Microsurgical resection of solitary intramedullary spinal cord metastases

Two cases of solitary intramedullary spinal cord metastasis treated primarily by surgical excision are presented. It has been generally thought that appropriate management for the rare metastasis within the spinal cord is radiation and corticosteroids. The excellent palliative results obtained in our patients suggest that, in selected cases, surgical removal is technically feasible and can be of considerable benefit to the patient.     

Determination of fluidized bed granulation end point using near-infrared spectroscopy and phenomenological analysis

Simultaneous real-time monitoring of particle size and moisture content by near-infrared spectroscopy through a window into the bed of a fluidized bed granulator is used to determine the granulation end point. The moisture content and particle size determined by the near-infrared monitor correlates well with off-line moisture content and particle size measurements. The measured particle size is modeled using a population balance approach, and the moisture content is shown to follow accepted models during drying. Given a known formulation, with predefined parameters for peak moisture content, final moisture content, and final granule size, the near-infrared monitoring system can be used to control a fluidized bed granulation by determining when binder addition should be stopped and when drying of the granules is complete.     

Carotid endarterectomy: a review

BACKGROUND: Since the validation of carotid endarterectomy (CEA) as an effective means of stroke prevention, there has been renewed interest in its best indications and methods, as well as in how it compares to carotid angioplasty and stenting (CAS). This review examines these topics, as well as the investigation of carotid stenosis and the role of auditing and reporting CEA results. INVESTIGATION: Brain imaging with CT or MRI should be obtained in patients considered for CEA, in order to document infarction and rule out mass lesions. Carotid investigation begins with ultrasound and, if results agree with subsequent, good-quality MRA or CT angiography, treatment can be planned and catheter angiography avoided. An equally acceptable approach is to proceed directly from ultrasound to catheter angiography, which is still the gold-standard in carotid artery assessment. INDICATIONS: Appropriate patients for CEA are those symptomatic with transient ischemic attacks or nondisabling stroke due to 70-99% carotid stenosis; the maximum allowable stroke and death rate being 6%. Uncertain candidates for CEA are those with 50-69% symptomatic stenosis, and those with asymptomatic stenosis > or = 60% but, if selected carefully on the basis of additional risk factors (related to both the carotid plaque and certain patient characteristics), some will benefit from surgery. Asymptomatic patients will only benefit if surgery can be provided with exceptionally low major complication rates (3% or less). Inappropriate patients are those with less than 50% symptomatic or 60% asymptomatic stenosis, and those with unstable medical or neurological conditions. TECHNIQUES: Carotid endarterectomy can be performed with either regional or general anaesthesia and, for the latter, there are a number of monitoring techniques available to assess cerebral perfusion during carotid cross-clamping. While monitoring cannot be considered mandatory and no single monitoring technique has emerged as being clearly superior, EEG is most commonly used. "Eversion" endarterectomy is a variation in surgical technique, and there is some evidence that more widely practiced patch closure may reduce the acute risk of operative stroke and the longer-term risk of recurrent stenosis. CAROTID ANGIOPLASTY AND STENTING: Experience with this endovascular and less invasive procedure grows, and its technology continues to evolve. Some experienced therapists have reported excellent results in case series and a number of randomized trials are now underway comparing CAS to CEA. However, at this time it is premature to incorporate CAS into routine practice replacing CEA. AUDITING: It has been shown that auditing of CEA indications and results with regular feed-back to the operating surgeons can significantly improve the performance of this operation. Carotid endarterectomy auditing is recommended on both local and regional levels.     

School based screening for hypothyroidism in Down's syndrome by dried blood spot TSH measurement.

OBJECTIVE: To determine the feasibility of annual hypothyroid screening of children with Down's syndrome by measuring thyroid stimulating hormone (TSH) on dried blood spots at school, and to describe the outcome in positive children. DESIGN: Establishment of a register of school children with Down's syndrome, and procedures for obtaining permission from parents, annual capillary blood samples, TSH measurement, and clinical assessment of children with TSH values > 10 mU/litre. SUBJECTS: All school age children with Down's syndrome within Lanarkshire and Glasgow Health Boards during 1996-7 and 1997-8. RESULTS: 200 of 214 school children with Down's syndrome were screened. Four of the unscreened children were receiving thyroxine treatment, and only 5 remained unscreened by default. 15 of the 200 children had capillary TSH > 10 mU/litre, and all but 1 had evidence of Hashimoto's thyroiditis. Seven of the 15 children started thyroxine treatment immediately, 6 with a pronounced rise in venous TSH and subnormal free thyroxine (fT4), and one with mildly raised TSH and normal fT4 but symptoms suggesting hypothyroidism. Eight children with mildly raised venous TSH and normal fT4 were left untreated; 1 year after testing positive, fT4 remained > 9 pmol/litre in all cases, but 4 children were started on thyroxine because of a rise in TSH. TSH fell in 3 of the 4 remaining children and there was a marginal rise in 1; all remain untreated. The prevalence of thyroid disease in this population is >/= 8.9%. CONCLUSION: Dried blood spot TSH measurement is effective for detecting hypothyroidism in Down's syndrome and capillary sampling is easily performed at school. The existing programme could be extended to the whole of Scotland within a few years.     

Randomly Amplified DNA Fingerprinting: A Culmination of DNA Marker Technologies Based on Arbitrarily-Primed PCR Amplification

Arbitrarily-primed DNA markers can be very useful for genetic fingerprinting and for facilitating positional cloning of genes. This class of technologies is particularly important for less studied species, for which genome sequence information is generally not known. The technologies include Randomly Amplified Polymorphic DNA (RAPD), DNA Amplification Fingerprinting (DAF), and Amplified Fragment Length Polymorphism (AFLP). We have modified the DAF protocol to produce a robust PCR-based DNA marker technology called Randomly Amplified DNA Fingerprinting (RAF). While the protocol most closely resembles DAF, it is much more robust and sensitive because amplicons are labelled with either radioactive 33P or fluorescence in a 30-cycle PCR, and then separated and detected on large polyacrylamide sequencing gels. Highly reproducible RAF markers were readily amplified from either purified DNA or alkali-treated intact leaf tissue. RAF markers typically display dominant inheritance. However, a small but significant portion of the RAF markers exhibit codominant inheritance and represent microsatellite loci. RAF compares favorably with AFLP for efficiency and reliability on many plant genomes, including the very large and complex genomes of sugarcane and wheat. While the two technologies detect about the same number of markers per large polyacrylamide gel, advantages of RAF over AFLP include: (i) no requirement for enzymatic template preparation, (ii) one instead of two PCRs, and (iii) overall cost. RAF and AFLP were shown to differ in the selective basis of amplification of markers from genomes and could therefore be used in complementary fashion for some genetic studies.     

β-adrenergic and muscarinic agonists modulate inactivation of l-type ca2+ Channel Currents in Guinea-Pig Ventricular Myocytes

The objective of this study was to examine the effects of isoproterenol (isoprenaline) and carbachol upon voltage-dependent inactivation of L-type Ca²⁺ current ( I _Ca,L). I _Ca,L was recorded in guinea-pig isolated ventricular myocytes in the presence and absence of extracellular Ca²⁺ to separate total inactivation and voltage-dependent inactivation. In the presence of Ca²⁺, isoproterenol and carbachol had 'competitive' effects upon the relationships between membrane voltage and I _Ca,L amplitude and inactivation. Neither agonist had a marked effect upon the decay of inward I _Ca,L carried by Ca²⁺. In the absence of Ca²⁺, isoproterenol severely reduced and slowed I _Ca,L inactivation; this effect was reversed by carbachol. Under control conditions decay was dominated by fast inactivation. Isoproterenol reduced fast-inactivating and increased time-independent currents in a dose-dependent manner. These effects were counteracted by carbachol. There was a reciprocal relationship between the amplitude of fast-inactivating and time-independent currents with agonist stimulation. It is concluded that agonist modulation of rapid voltage-dependent inactivation of L-type Ca²⁺ channels involves an 'on-off' switch.     

A novel serine protease of the mammalian HtrA family is up-regulated in mouse uterus coinciding with placentation

This paper characterizes a novel gene, previously identified as uniquely regulated at implantation in mouse uterus. We cloned its full mRNA sequence encoding a serine protease possessing an IGF-binding domain and named it pregnancy-related serine protease (PRSP). PRSP is structurally similar to mammalian HtrA1 (56% amino acid similarity). Northern analysis revealed that the expression of PRSP mRNA was low before pregnancy, but it was increased at implantation and markedly up-regulated post-implantation. In-situ hybridization localized low levels of mRNA expression to the epithelium and stroma during very early pregnancy, but high expression to the decidual cells on day 8.5, primarily at the mesometrial pole where the placenta was forming. By day 10.5, PRSP mRNA was detected in the placenta. We also cloned an alternatively spliced PRSP mRNA that is expressed at a very low level. We located PRSP gene on chromosome 5 and established its intron/exon structure, which unambiguously explains how the two mRNA variants are produced through alternative splicing. Based on PRSP protein domain structure and its unique expression during pregnancy, we propose that PRSP plays an important role in the formation/function of the placenta.     

A pilot study to assess the effect of three short-term treatments on frequent and/or prolonged bleeding compared to placebo in women using Implanon

BACKGROUND: The major side-effect of progestogen-only contraception is disruption of menstrual bleeding patterns, which can lead to a high incidence of early discontinuation. The aim of this study was to compare three treatments with placebo on the duration and recurrence of frequent and/or prolonged bleeding in Implanon users. METHOD: Women between the ages of 18 and 45 years, who had used Implanon for > or =3 months and were experiencing prolonged or frequent bleeding patterns, were recruited at four Australian sites. Subjects were randomized to treatment using computer-generated random number table if they met the World Health Organization criteria for prolonged and/or frequent bleeding in the previous 90 days [Belsey, E.M., Pinol, A.P.Y. and Taskforce on Long-Acting Systemic Agents for Fertility Regulation, World Health Organization (1997) Contraception 55,57-65]. Treatments were: (1) mifepristone 25 mg given twice on day 1 followed by 4 days of twice daily placebo; (2) mifepristone 25 mg given twice on day 1 followed by 4 days of ethinyl estradiol (EE) 20 microg in the morning and placebo at night; (3) doxycycline 100 mg twice daily for 5 days; and (4) placebo twice daily for 5 days. Analysis was by intention to treat. The primary endpoint was the number of days of bleeding and spotting immediately following initiation of the 5 day course of each active therapy compared with placebo. RESULTS: A total of 179 women was assigned to treatment. Both mifepristone in combination with EE and doxycycline alone were significantly more effective in stopping an episode of bleeding {mean 4. 3 days [confidence interval (CI) 3.5-5.2], and 4.8 days (CI 3.9-5.8) respectively} than mifepristone alone or placebo [5.9 days (CI 4.8-7.2) and 7.5 days (CI 6.1-9.1) respectively]. No effect on subsequent bleeding patterns was observed in any treatment group. CONCLUSION: Both mifepristone plus EE and doxycycline alone were significantly more effective than placebo in terminating an episode of bleeding in women with prolonged and/or frequent bleeding using Implanon. We believe that the observed reduction in the number of bleeding days by almost 50% compared to placebo in both the mifepristone combination group and the doxycycline group demonstrates a clinically significant improvement in bleeding patterns and that further trials are needed to compare different combinations of therapy as well as multiple dosing regimens in order to establish which is the most effective treatment option. The effect of repeat administration or combinations of these preparations on long-term bleeding patterns requires further investigation.     

Effective oral chemotherapy for breast cancer: pillars of strength.

Traditionally, anticancer therapy has been dominated by intravenous drug therapy. However, oral agents provide an attractive approach to chemotherapy and use of oral treatments is increasing. We discuss the benefits and challenges of oral chemotherapy from the perspectives of patients, healthcare providers and healthcare funders. Important issues include patient preference, efficacy, compliance, bioavailability, reimbursement, use in special patient populations, financial and staff time savings and flexibility of dosing. We review data for traditional oral agents (e.g. cyclophosphamide, methotrexate), newer oral chemotherapies (e.g. capecitabine), oral formulations of traditionally intravenous agents (e.g. vinorelbine, idarubicin) and new biologic agents under evaluation in breast cancer (e.g. tyrosine kinase inhibitors). Lastly, we review studies of all-oral combination regimens. The wealth of data available and the increasing use of oral agents in breast cancer suggest that many of the concerns and perceptions about oral therapy, including efficacy and bioavailability, have been overcome, and that oral therapy will play a major role in breast cancer management in the future in both the metastatic and adjuvant settings.