Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.The subthalamic nucleus (STN) has long been a structure of interest for researchers and clinicians alike. There is ample evidence that high-frequency stimulation of the STN improves symptoms such as tremor, rigidity, and slowness of movement, so called bradykinesia, in patients with Parkinson disease (see ref. 1 for review), but the mechanism through which this is achieved is still unknown. Some studies suggest that electrical stimulation causes a hyperexcitation of this structure (2), whereas others find evidence that the opposite is true (3–5). Other possible interpretations include the activation of the zona incerta, a neighboring white-matter structure (6) or of fibers coming from the motor cortex (7). Bilateral lesions of the STN improve locomotion (8), a result that is consistent with the inactivation hypothesis. However, previous studies have also found cognitive side effects when using high-frequency stimulation of the STN (9), findings supported by lesion studies in experimental animals, which led to abnormalities in operant tasks involving attention and impulsivity (10, 11). The projections of the STN to other regions help explain the multiple roles of this structure: It sends projections to other targets in the basal ganglia, such as the internal segment of the globus pallidus [also termed the entopeduncular nucleus (EP) in rodents] and the substantia nigra pars reticulata (SNr) (12, 13). The STN is also part of a circuit that includes the prefrontal cortex and the nucleus accumbens (14). It is currently unknown, however, whether these different roles reflect a heterogeneous population of cells, characterized by distinct gene expression. If that is the case, it would allow direct control over each cell population, facilitating the investigation of their respective roles. In rodents, the STN is believed to be composed solely of glutamatergic neurons, characterized by expression of the subtype 2 Vesicular glutamate transporter (Vglut2), whereas the other two subtypes (Vglut1 and Vglut3) have not been detected (15, 16). Selective targeted deletion of Vglut2 expression in this nucleus would therefore provide a specific loss-of-function model that would bypass a common problem presented by traditional lesions with pharmacological agents, which have patterns of diffusion that likely affect surrounding structures (17). It is known, however, that Vglut2 is expressed in many other parts of the brain (18), and a complete knockout in the mouse is not viable (19, 20). There is also evidence that the promoter driving expression of the Paired-like homeodomain 2 (Pitx2) gene is strong in the mouse STN (21) but is also not specific to this structure and a full knockout of Pitx2 expression results in premature death (22). To achieve the desired level of specificity, using a conditional knockout technique previously used to eliminate glutamatergic transmission in other cell types (23), we crossed Pitx2-Cre and Vglut2-lox mice, producing Vglut2^{f/f;Pitx2-Cre} conditional knockout (cKO) mice in which Vglut2 expression in the STN was strongly reduced in comparison with expression levels in littermate control mice. To understand the physiological contribution of the selected subpopulation of STN cells, we characterized these cKO mice with regard to anatomical, electrophysiological, and molecular properties, as well as their performance in a range of behavioral tasks.     

Evaluating changes in pulse transit time drop index in patients with obstructive sleep apnea before and during CPAP therapy

Airflow limitation in patients with obstructive sleep apnea (OSA) leads to arousal, increased sympathetic nervous system activity, and elevated blood pressure, which causes a decrease in pulse transit time (PTT). The present study aims to evaluate the effect of CPAP therapy on PTT in patients with moderate to severe OSA. This was a cross‐sectional study. Split‐night polysomnography (PSG) study was performed for each participant with apnea‐hypopnea index (AHI) ≥ 15 before and during CPAP therapy. The PTT was calculated as the time interval between the R wave of the electrocardiogram and the following arrival point in fingertip photoplethysmography. PTT drop was defined as a fall in the PTT curve of ≥15 ms lasting at least for 3 s and at most for 30 s. PTT drop index was defined as the number of drops in PTT that occur per hour of sleep. A total of 30 patients were included. PTT significantly increased, and PTT drop index significantly decreased during CPAP therapy (P < 0.001). PTT was significantly correlated to sleep efficiency (r _s = −0.376, P = 0.049) and oxygen desaturation index (ODI) (r _s = −0.428, P = 0.018). PTT drop index was strongly correlated to AHI (r _s = 0.802, P < 0.001), respiratory disturbance index (RDI) (r _s = 0.807, P < 0.001), ODI (r _s = 0.693, P < 0.001), arousal index (r _s = 0.807, P < 0.001), and periodic leg movement (PLM) index (r _s = 0.400, P = 0.035). Overall, the findings from this study indicated that the PTT drop index is a non‐invasive and useful marker for evaluating the severity of OSA and the effectiveness of treatment in patients with moderate to severe OSA.     

Pregnancy outcomes in women with ankylosing spondylitis: a scoping literature and methodological review

Clinical Rheumatology - In this scoping review, we sought to summarize the types of outcomes collected in pregnant patients with ankylosing spondylitis (AS), and to identify some methodological...     

Sick Building Syndrome. III. Stachybotrys chartarum

Increasingly, physicians are being asked to evaluate patients with putative environmentally associated illnesses. These can include a variety of problems, including infectious illnesses (Legionnaire's disease), chemical exposure in the workplace, and sick building syndromes. The latter has been an issue particularly in asthma because of the association of mold and increased bronchial responsiveness. Recently, attention has been focused on the mold Stachybotrys in human disease. Stachybotrys was first identified more than 60 years ago following an epidemic of stomatitis, rhinitis, conjunctivitis, pancytopenia, neurologic disorders, and death in horses. Since then, Stachybotrys has been identified in several outbreaks of disease in animals. It has also attracted attention as a possible agent in idiopathic pulmonary hemorrhage in infants. Stachybotrys is a relatively uncommon fungus but has been isolated from a variety of sources, including contaminated grains, tobacco, indoor air, insulator foams, and water-damaged buildings with high humidity. This fungus is particularly important because it is one of a series of fungi that produces trichothecenes mycotoxins; these mycotoxins are biologically active and can produce a variety of physiological and pathologic changes in humans and animals, including modulation of inflammation and altered alveolar surfactant phospholipid concentrations. The presence of Stachybotrys in a building does not necessarily imply a cause-and-effect relationship with illness, but should alert physicians and healthcare professionals to do more vigorous environmental testing. Guidelines are presented herein for intervention measures in the maintenance of heating, ventilation, and air-conditioning systems.     

Effects of Increasing Levels of Nickel Contamination on Structure of Offshore Nematode Communities in Experimental Microcosms

A microcosm experiment was used to examine the effects of nickel on offshore nematode communities of a Tunisian coastal zone (Southwestern Mediterranean Sea). Sediments were contaminated with three nickel concentrations [low (250 ppm), medium (550 ppm) and high (900 ppm)], and effects were examined after 30 days. Results showed significant differences between nematode assemblages from undisturbed controls and those from nickel treatments. Most univariates measures, including diversity and species richness, decreased significantly with increasing level of Ni contamination. Results from multivariate analyses of the species abundance data demonstrated that responses of nematode species to the nickel treatments were varied: Leptonemella aphanothecae was eliminated at all the nickel doses tested and seemed to be intolerant species to nickel contamination; Daptonema normandicum, Neochromadora trichophora and Odontophora armata which significantly increased at 550 ppm nickel concentration appeared to be “opportunistic” species at this dose whereas Oncholaimus campylocercoides and Bathylaimus capacosus which increased at all doses tested (250, 550 and 900 ppm) seemed to be “nickel-resistant” species.     

Proinflammatory Cytokine Gene Polymorphisms in Irritable Bowel Syndrome

Introduction

Irritable bowel syndrome (IBS) is a multifactorial functional gastrointestinal disorder, characterized by recurrent abdominal pain and altered bowel habits. Proinflammatory cytokines can play an important role in intestinal inflammation, while their production is under genetic control.

Methods

This study was performed in a group of patients with IBS to analyze the genotype frequencies of a number polymorphic genes coding for proinflammatory cytokine (interleukin-6 (IL), tumor necrosis factor-alpha (TNF-α), and IL-1 group). Using polymerase chain reaction with sequence-specific primers method, the cytokine genes were amplified, and alleles and genotypes of 71 patients with IBS were detected on gel electrophoresis, and the results were compared with healthy control subjects.

Results

Results of the analyzed data showed that the frequencies IL-1R C allele at position Pst-I 1970 (P?=?0.017), IL-6 G allele at position ?174 (P?=?0.002), and TNF-α G allele at position ?238 (P?<?0.001) in the patient group were significantly higher than the control group. IL-6 GG genotype (?174) and TNF-α GG genotype (?238) in the patient group were also significantly overrepresented (P?<?0.001), while IL-6 CG genotype (?174) and TNF-α GA genotype (?238) were significantly decreased in the patients with IBS (P?<?0.001). The frequencies of IL-6 (?174, nt565) GG haplotype and TNF-α (?308, ?238) GG haplotype were also significantly higher in the patient group (P?<?0.001), whereas the frequencies of the haplotypes IL-6 CG and TNF-α GA were significantly decreased in the patients with IBS (P?<?0.001).

Conclusion

IL-6 and TNF-alpha proinflammatory cytokine gene polymorphisms could change individual susceptibility to IBS and might have a role in pathophysiology of disease.