Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.

BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5-/y rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Frequency Rhythmic Electrical Modulation System (FREMS) to alleviate painful diabetic peripheral neuropathy: A pilot, randomised controlled trial (The FREMSTOP study).

BACKGROUND: Frequency Rhythmic Electrical Modulated System (FREMS) is a non-invasive treatment for chronic pain conditions, but its place in the treatment algorithm for painful diabetic peripheral neuropathy (PDPN) is unknown. METHODS: A pilot, open-label, randomised controlled trial in individuals with PDPN inadequately controlled on at least dual neuropathic pain treatments recruited from primary and secondary care. Participants were randomised 1:1 to FREMS + usual care (n = 13) versus usual care (n = 12). Primary outcome was change from baseline in perceived pain (assessed by visual analogue scale) at 12 weeks between treatment groups. RESULTS: Of 25 participants, 14 (56%) were men, and 21 (84%) were White Europeans. Median (IQR) age and duration of diabetes were 64 (56, 68) and 14 (10, 20) years, respectively. At 12 weeks, FREMS showed improvements in perceived pain compared with baseline, although the change was not statistically significant from control group (-4.0[-5.0,0.4] vs. 0[-0.3,0.7], p = 0.087). There were significant improvements in pain with FREMS, assessed by McGill Pain questionnaire (p = 0.042) and Douleur neuropathique-4 questionnaire (p = 0.042). More participants on FREMS had greater than 30 percent reductions in perceived pain compared with controls [7/13(54%) vs 0/12(0%), p = 0.042] and significant improvements in Patient Global Impression of Change (p = 0.005). FREMS intervention had moderate benefits in quality of life, sleep, depression and pain medication use, but these were not statistically significant. CONCLUSIONS: FREMS might be used to treat individuals with PDPN inadequately controlled on two classes of neuropathic pain medications and is associated with improvements in pain severity and perceived impact of treatment. A larger, appropriately designed trial assessing its impact in this population is needed.

Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels.

"The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre+post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups."

Microbial transformation of the steroidal alkaloid dictyophlebine by Rhizopus stolonifer.

The microbial transformation of a steroidal alkaloid, dictyophlebine (1) with Rhizopus stolonifer (ATCC 10404) afforded three oxidized metabolites 2-4. Compound 2 was found to be a new product. These metabolites were structurally characterized on the basis of modern spectroscopic techniques. Their inhibitory activity towards acetyl- and butyrylcholinesterase has been evaluated and the new product 2 has been found to be more potent than the parent compound and other metabolites.

Eventration of the diaphragm and associations.

Eventration of the diaphragm, most often an isolated entity and detected incidentally, has been known to be associated with several genetic syndromes. Authors report their experience of seeing diaphragmatic eventration in association with Poland syndrome and wandering spleen syndrome and briefly discuss the literature.