sub-effective dose of intrathecal (i.t.) ketamine could convert non-responders into responders in rats with chronic neuropathic pain. Rats received a partial ligation of the sciatic nerve for the induction of neuropathic pain. Animals with tactile hypersensitivity to von Frey monofilaments (n=15) received 30 min of SCS. Non-responders to SCS (n=8) received their individually determined sub-effective i.t. dose of ketamine followed by 30 min of SCS. No side effects of the sub-effective dose of ketamine could be noted. The combined treatment of SCS and sub-effective dose of i.t. ketamine in non-responders resulted in a significant reduction of the withdrawal threshold in all previous non-responders to SCS, thereby converting them into responders to SCS.

Impairment of organ function after oral ingestion of refined petrol.

After oral ingestion of 600 ml of refined petrol a 23-year-old male developed multiple organ failure. Acute renal insufficiency due to nephrotoxic tubular necrosis requiring hemodialysis was a major manifestation. Moreover, respiratory failure, seizures, hemolysis, disseminated intravascular coagulation, liver damage and erosions of mucous membranes occurred. The patient subsequently recovered completely. In spite of the poor absorption from the gastrointestinal tract and the high first-pass effect in the liver, massive petrol intoxication may lead to reversible multisystemic lesions.