The cell cycle and induction of apoptosis in a hamster fibrosarcoma cell line treated with anti-cancer drugs: Its importance to solid tumour chemotherapy*

The induction of apoptosis by anticancer drugs and its relationship to stages of the cell cycle was studied in cells derived from a solid tumour; a highly malignant hamster fibrosarcoma (Met B). Asynchronously proliferating cells were treated with a wide variety of agents such as actinomycin-D, 1--D-arabinofuranosyl cytosine, camptothecin, cisplatin, cyclophosphamide, daunorubicin, 5-flurouracil, 6-mercaptopurine, hydroxyurea, ionomycin, methotrexate and vincristine. With the exception of cyclophosphamide and hydroxyurea, a 36 h exposure to these drugs resulted in inhibition of cell growth and apart from cyclophosphamide, hydroxyurea, 6-mercaptopurine and cisplatin the induction of apoptosis. Studies using a decreased concentration of drug and exp osure time (12 h) followed by examination of cells using flow cytometry indicated that most drugs were capable of affecting cell cycle progression without induction of apoptosis. However when cells were synchronised at G₀/G₁, S and G₂/M phases and then exposed to these decreased concentrations of drug apart from 6MP an HU, apoptosis was observed and for the majority of drugs it took place in the same phase in which progression through the cell cycle was blocked by the drug. Cells synchronised in G₀/G₁ phase were more susceptible to methotrexate, whereas S-phase cells were more susceptible to camptothecin and 5-flurouracil and G₂/M phase cells more susceptible to actinomycin D, 1--D-arabinofuranosyl cytosine, daunorubicin and cisplatin. In contrast, vincristine blocked cells in G₂/M phase but exerted its apoptotic effect in S-phase cells, ionomycin had no effect on the cell cycle, but G₂/M cells appeared to be more susceptible to the effect of this drug. These data indicate that entry into apoptosis by this fibrosarcoma may occur at any point in the cell cycle. They also demonstrate a correlation between the action of some anticancer drugs on the cell cycle and the subsequent induction of apoptosis which may be useful in chemotherapeutic design.     

Induction of a low voltage-activated,fast-inactivating Ca2+ channel in cultured bone marrow stromal cells by dexamethasone

The production of biochemical markers associated with the osteoblastic phenotype, and accompanying changes in the expression of voltage-operated Ca²⁺ channels, have been examined in rat bone marrow stromal cell cultures treated with dexamethasone (10^-8 M). Whole cell clamp analysis of voltage-operated Ca²⁺ channels in control cultures (using Ba²⁺ as the charge carrier) revealed primarily a high voltage-activated (HVA), slowly inactivating current, which was enhanced two- to threefold by treatment of the cells with Bay K 8644 (300 nM) and inhibited by nifedipine (4 M). In dexamethasone-treated cultures, the I–V relationship for inward current was shifted to more positive potentials in comparison with control cells. Most cells in these cultures possessed both the HVA current and also a faster inactivating, low-voltage-activated (LVA), nifedepineresistant current. These two currents could be separated both by nifedipine and by the use of steady state inactivation of the LVA current. The two components of the Ba²⁺ current varied widely in their relative size. The combination of LVA and HVA currents seen in dex-induced stromal cells resembles records of voltage-operated Ca²⁺ channels from cultures of calvarial osteoblasts.     

Doppler sonographic parameters for detection of carotid stenosis: is there an optimum method for their selection?

OBJECTIVE: A wide range of Doppler threshold values for carotid stenosis is found in the literature. We undertook this study to compare methods of derivation and to determine if an optimum strategy of threshold selection exists for a high-risk population. MATERIALS AND METHODS: From the sonograms of all patent internal carotid arteries, peak systolic velocity in the internal carotid artery (ICA(PSV)) and the ratio of peak systolic velocity in the internal carotid artery to that of the common carotid artery (ICA(PSV)/ CCA(PSV)) were compared with the percentage of angiographically determined stenosis. Receiver operating characteristic curves were generated for levels of stenosis > or =60% and > or =70%. Doppler thresholds were chosen on the basis of maximum accuracy and on the basis of > or =90% sensitivity and specificity. Patients were then segregated into symptomatic and asymptomatic cohorts, and the above process was repeated. An effectiveness analysis was also conducted using various Doppler thresholds. Thresholds derived using these three methods were compared and optimal values chosen. RESULTS. Of 333 carotid arteries that fit inclusion criteria, 132 were found in asymptomatic patients and 201 in symptomatic patients. Maximum accuracy, > or =90% sensitivity and specificity, and effectiveness analysis each produced different ranges of thresholds. We chose final thresholds that maintained patient outcome profiles. For asymptomatic patients at the > or =60% stenosis level, thresholds were ICA(PSV) = 200 cm/sec and ICA(PSV)/CCA(PSV) = 3.0. For symptomatic patients with stenosis > or =70%, thresholds were ICA(PSV) = 175 cm/sec and ICA(PSV)/CCA(PSV) = 2.5. CONCLUSION: Considerable latitude exists in the choice of carotid Doppler thresholds. We propose a rational strategy for threshold selection based on a combination of three commonly used methods. Our observations indicate that it appears advisable to consider symptomatic and asymptomatic patients separately and to apply appropriately derived thresholds.     

Influence of surgery on renal amyloidosis

It is well known that renal amyloidosis (RA) leads to ESRD in a few years. This evolution may be accelerated by several factors such as steroids, renal vein thrombosis, infections or surgery. We report 22 patients (14M,8F) mean age = 41.6 years (13-72) with RA in whom surgery revealed or aggravated renal disease. The group I includes 15 patients with no previous history of renal disease and who developed oedema few days after surgery with acute renal failure in 5 of them. Proteinuria was present in all the cases with a nephrotic syndrome in 10. Percutaneous kidney biopsy (KB) showed renal amyloidosis in all patients (AA+ = 8 cases, AA- = 3 cases). Only 9 patients were followed-up (mean period = 40 months): 2 patients are stationary; 1 is on complete remission 2 are on HD and 4 died. The group II includes 7 patients with a previous history of nephropathy (Histologically proven amyloidosis: 3 CRF = 1, Oedema: 3). All these patients developed oedema few days after surgery with acute RF in 4 patients. KB performed in all of them showed RA (AA+ = 33, AA- = 1). 6 patients were followed up for a mean period of 11 months: 5 died, 1 patient is on HD. The influence of surgery on renal amyloidosis is often unforeseeable. It may have no effect on renal disease, but very often it reveals RA and sometimes dramatically aggravates the course of the disease with occurrence of irreversible CRF. The pathogenic role of surgery on RA is discussed.     

Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies

Deformable vesicles and traditional liposomes were compared as delivery systems for oestradiol to elucidate possible mechanisms of drug delivery through human skin. Accordingly, epidermal permeation of oestradiol from optimized deformable vesicles and traditional liposome formulations was studied under low dose non-occluded conditions. Five mechanisms were investigated. A free drug mechanism compared low-dose permeation through skin with drug release determined after separation of the free drug. Penetration enhancement was researched by studying skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored by dipping stratum corneum into different formulations for 10 min and determining drug uptake. The possibility that intact vesicles permeate through the epidermis was tested by comparing permeation from 136-nm vesicles with that from >500-nm vesicles, assuming that penetration depends on vesicle size. The possibility that different entrapment efficiencies in alternative formulations could be responsible for the difference in delivery was also evaluated. Lipid vesicles improved the skin delivery of oestradiol compared with delivery from an aqueous control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable vesicles were thus superior to traditional liposomes. Drug release was negligible over the period during which skin flux was maximum. Pretreatment with empty vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29-fold. Relative flux values obtained from small and large vesicles were similar. No correlation was found between entrapment efficiency and skin delivery. The results showed no evidence of a free drug mechanism, but revealed a possible penetration-enhancing effect for pure PC vesicles, although this was not the only mechanism operating. The positive uptake suggested that lipid vesicles increased drug partitioning into the skin. The data provided no evidence for in-vitro liposome penetration through skin as distinct from vesicle penetration into the stratum corneum.     

Reliability of the International Prostate Symptom Score in the Assessment of Patients With Lower Urinary Tract Symptoms and/or Benign Prostatic Hyperplasia

Purpose

The reliability of the International Prostate Symptom Score (I-PSS) was tested in patients with lower urinary tract symptoms and/or benign prostatic hyperplasia.

Materials and Methods

A total of 71 consecutive men with benign prostatic hyperplasia and/or lower urinary tract symptoms was asked to complete the I-PSS at baseline and 8 weeks later. At the second visit the physician also completed the I-PSS according to the complaints of the patient. Variability between both scores was evaluated by calculation of duplo errors and results were compared to the clinical data.

Results

A considerable variability existed between the I-PSS results obtained at baseline and 8 weeks. The duplo error was 4.3. In a regression analysis of I-PSS, including all clinical parameters, only free flow had some predictive value for I-PSS outcomes.

Conclusions

It is important to consider the variability of the I-PSS score when making decisions concerning treatment.     

Screening of some food poisoning bacteria in sausage and hamburger meat

Microbial investigation of 30 samples of sausage meat and 30 samples of hamburger meat, freshly prepared, were collected randomly from different markets in Alexandria city, to determine the bacteriological status of these products. The average counts/gm of total bacteria, total coliforms and fecal coliform in sausage meat were 1.33 x 10(7), 9.16 x 10(5) and 1.11 x 10(3) respectively, and in hamburger samples were 8.47 x 10(5), 2.63 x 10(3) and 1.35 x 10(3) respectively. Shigella, Escherichia coli, Staphylococcus aureus and Proteus spp were isolated with various percentages, whereas Salmonella spp was isolated from sausage only. The public health importance of the isolated microorganisms are fully discussed.     

GABA-Mediated Presynaptic Inhibition in Crayfish Primary Afferents by Non-A,Non-B GABA Receptors

GABAergic presynaptic inhibition has been investigated in primary afferents using an in vitro preparation of the crayfish, Procambarus clarkii. Presynaptic terminals of a leg proprioceptor, the coxo-basal (CB) chordotonal organ, were impaled in the neuorpil of the 5th thoracic ganglion. Pressure ejection of small volumes of the GABAA or GABAB receptor agonists, muscimol and 3-aminopropylphosphinic acid (3-APA), both induce depolarizing responses in the impaled CB sensory terminal. These depolarizations are not blocked by the specific GABAA and GABAB receptor antagonists, SR-95531 and phaclofen, but they are abolished by picrotoxin. Both muscimol- and 3-APA-induced depolarizations are carried by an increase in conductance to Cl-. The presynaptic increase in conductance to Cl- by GABA receptor activation leads to a depression of sensory synaptic transmission through a shunting of the incoming spikes. Monosynaptic EPSPs elicited in motor neurons by CB sensory nerve stimulation are depressed by muscimol and 3-APA. GABA-mediated presynaptic modulation occurs in crayfish primary afferents which can adjust the gain of reflexes. These results show that GABA-activated Cl- channels can induce a modulation of synaptic transmission, but also that the distinction between GABAA and GABAB receptors, as in vertebrates, is not applicable to the crustacean primary afferents.     

Cultural aspects of delusions: a psychiatric study of Egypt.

This paper deals with the cultural elements of the delusions of a sample of Egyptian psychiatric patients. After examination of clinical records, interviewing psychiatrists and reviewing literature, the author reaches the conclusion that the content of the patient's delusion varies directly in relation to his social class. For most of the low class men and women, the delusional symptoms, either megalomaniac or persecutory were fantasied in terms of the cultural religious institutions. Middle and upper class patients, however, much more frequently "secularized" their restitutive narcissistic and self esteem delusions in terms of science and class conception of power.