The equilibrium potential for GABA-A receptor mediated currents (EGABA) in neonatal central neurons is set at a relatively depolarized level, which is suggested to be caused by a low expression of ...K+/Cl- co-transporter (KCC2) but a relatively high expression of Na+-K+-Cl- cotransporter (NKCC1). Theta-burst stimulation (TBS) in stratum radiatum induces a negative shift in EGABA in juvenile hippocampal CA1 pyramidal neurons. In the current study, the effects of TBS on EGABA in neonatal and juvenile hippocampal CA1 neurons and the underlying mechanisms were examined. Metabotropic glutamate receptors (mGluRs) are suggested to modulate KCC2 and NKCC1 levels in cortical neurons. Therefore, the involvement of mGluRs in the regulation of KCC2 or NKCC1 activity, and thus EGABA, following TBS was also investigated. Whole-cell patch recordings were made from Wistar rat hippocampal CA1 pyramidal neurons, in a slice preparation. In neonates, TBS induces a positive shift in EGABA, which was prevented by NKCC1 antisense but not NKCC1 sense mRNA. (RS)-a-Methyl-4-carboxyphenylglycine (MCPG), a group I and II mGluR antagonist, blocked TBS-induced shifts in both juvenile and neonatal hippocampal neurons. While blockade of mGluR1 or mGluR5 alone could interfere with TBS-induced shifts in EGABA in neonates, only a combined blockade could do the same in juveniles. These results indicate that TBS induces a negative shift in EGABA in juvenile hippocampal neurons but a positive shift in neonatal hippocampal neurons via corresponding changes in KCC2 and NKCC1 expressions, respectively. mGluR activation seems to be necessary for both shifts to occur while the specific receptor subtype involved seems to vary.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Insufficient sleep has been correlated to many physiological and psychoneurological disorders. Over the years, our understanding of the state of sleep has transcended from an inactive period of rest ...to a more active state involving important cellular and molecular processes. In addition, during sleep, electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system (CNS). Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour. Memory consolidation and learning that take place during sleep cycles, can be affected by changes in synaptic plasticity during sleep disturbances. G-protein coupled receptors (GPCRs), with their versatile structural and functional attributes, can regulate synaptic plasticity in CNS and hence, may be potentially affected in sleep deprived conditions. In this review, we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). ...However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5).
To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2). Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/-) and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.
This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The passive immunization of patients with SARS‐CoV2 with convalescent plasma (CP) is theoretically beneficial in patients with end‐stage renal disease who are immunosuppressed and unable ...to mount an adequate immune response. Hence, this study was conducted to evaluate the safety and efficacy of CP in patients with chronic kidney disease on hemodialysis with moderate‐to‐severe SARS‐CoV2 infection.
Methods
A prospective observational cohort study was conducted in consecutive 68 moderate‐to‐severe SARS‐CoV2 infected patients who were on maintenance hemodialysis or with acute worsening of chronic kidney disease which required initiation of hemodialysis. Patients who received CP were compared with those who did not. The primary outcome was death during hospitalization. Clinical characteristics, duration of hospitalization and inflammatory parameters were compared between the two groups. A subgroup analysis was done to find whether early initiation of plasma was associated with better outcome.
Results
Sixteen patients (44%) in the plasma group and 14 (45%) patients in the control group died during hospitalization (p = 0.95). The median duration of hospitalization was 9 (6–14) days in the plasma group and 9 (6–16) in the control group (p = 0.60). There was no difference in mortality or duration of hospitalization with respect to early initiation of CP (p = 0.29). Fistula thrombosis occurred in two patients (11.1%) in the plasma group.
Conclusion
Therapy with CP does not appear to confer any clinical benefit in moderate‐to‐severe SARS‐CoV‐2 infected patients with chronic kidney disease on hemodialysis.
Long term depression (LTD) in the CA1 region of the hippocampus, induced with a 20-Hz, 30 s tetanus to Schaffer collaterals, is enhanced in sleep-deprived (SD) rats. In the present study, we ...investigated the role of metabotropic glutamate receptors (mGluRs), γ-aminobutyric acid (GABA) B receptors (GABA(B)-Rs) and N-methyl-D-aspartic acid receptors (NMDARs) in the LTD of the population excitatory postsynaptic potential (pEPSP). The requirement of Ca(2+) from L- and T-type voltage-gated calcium channels (VGCCs) and intracellular stores was also studied. Results indicate that mGluRs, a release of Ca(2+) from intracellular stores and GABA(B)-Rs are required for LTD. Interestingly, while mGlu1Rs seem to be involved in both short-term depression and LTD, mGlu5Rs appear to participate mostly in LTD. CGP 55845, a GABA(B)-R antagonist, partially suppressed LTD in normally sleeping (NS) rats, while completely blocking LTD in SD rats. Moreover, GS-39783, a positive allosteric modulator for GABA(B)-R, suppressed the pEPSP in SD, but not NS rats. Since both mGluRs and GABA(B)-Rs seem to be involved in the LTD, especially in SD rats, we examined if the receptor expression pattern and/or dimerization changed, using immunohistochemical, co-localization and co-immunoprecipitation techniques. Sleep-deprivation induced an increase in the expression of GABA(B)-R1 and mGlu1αR in the CA1 region of the hippocampus. In addition, co-localization and heterodimerization between mGlu1αR/GABA(B)-R1 and mGlu1αR/GABA(B)-R2 is enhanced in SD rats. Taken together, our findings present a novel form of LTD sensitive to the activation of mGluRs and GABA(B)-Rs, and reveal, for the first time, that sleep-deprivation induces alterations in the expression and dimerization of these receptors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long term depression (LTD) in the CA1 region of the hippocampus, induced with a 20-Hz, 30 s tetanus to Schaffer collaterals, is enhanced in sleep-deprived (SD) rats. In the present study, we ...investigated the role of metabotropic glutamate receptors (mGluRs), γ-Aminobutyric acid (GABA) B receptors (GABAB-Rs) and N-methyl-D-aspartic acid receptors (NMDARs) in the LTD of the population excitatory postsynaptic potential (pEPSP). The requirement of Ca2+ from L- and T- type voltage-gated calcium channels (VGCCs) and intracellular stores was also studied. Results indicate that mGluRs, a release of Ca2+ from intracellular stores and GABAB-Rs are required for LTD. Interestingly, while mGlu1Rs seem to be involved in both short-term depression and LTD, mGlu5Rs appear to participate mostly in LTD. CGP 55845, a GABAB-R antagonist, partially suppressed LTD in normally sleeping (NS) rats, while completely blocking LTD in SD rats. Moreover, GS-39783, a positive allosteric modulator for GABAB-R, suppressed the pEPSP in SD, but not NS rats. Since both mGluRs and GABAB-Rs seem to be involved in the LTD, especially in SD rats, we examined if the receptor expression pattern and/or dimerization changed, using immunohistochemical, co-localization and co-immunoprecipitation techniques. Sleep-deprivation induced an increase in the expression of GABAB-R1 and mGlu1αR in the CA1 region of the hippocampus. In addition, co-localization and heterodimerization between mGlu1αR/GABAB-R1 and mGlu1αR/GABAB-R2 is enhanced in SD rats. Taken together, our findings present a novel form of LTD sensitive to the activation of mGluRs and GABAB-Rs, and reveal, for the first time, that sleep-deprivation induces alterations in the expression and dimerization of these receptors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There are scarce data regarding the use of remdesivir in patients with severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) and end-stage renal disease as US Food and Drug ...Administration cautions against its use in patients with an estimated glomerular filtration rate <30 ml/min/1.73m2 unless the potential benefits outweigh the potential risks. We studied the compassionate use and safety profile of remdesivir in patients with end-stage renal disease and moderate to severe SARS-CoV-2 infection.
We conducted an observational prospective study in 48 dialysis-dependent patients with SARS-CoV-2 infection who received remdesivir as part of institutional treatment protocol. During the treatment period, 100 mg of remdesivir was given 4 hours before hemodialysis sessions. Liver function tests, inflammatory markers such as serum C-reactive protein, serum ferritin and lactate dehydrogenase levels, and oxygen requirement before and after remdesivir treatment were compared.
There were no events of significant liver function test alterations with the administration of 2 to 6 doses of remdesivir. A significant decline in serum C-reactive protein level (P < 0.001) was noted. More than two thirds (68.57%) of patients showed an improvement in oxygen requirement. Early administration of remdesivir within 48 hours of hospital admission shortened the duration of hospitalization by a mean of 5.5 days (P = 0.001).
Remdesivir was well tolerated and found safe in our study. If initiated within 48 hours of hospitalization, it reduces recovery time. Assessing the mortality benefits of remdesivir in these patients requires a randomized controlled trial with a larger population.
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Cavitary pulmonary disease in a patient on dialysis Lamech, Tanuj M.; Nithya, Govindasamy; Aiswarya, Dhanapalan ...
Seminars in dialysis,
July/August 2021, 2021-07-00, Letnik:
34, Številka:
4
Journal Article
Recenzirano
A 24‐year‐old man on maintenance hemodialysis presented with bilateral cavitary consolidations and methicillin‐sensitive Staphylococcus aureus (MSSA) bacteremia following ulceration of the skin over ...his arteriovenous (AV) fistula cannulation site. A diagnosis of septic pulmonary embolism was made, which presumptively originated from a localized MSSA infection of his AV access. He had an excellent response to a 28‐day course of cloxacillin, with the resolution of the pulmonary lesions.
Introduction
In this observational study, we describe the change in the clinical profile and outcome of Corona Virus Disease 2019 (COVID-19) over the course of the outbreak, among patients requiring ...dialysis, including chronic haemodialysis therapy.
Methods
This is a single-centre prospective observational study of patients with COVID-19 (as confirmed by RT-PCR) and renal failure requiring haemodialysis. Their clinical profiles and outcomes were analysed, vis-à-vis the changing disease severity.
Findings
A total of 483 patients were included, of whom 416 had end-stage renal disease and were on maintenance haemodialysis. Patients who were symptomatic at presentation had significantly higher levels of Neutrophil–lymphocyte ratio (NLR) (
p
< 0.001), C-reactive protein (CRP) (
p
< 0.001), lactate dehydrogenase (LDH) (
p
< 0.001), higher degrees of lung involvement (
p
< 0.001) and required more respiratory support (
p
< 0.001). The overall mortality observed was 18.8%. In the late phases of the outbreak, there was a significant increase in disease severity without a statistically significant increase in mortality. Predictors of mortality on univariate analysis were age, diabetes mellitus, acute on chronic kidney disease, presence of symptoms on admission, NLR, CRP, LDH, computed tomography (CT) chest grades 3 and 4, and need for respiratory support; however, only age and the renal syndrome of acute on chronic kidney disease retained significance on multivariate analysis (
p
0.003 and
p
0.019, respectively).
Conclusion
Among patients on haemodialysis, higher mortality was observed in patients who were older, and among those with acute on chronic kidney disease. In the late phase of the outbreak, there was a statistically significant increase in disease severity without a corresponding increase in mortality.
Graphic abstract
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