Dysequilibrium of ageing (presbyastasis)

We reviewed clinical findings in 740 patients over age 65 who consulted the Otological Medical Group, Inc., during a one-year period for dizziness. A thorough neurotologic evaluation is indicated in every such case to determine the specific cause of dizziness. In 21 per cent of these patients, a specific cause of dizziness was found. In the remaining 79 per cent, the diagnosis of primary dysequilibrium of ageing (presbyastasis) was made. We classified dysequilibrium of ageing (presbyastasis) according to the character, time course, and precipitating factors of dizziness. Two clinical types were described: constant and episodic; episodic dizziness was subdivided into orthostatic, positional, and unclassified. The histological findings in the temporal bones of four cases with dysequilibrium of ageing were reviewed. Pathological changes other than those in the peripheral vestibular system seem to be responsible for dysequilibrium of ageing. In the present series, about three-fourths of the patients had a daily dose of nicotinic acid to produce flushing of the skin. In 16 per cent, the dizziness was minor, requiring no special treatment. In the remaining 9 per cent with incapacitating vertigo, a vasodilator regimen, antivertiginous drugs, and Cawthorne's vestibular exercises were prescribed.     

In vivo requirement of TGF-β/GDNF cooperativity in mouse development: focus on the neurotrophic hypothesis

Neurotrophic factors are well-recognized extracellular signaling molecules that regulate neuron development including neurite growth, survival and maturation of neuronal phenotypes in the central and peripheral nervous system. Previous studies have suggested that TGF-β plays a key role in the regulation of neuron survival and death and potentiates the neurotrophic activity of several neurotrophic factors, most strikingly of GDNF. To test the physiological relevance of this finding, TGF-β2/GDNF double mutant (d-ko) mice were generated. Double mutant mice die at birth like single mutants due to kidney agenesis (GDNF−/−) and congential cyanosis (TGF-β2−/−), respectively. To test for the in vivo relevance of TGF-β2/GDNF cooperativity to regulate neuron survival, mesencephalic dopaminergic neurons, lumbar motoneurons, as well as neurons of the lumbar dorsal root ganglion and the superior cervical ganglion were investigated. No loss of mesencephalic dopaminergic neurons was observed in double mutant mice at E18.5. A partial reduction in neuron numbers was observed in lumbar motoneurons, sensory and sympathetic neurons in GDNF single mutants, which was further reduced in TGF-β2/GDNF double mutant mice at E18.5. However, TGF-β2 single mutant mice showed no loss of neurons. These data point towards a cooperative role of TGF-β2 and GDNF with regard to promotion of survival within the peripheral motor and sensory systems investigated.     

Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity

Hereditary spastic paraplegias (HSP) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. We performed the first clinical, epidemiological and genetic study of HSP in Southern Tunisia. We investigated 88 patients belonging to 38 unrelated Tunisian HSP families. We could establish the minimal prevalence of HSP in the district of Sfax at 5.75/100,000. Thirty‐one percent of the families had a pure HSP, whereas 69% had a complicated form. The mode of inheritance was almost exclusively compatible with an autosomal recessive trait (97%, 37/38). Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each. The linkage results could be validated through the identification of two recurrent truncating mutations (R2034X and M245VfsX246) in the SPG11 gene, three different mutations (Q493X, F683LfsX685 and the novel S2004T/r.?) in the SPG15 gene, the recurrent R499C mutation in the SPG4 gene as well as the new R112X mutation in the SPG5 gene. SPG11 and SPG15 are the major responsible HSP genes in Tunisia.     

PI3 kinase integrates Akt and MAP kinase signaling pathways in the regulation of prostate cancer

PI3 kinase (PI3K), Akt and MAP kinase (MAPK) pathways are central to many classical signaling cascades and are often de-regulated in many cancers. Due to this, inhibitors for a number of key signaling molecules in these pathways such as PI3K, Akt, mTOR, Raf and ERK are currently in clinical trials. In the current study, we investigated the effects of specific inhibition of these signaling molecules, alone or in combinations, on prostate cancer cells. Our study showed that integration of Akt-mTOR and MAPK signaling by PI3K was essential for the EGF-stimulated TRAMP cell migration, proliferation, survival and invasion as well as PC3 and LNCaP C4-2 (C4-2) colony/foci formation. Adenovirus-mediated expression of constitutively active Akt (Ad-myrAkt) in PC3 cells resulted in significant increase in number of foci. Even though PI3K inhibition significantly reduced foci formed by C4-2 cells, none of the Akt, ERK or mTOR inhibitors showed any significant inhibition. This indicated that functional redundancies and/or feed back loops between Akt-mTOR and MAPK signaling exist in prostate cancer. Further studies on cotargeting these signaling molecules revealed that combined inhibition of Akt (or mTOR) and ERK, but not Akt and mTOR, resulted in significant reduction in number of foci formed by the C4-2 cells. Overall, our study demonstrated that the effects of PI3K-mediated prostate cancer growth necessitates a synergism between the Akt and MAPK pathways and suggests cotargeting Akt (or mTOR) and MAPK as an effective method for prostate cancer therapeutic interventions.     

Comparative study of two versatile multi-analyte chromatographic methods for determination of diacerein together with four non-steroidal anti-inflammatory drugs: Greenness appraisal using Analytical Eco-Scale and AGREE metrics

According to green analytical chemistry (GAC) principles, multi-analyte methods are usually more preferred than methods determining one analyte at a time (principle 8) as they allow saving resources (time, reagents and money) (principle 9) and permit the reduction of generated waste (principle 7) as well as reduction of needed samples (principle 2). The present work herein, describes for the first time the development, validation and comparison of novel green versatile multi-analyte HPLC-DAD and HPTLC methods for the quantitative estimation of five drugs (diacerein, aceclofenac, diclofenac sodium, celecoxib and meloxicam) within a single run in a short analysis time. For HPLC-DAD, separation was performed through using Zorbax SB C18 (4.6 × 250 mm, 5 μm particle size) with the mobile phase composed of 0.05 M phosphate buffer pH 3.0 and acetonitrile (42:58, v/v) at a flow rate of 1 mL/min. The chromatograms were extracted at 258, 276 and 355 nm. In HPTLC procedure, precoated TLC silica gel aluminum plates 60 F₂₅₄ were used with a mobile phase consisting of mixture of (chloroform: methanol: acetic acid, 92:8:0.25, v/v/v). The developed plates were scanned densitometrically at 258, 280 and 360 nm. Validation of the proposed methods was performed following the ICH guidelines for linearity, ranges, precision, accuracy, robustness, detection and quantification limits. Good linearities were confirmed by the high values of correlation coefficients (r > 0.9992). Appraisal of the greenness of the developed methods and comparison with different reported chromatographic methods was performed using the analytical Eco-scale (AES) approach and the novel Analytical GREEnness (AGREE) metric.     

Intrafamilial phenotypic variability of Hallervorden-Spätz syndrome in a Tunisian family

We report clinical features, CT-scan and MRI findings of three siblings with Hallervorden-Sp?tz disease, one of them followed for more than 20years. Patient 1 presented at age 10 with progressive generalized dystonia. Five years later she had violent dystonic spasms with opisthotonos and marked oro-mandibular involvement. Later, dystonia stabilized and examination showed dysarthria, multiple deformities related to dystonic posturing, retinal degeneration and no cognitive impairment. Cerebral CT-scan showed bilateral pallidal lucencies and T2 cerebral MRI showed the "eye of the tiger" sign.Patient 2 developed delusions and hallucinations at age 18 with acute phases of hetero-aggressivity diagnosed as "schizophrenic" in a psychiatric hospital. At age 20, he developed oromandibular dystonia, severe dysarthria and epilepsy. Cerebral MRI showed the same "eye of the tiger" sign.Patient 3 presented at age 37 with isolated psychiatric features similar to those of patient 2, also diagnosed "schizophrenic" in a psychiatric hospital. Neurological examination showed mild postural tremor of the hands and intermittent cervical dystonia. He was stabilized with neuroleptic treatment.This family shows marked intrafamilial variability of age at onset, symptom at onset (with "schizophrenic" features unusually described and leading to misdiagnosis), clinical presentation (almost entirely dystonic in one patient and almost entirely psychiatric in two others) and course of the disease (slowly progressive in one sibling, rapidly deteriorating in the second and stabilization in the third). Classification and nosology of subtypes of HSD are discussed.     

Pulmonary metastatectomy for soft tissue sarcomas: is it valuable?

BACKGROUND: A retrospective study and analysis was performed to determine the value and benefit of pulmonary metastatectomy for soft tissue sarcomas, and which factors predict prognosis following resection. METHODS: Twenty-three patients underwent resections for pulmonary metastases from a soft tissue sarcoma (STS) at King Faisal Specialist Hospital and Research Center (KFSH&RC), between January 1985 and December 1998. There were 11 male and 12 female patients. Thirteen of 23 patients (57%) had one to three metastases, and 10 (43%) had four or more metastases. A total of 41 thoracic explorations was performed for the 23 evaluable patients. Median sternotomy was used only for three patients and lateral thoracotomy was used for 20 patients as an initial surgical approach. Pulmonary resections performed included one or more wedge resections (n=16), segmentectomy (n=5), and lobectomy (n=2). No one in this series underwent pneumonectomy. The number of resected metastatic nodules ranged from one-six with average three. Eight patients (35%) received various kinds of postoperative adjuvant chemotherapy. RESULTS: The overall and disease-free survival rate post-metastatectomy at five years was 24% and 21%, respectively. Various prognostic indicators were examined to evaluate their association with improved survival. Age, sex localization of the primary site and histologic type, tumor grade, size of the resected nodules, laterality (unilateral or bilateral), types of resection, adjuvant chemotherapy, and local recurrence did not significantly affect survival. However, patient with disease free interval >6 months, and those with three or fewer metastases showed a trend toward a higher five-year overall survival (p=0.06, 0.07, respectively). CONCLUSIONS: Surgical excision of lung metastases from soft tissue sarcomas is well accepted and should be considered as a first line of treatment if preoperative evaluation indicated that complete resection of the metastases is possible. Further investigation is needed before chemotherapy can be recommended as additional therapy.     

Does the patient's position influence the detection of detrusor overactivity?

AIMS: The demonstration of preoperative detrusor overactivity (DO) with associated overactive bladder symptoms (OAB) is known to have an adverse effect on surgery performed for stress incontinence or for prostatic obstruction. The purpose of this review is to examine the best position, when filling the bladder during urodynamics, to demonstrate detrusor overactivity and reproduce the OAB symptoms, when the demonstration of DO might be important. MATERIALS AND METHODS: MEDLINE and PUBMED literature searches were performed, spanning the period from 1956 to August 2005 using the keywords "detrusor overactivity" or "detrusor instability" combined with "posture or position or standing or sitting" and "urodynamics." Other studies were identified by reviewing secondary references in the original citations. RESULTS: Sixteen studies looked at the effect of position on the detection rate of DO. There is good consistency between the studies analyzed. All but two [Ramsden et al., Br J Urol 49:633-9, 1977; Choe et al., J Urol 161:1541-4, 1999] showed a clear effect, with an increase in DO when the patient is filled in the vertical position or is asked to sit or stand, with a full bladder, after being filled supine. Performing the urodynamics (UDS) in the supine position would have missed a large proportion of DO diagnoses ranging from 33% to 100%. CONCLUSIONS: This review confirms that the patient's position is a significant variable during urodynamics and that supine cystometry will fail to detect a significant percentage of patients with DO. We suggest that all patients should be filled sitting or standing, unless physically disabled. It seems desirable for the International Continence Society (ICS) to extend its "Good urodynamic practice guideline" [Schafer et al., Neurourol Urodyn 21:261-74, 2002] to cover this important issue.