Classification of walking ability of household walkers versus community walkers based on K-BBS, gait velocity and upright motor control.

BACKGROUND: Few guidelines are available to assist clinicians with assessment of whether a patient is a household or community walker. AIM: To assess the Korean Berg balance scale (K-BBS) and gait velocity cut-off points of a household walker versus a community walker and evaluate which combinations of the three scales (K-BBS, upright motor control test (UMCT), and gait velocity) best assessed walking ability. DESIGN: Cross-sectional study. SETTING: Outpatient. POPULATION: A total of 124 stroke patients with walking difficulty. METHODS: Participants were classified into one of six walking classifications (three household walkers and three community walkers) and K-BBS, UMCT, and gait velocity were evaluated. The optimal cut-off scores for walking classification were determined based on received operator characteristic (ROC) analyses. RESULTS: The cut-off value of K-BBS for dividing the household walker versus the community walker was 42 points. The cut-off value of gait velocity was 48 m/s for the community walker. The area under the ROC curve of the combined K-BBS and gait velocity values was larger than that of each individual scale and those of the other combined scales. CONCLUSION: The results suggest that K-BBS, gait velocity, and UMCT are useful instruments for classifying household ambulation and community ambulation. The authors recommend K-BBS as single scale and K-BBS and gait velocity as combined scales for evaluating community ambulation in stroke patients CLINICAL REHABILITATION IMPACT: In this report, we have some clinical implication. We recommend 3 outcome measures to assess walking ability about home or community; K-BBS (>42 points), gait speed (>48 m/min), UMCT (strong grade in either knee flexion of extension). Suggesting cut-off points of Korean Berg balance scale, gait velocity, and level of upright motor control test for community ambulation could be used as outcome measures to evaluate patient's actual performance level. It is also important to combine several scales for determining walking classification. We suggest to evaluate walking ability by combining K-BBS and UMCT to best predict community ambulation.

Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition.

Twist1 is highly expressed in primary and metastatic non-small cell lung cancer (NSCLC), and thus acts as a critical target for lung cancer chemotherapy. In the current study, we investigated the underlying mechanism initiated by silencing of Twist1 that sensitizes NSCLC cells to cisplatin. Silencing of Twist1 triggered ATP depletion, leading to AMP-activated protein kinase (AMPK)-activated mammalian target of rapamycin (mTOR) inhibition in NSCLC cells. AMPK-induced mTOR inhibition, in turn, resulted in downregulation of ribosome protein S6 kinase 1 (S6K1) activity. Downregulation of mTOR/S6K1 reduced Mcl-1 protein expression, consequently promoting sensitization to cisplatin. Overexpression of Mcl-1 reduced PARP cleavage induced by cisplatin and Twist1 siRNA, suggesting that this sensitization is controlled through Mcl-1 expression. Interestingly, cells treated with Twist1 siRNA displayed upregulation of p21(Waf1/CIP1), and suppression of p21(Waf1/CIP1) with specific siRNA further enhanced the cell death response to cisplatin/Twist1 siRNA. In conclusion, silencing of Twist1 sensitizes lung cancer cells to cisplatin via stimulating AMPK-induced mTOR inhibition, leading to a reduction in Mcl-1 protein. To our knowledge, this is the first report to provide a rationale for the implication of cross-linking between Twist1 and mTOR signaling in resistance of NSCLC to anticancer drugs.

Metallothionein gene expression in human adipose tissue from lean and obese subjects.

Expression of the gene encoding metallothionein, a low molecular-weight cysteine-rich, stress-response and metal-binding protein was examined in human adipose tissue. The mRNA for MT-2A, a major metallothionein isoform in humans, was detected in subcutaneous fat using a specific antisense oligonucleotide probe. The level of MT-2A mRNA was significantly higher in a group of obese subjects than in a lean group, paralleling a similar increase in ob mRNA. A two-week period on a diet of 800 calories/day did not lead to any significant change in MT-2 mRNA levels. Separation of mature adipocytes from the cells of the stromal vascular fraction indicated that in human adipose tissue the metallothionein (MT-2A) gene is expressed both in adipocytes and in other cells of the tissue.

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

Hemophilic pseudotumor of the ulna treated with low dose radiation therapy: a case report.

We report a case of hemophilic pseudotumor in the ulna of a 6-year-old boy treated with radiation therapy. A total dose of 900 cGy in 6 fractions was given in 6 consecutive days. Progression of cystic changes was halted within a month. New bone formation and trabeculation were found on the 4th month. Complete healing of the lesion and bony replacement were found on the 12th month. The patient was followed up to 72 months and there was no evidence of recurrence and no bone growth disturbance. Radiation therapy can be an effective alternative modality in treating hemophilic pseudotumor.

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.

Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain.

Long-term comparison of a newly designed gold implant with the conventional implant in facial nerve paralysis.

Patients with complete facial nerve palsy are at risk for eye complications resulting from exposure of the cornea and loss of the blinking reflex. Failure of protection predisposes the patient to exposure keratitis, corneal abrasion and, in rare cases, blindness. The mainstays of non-surgical therapy are cumbersome, obscure vision, and are mostly helpful in patients with acute facial paralysis in whom recovery of orbicularis oculi function is expected. Methods of lid-loading using metal implants and gold eyelid weights have been reported in the literature. Between October of 1988 and March of 1995, 32 patients with lagophthalmos due to facial nerve palsy underwent a total of 34 procedures for the insertion of a gold eyelid weight. Each patient had a gold weight inserted into a small pocket between the orbicularis oculi and the tarsal plate of the upper eyelid. The gold implant is curved to fit the curvature of the eye and contains holes for fixation to the tarsus with sutures. Ingrowth of fibrous tissue through the holes may also help fix the weight in position. Between 1988 and 1991, 10 patients received 10 commercially available rectangular gold implants with 2 holes; these implants resulted in adverse effects, such as infection and exposure in up to 30 percent of the cases. Because of the high complication rate with the rectangular gold implant, the authors began using a new, elliptical gold implant with 3 holes, which is longer, thinner, wider in the center, and narrower in the peripheral portion. This new elliptical implant was used on 22 patients (24 implants) from December of 1991 through March of 1995. The mean follow-up time for the 32 patients in the study was 41.3 months (range, 6 to 63 months), 49.8 months for patients with rectangular implants and 32.8 months for patients with elliptical implants. The elliptical gold implant resulted in dynamic closure of the eyelid and in excellent protection and cosmesis. Lagophthalmos and exposure keratitis resolved, visual acuity significantly improved without complications, and most patients could dispense with eyedrops and salves. A lower eyelid supporting procedure (conchal cartilage graft) should be performed simultaneously in patients with lagophthalmos of a moderate or severe degree to achieve complete closure of the eyelid. Use of a tall pillow decreased the incidence of eyelid opening during sleep. Double eyelid fold operations'were performed on the contralateral eyelid after 6 months, resulting in a symmetrical and beautiful eyelid.

Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.

Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.

Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia.

Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.

Pharmacological and physiological properties of a putative ganglionic nicotinic receptor, alpha 3 beta 4, expressed in transfected eucaryotic cells.

Neuronal nicotinic acetylcholine receptor subunits alpha 3 (PCA48E) and beta 4S (ZPC13) were expressed in human embryonic kidney (HEK)-293 cells by calcium phosphate transfection. In the presence of atropine, acetylcholine (ACh) induced fast activating currents which exhibited desensitization and inward rectification. The EC50 for ACh was 202 +/- 32 microM with a Hill coefficient of 1.9 +/- 0.4. The rank order of nicotinic agonist potency was 1,1-dimethyl-4-phenylpiperozinium (DMPP) > cytisine = nicotine approximately equal to ACh. The maximal response elicited by DMPP was substantially less than that elicited by other agonists, suggesting that DMPP is a partial agonist. ACh (500 microM) responses were very effectively blocked by equimolar concentrations (100 microM) of the ganglionic antagonists d-tubocurarine, mecamylamine and hexamethonium. Equal concentrations of the potent muscle receptor antagonist decamethonium and the competitive antagonist dihydro-beta-erythroidine were much less effective. alpha bungaro-toxin (1 microM) had little effect on ACh-induced responses. This physiological and pharmacological profile is consistent with a ganglionic nicotinic response.