Meerana Lim

Over 70% of patients with cystic fibrosis have the DeltaF508 mutation. This protein is a partially functional chloride (Cl-) channel that is prematurely degraded in the endoplasmic reticulum. Specific members of the flavonoid class of compounds have been shown to increase Cl- conductance of wild-type and DeltaF508 cystic fibrosis transmembrane regulator (CFTR). Although flavonoid effects on CFTR processing are unknown, evidence of effects on heat shock proteins, specifically those that have been shown to interact with CFTR, led us to believe that there would be an effect on CFTR processing through modulation of CFTR-chaperone interactions. We sought to determine (i) the effect of apigenin, genistein, kaempferol, and quercetin on CFTR processing in IB3-1 cells (F508/W1282X) and (ii) whether sequential treatment with 4-phenylbutyrate (4-PBA) to increase CFTR processing and flavonoid to directly stimulate CFTR would increase Cl- conductance. Our results show no significant effect on CFTR processing as measured by immunoblotting with 1 microM or 5 microM of apigenin, genistein, kaempferol, or quercetin. However, despite no effect on CFTR processing as determined by immunoblot, immunofluorescence demonstrated a favorable change in the intracellular distribution of CFTR with 24 h treatments of apigenin, kaempferol, and genistein. Furthermore, we observed an increase in Cl- conductance as measured by Cl- efflux in cells that were treated for 24 h with 4-PBA and then assayed with forskolin and 1 microM or 5 microM genistein, and also with cells treated for 24 h with either 4-PBA, 5 microM apigenin, or 1 microM quercetin. Thus, a combination of chronic treatment with 4-PBA or select flavonoids, followed by acute flavonoid exposure, may be beneficial in cystic fibrosis.

Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with cystic fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy taken with each meal. The highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to the complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.

We studied the effects of altered sensory information on standing balance in 25 patients with cortical cerebellar atrophy (CCA), nine patients with olivoponto-cerebellar atrophy (OPCA), and 10 normal subjects. The total sway path and its components, the anteroposterior (AP) sway path and the lateral sway path, were measured under six conditions: (1) standing on a fixed platform with the eyes open and visual surroundings fixed, (2) standing on a fixed platform with the eyes closed, (3) standing on a fixed platform with the eyes open and visual surroundings AP sway referenced, (4) standing on an AP sway-referenced platform with the eyes open and visual surroundings fixed, (5) standing on an AP sway-referenced platform with the eyes closed, and (6) standing on an AP sway-referenced platform with the eyes open and visual surroundings AP sway referenced. Patients swayed more than normal subjects during normal stance (condition 1), when the visual information was absent (condition 2) or distorted (condition 3), and when the proprioceptive information from the ankles was distorted (condition 4). Patients swayed much more than normal, and most fell, when two sensory modalities were affected under condition 5 (proprioceptive information distorted and visual information absent) and condition 6 (both proprioceptive information and visual information distorted). When the patients' sway was normalized to that of the first condition, however, only their lateral sway was greater than the sway in normal subjects. Unlike in normal subjects, the patients' lateral sway varied with the AP sway to approximately the same degree in each condition for conditions 1-5. Clinical ratings of gait and balance were highly correlated with the sway measures. Quantitative testing of standing balance with altered sensory information has better sensitivity than normal stance testing.