The changing role for extended resections in an era of advanced radiotherapy techniques and novel therapies in gynaecological malignancy.

Pelvic exenteration, first described in 1948 and subsequently refined, may be offered as a last hope of cure to patients with recurrent or locally advanced pelvic tumours, where radiotherapy is not an option. It is a complex, morbid, ultra-radical procedure involving en-bloc resection of the female reproductive organs, lower urinary tract, and a portion of the rectosigmoid. This article discusses the evolution of and current indications for pelvic exenteration in gynaecologic oncology as well as the reasons for its decline: primary and secondary prevention of cervical cancer (the recurrence of which is the most common indication for exenteration); improvements in treatment of cervical, endometrial, vaginal and vulvar cancer in the primary and recurrent setting; and the advent of novel therapies.

Evaluating the impact of dose reductions and delays on progression-free survival in women with ovarian cancer treated with either three-weekly or dose-dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort study.

OBJECTIVES: To determine the impact of chemotherapy dose reductions and dose delays on progression-free survival (PFS) in women with ovarian cancer receiving first line chemotherapy in a real world prospective cohort study. METHODS: Patients with newly diagnosed epithelial ovarian (or peritoneal, fallopian tube) cancer enrolled in a national Australian prospective study, OPAL, who commenced three-weekly carboplatin (AUC 5 or 6) and paclitaxel 175 mg/m2 (CP) or carboplatin (AUC 5 or 6) and dose-dense weekly paclitaxel 80 mg/m2 (DD-CP) were eligible. Primary endpoint was PFS. RESULTS: 634 evaluable patients, 309 commenced CP and 325 DD-CP. Patient's age was similar in the two groups (median 62 years, range 21-79). All planned chemotherapy doses were completed by 66% vs 40% (p < 0.001) in the CP and DD-CP groups respectively. There was at least one treatment delay in 28% vs 58% (p < 0.001) in the CP and DD-CP groups, respectively, and 29% vs 49% (p < 0.001), respectively, required at least a 15% dose reduction for either carboplatin or paclitaxel. Median PFS was 29.2 [22.9, 43.8] and 21.5 [19.4, 23.1] months in the CP and DD-CP groups respectively. Adjusting for age, histology and FIGO stage PFS did not differ between treatment groups. Median PFS was similar in patients irrespective of dose reduction or dose delay. CONCLUSION: Patients receiving DD-CP required more dose reductions and delays due to haematological toxicities and lower completion rates than CP without significant difference in median PFS between CP and DD-CP. Median PFS was similar in patients irrespective of dose reduction or dose delay.

Hong Kong's domestic health spending--financial years 1989/90 through 2004/05.

This report presents the latest estimates of Hong Kong's domestic health spending between fiscal years 1989/90 and 2004/05, cross-stratified and categorised by financing source, provider and function on an annual basis. Total expenditure on health was HK$67,807 million in fiscal year 2004/05. In real terms, total expenditure on health showed positive growth averaging 7% per annum throughout the period covered in this report while gross domestic product grew at 4% per annum on average, indicating a growing percentage of health spending relative to gross domestic product, from 3.5% in 1989/90 to 5.2% in 2004/05. This increase was largely driven by the rise in public spending, which rose 9% per annum on average in real terms over the period, compared with 5% for private spending. This represents a growing share of public spending from 40% to 55% of total expenditure on health during the period. While public spending was the dominant source of health financing in 2004/05, private household out-of-pocket expenditure accounted for the second largest share of total health spending (32%). The remaining sources of health finance were employer-provided group medical benefits (8%), privately purchased insurance (5%), and other private sources (1%). Of the $67,807 million total health expenditure in 2004/05, current expenditure comprised $65,429 million (96%) while $2378 million (4%) were capital expenses (ie investment in medical facilities). Services of curative care accounted for the largest share of total health spending (67%) which were made up of ambulatory services (35%), in-patient curative care (28%), day patient hospital services (3%), and home care (1%). The next largest share of total health expenditure was spent on medical goods outside the patient care setting (10%). Analysed by health care provider, hospitals accounted for the largest share (46%) and providers of ambulatory health care the second largest share (30%) of total health spending in 2004/05. We observed a system-wide trend towards service consolidation at institutions (as opposed to free-standing ambulatory clinics, most of which are staffed by solo practitioner). In 2004/05, public expenditure on health amounted to $35,247 million (53.9% of total current expenditure), which was mostly incurred at hospitals (76.5%), whilst private expenditure ($30,182 million) was mostly incurred at providers of ambulatory health care (54.6%). This reflects the mixed health care economy of Hong Kong where public hospitals generally account for about 90% of total bed-days and private doctors (including Western and Chinese medicine practitioners) provide 75% to 80% of out-patient care. While both public and private spending were mostly expended on personal health care services and goods (92.9%), the distributional patterns among functional categories differed. Public expenditure was targeted at in-patient care (54.2%) and substantially less on out-patient care (24.5%), especially low-intensity first-contact care. In comparison, private spending was mostly concentrated on out-patient care (49.6%), whereas medical goods outside the patient care setting (22.6%) and in-patient care (18.8%) comprised the majority of the remaining share. Compared to OECD countries, Hong Kong has devoted a relatively low percentage of gross domestic product to health in the last decade. As a share of total spending, public funding (either general government revenue or social security funds) was also lower than in most comparably developed economies, although commensurate with its public revenue collection base.

Dual fortification of salt with iron and iodine in women and children in rural Ghana.

OBJECTIVE: To test the efficacy of double-fortified salt (DFS) on the anaemia and iodine deficiency (ID) status of women and their children. DESIGN: Double-blind randomised controlled trial. SETTING: Sekyere West District of Ghana. SUBJECTS: In this eight-month trial, mildly anaemic or non-anaemic, non-pregnant, non-lactating women were randomised into three groups receiving: DFS plus weekly placebo (n = 61); iodised salt plus weekly 70 mg iron supplement (n = 65); or iodised salt (IS) plus weekly placebo (control group, n = 58). Correspondingly, their mildly anaemic and non-anaemic children aged 1-5 years were randomised into two groups receiving either the DFS (n = 23) or IS alone (control group, n = 59). RESULTS: At the end of the intervention, prevalence of anaemia in women remained unchanged in the DFS or IS plus weekly iron supplement group, but significantly increased by 19.5% in the control group (P = 0.039). In children, prevalence of anaemia in the DFS group significantly decreased by 21.7% (P = 0.025) while no change was observed in the control group. ID decreased significantly in all groups of women (P < 0.001) and children (P < 0.05), with no difference among groups of women and children. CONCLUSION: While the use of DFS prevented anaemia in women, it had a significant role in both the prevention and treatment of anaemia in children. Both the DFS and IS significantly reduced ID in women and children to a similar degree.

Inter-relationships between DNA damage, ascorbic acid and glycaemic control in Type 2 diabetes mellitus.

AIMS: The onset of complications in Type 2 diabetes mellitus (DM) patients cannot be predicted in individuals. Evidence suggests a link between complications and hyperglycaemia, oxidative stress and antioxidants, but causality is unclear. This study investigated baseline (entry) fasting plasma ascorbic acid, lymphocytic DNA damage and glycaemic control in Type 2 DM as part of a long-term study, the aim of which is to explore a biomarker profiling approach to identify and improve outcome in high-risk subjects. METHODS: A cross-sectional study, in which DNA damage, glycated haemoglobin (HbA(1c)), fasting plasma glucose (FPG) and ascorbic acid (AA) were measured on fasting blood samples collected from 427 Type 2 DM subjects. RESULTS: DNA damage was significantly (P < 0.0001) and directly correlated to both FPG (r = 0.540) and HbA(1c) (r = 0.282), and was significantly (P < 0.0001), independently and inversely correlated to plasma AA (r = -0.449). In those subjects with both poor glycaemic control and low AA (< 48 microm, the overall mean value for the study group), DNA damage was significantly (P < 0.005) higher compared with those subjects with a similar degree of hyperglycaemia but with AA above the mean. CONCLUSIONS: The novel finding of a significant inverse relationship between plasma AA and DNA damage in Type 2 DM indicates that poorly controlled diabetic subjects might benefit from increased dietary vitamin C. The data also have important implications for biomarker profiling to identify those subjects who might benefit most from intensive therapy. Longer-term follow-up is underway.

Treatment of anemia with microencapsulated ferrous fumarate plus ascorbic acid supplied as sprinkles to complementary (weaning) foods.

BACKGROUND: Standard therapy for anemia in infants is ferrous sulfate drops administered 3 times/d. Adherence to treatment, however, is often poor. One likely reason for poor adherence is the unpleasant side effects associated with drops. OBJECTIVE: The objective was to evaluate the use of a new form of iron and a delivery system to treat anemia in infants that is likely to produce better adherence to treatment. DESIGN: Using a prospective, randomized, controlled design, we studied 557 anemic children aged 6-18 mo (hemoglobin: 70-99 g/L) in rural Ghana. One group received a daily sachet of microencapsulated ferrous fumarate (80 mg elemental Fe) in powder form plus ascorbic acid to be sprinkled onto any complementary food eaten (sprinkles group); a control group received ferrous sulfate drops 3 times/d for 2 mo (total dose: 40 mg elemental Fe). Hemoglobin and serum ferritin concentrations were measured at baseline and at the end of treatment. RESULTS: Successful treatment of anemia (hemoglobin > 100 g/L) occurred in 58% of the sprinkles group and in 56% of the drops group, with minimal side effects in both groups. Geometric mean ferritin concentrations increased significantly in each group from baseline to the end of treatment (P < 0.001). CONCLUSION: Use of ferrous sulfate drops or a single daily dose of microencapsulated ferrous fumarate sprinkles plus ascorbic acid resulted in a similar rate of successful treatment of anemia without side effects. To our knowledge, this is the first demonstration of the use of microencapsulated iron sprinkles to treat anemia. Improved ease of use may favor the use of sprinkles to deliver iron.

Randomized, controlled trial of single versus 3-times-daily ferrous sulfate drops for treatment of anemia.

OBJECTIVE: Adherence to treatment of iron-deficiency anemia often is poor in both developed and developing countries. The current standard therapy is ferrous sulfate drops (or syrup) administered 3 times daily. It is possible that adherence would improve with a single-dose daily treatment regimen. We compared the use of single versus 3-times-daily ferrous sulfate drops, at the same total iron dose, on treatment of anemia in infants. METHODS: To obtain a large enough cohort of anemic subjects, we performed the study in rural Ghana. Using a prospective, randomized, controlled design, we studied 557 anemic children (age range: 6-24 months; hemoglobin values: 70-99 g/L). One group (n = 280) received ferrous sulfate drops once daily (40 mg elemental iron), and the control group (n = 277) received ferrous sulfate drops 3 times per day (total dose, 40 mg elemental iron). Treatment lasted for 2 months. Hemoglobin and serum ferritin values were measured at baseline and at the end of the study. RESULTS: Successful treatment of anemia (hemoglobin >100 g/L) occurred in 61% of the single-dose and in 56% of the 3-times-daily group. Geometric mean ferritin levels increased significantly in each group from baseline to the final visit. Side effects were minimal and similar between the 2 groups. CONCLUSION: A single versus a 3-times-daily dose of ferrous sulfate drops over 2 months resulted in a similar rate of successful treatment of anemia, without side effects. To our knowledge, this is the first demonstration of the use of a single-dose daily regimen to treat anemia. Although not examined in the current study, use of a single-dose daily regimen may improve adherence to treatment of anemia in infants.

Intravenous cannula: an instrument and a port in laparoscopic surgery.

BACKGROUND: An intravenous cannula was used experimentally as a cheap and scarless alternative to an endoloop to provide retraction and lumen occlusion. It is also a miniport for introduction of ligatures and small catheters. METHODS: This possibility was explored during standard procedures such as laparoscopic cholecystectomy and laparoscopic appendectomy. RESULTS: This technique was successfully applied in 89% of laparoscopic cholecystectomies and 86% of laparoscopic appendectomies. CONCLUSIONS: In many instances a standard port for laparoscopic instruments was unnecessary, despite the fact that the authors did not intentionally work towards port number reduction for laparoscopic procedures.

Is loss of attachment due to root planning and scaling in sites with minimal probing depths a statistical or real occurrence?

BACKGROUND: Following root planing and scaling many studies have implied an association between a loss of clinical attachment at sites with initially shallow pockets (1 to 3 mm) and gains in attachment level for deeper probing depths. However, these effects are also consistent with a statistical phenomenon referred to as regression towards the mean. This principle suggests that extreme values will moderate the next time they are recorded. The purpose of this report was to estimate the effect that regression towards the mean has on perceived changes in attachment level after root planing and scaling. METHODS: During the initial examination, 2 different investigators conducted 2 full-mouth probings. Two quadrants were randomly selected to be root planed and scaled until the root surfaces were smooth by tactile touch of an explorer. The 2 remaining quadrants were not treated. At 4 to 6 weeks after treatment, another full mouth probing was done. An examiner who was blind to the quadrants that had been scaled measured attachment level and probing depth after therapy. This study design provided periodontal measurements before and after root planing and scaling, measurements before and after a period of 4 to 6 weeks of no therapy, and duplicate measurements at the beginning of the study. RESULTS: Using the repeat examination when no true change could occur, shallow sites (< or =3 mm of probing depth) showed average negative differences between repeat attachment level measurements (-0.23 mm), which mimicked loss of periodontal attachment. Deep sites, (>6 mm) showed average positive values (0.40) mimicking gain in attachment level. These results suggest that regression towards the mean is a significant effect in this data set. Both shallow non-scaled and scaled sites had similar differences in repeat measures (-0.28 mm, -0.25 mm) which were also similar to and not statistically different from changes after therapy for both non-scaled (-0.21 mm) and scaled sites (-0.08 mm). Thus not only does this data set exhibit regression towards the mean, but it explains the majority of perceived loss of periodontal attachment after scaling at sites that have minimal probing depth. CONCLUSIONS: These results suggest that the majority of perceived loss of attachment due to scaling at sites of minimal probing depth that have been reported in many studies may be due a statistical phenomenon called regression towards the mean.

Fractional zinc absorption using a single isotope tracer.

BACKGROUND: Fractional absorption of zinc (Zn) has been measured using dual isotopes of Zn given simultaneously. An oral test dose and an intravenous (i.v.) reference dose are administered, followed by the measurement of the double isotopic enrichment (E) in urine 48 h after administration. We postulated that an estimate of the %E in urine for a given i.v. dose of Zn may be used to eliminate the need for venipuncture and the second Zn isotope. OBJECTIVES: To determine a constant (k) for the Zn enrichment of urine after i.v. administration of a dose of labeled Zn in Zn-replete subjects. To use 'k' to calculate fractional absorption of Zn, and to compare these values to values obtained using the standard dual isotope method. DESIGN: Single-arm cohort. SETTING: The Hospital for Sick Children, Toronto, Canada. SUBJECTS: Twenty-three healthy adults were recruited from the Metropolitan Toronto area. Seventeen subjects completed the study. INTERVENTIONS: A 2.29 mg i.v. dose of (67)Zn followed immediately by a 2.50 mg oral dose of (70)Zn. RESULTS: Population mean percentage enrichment (%E) of (67)Zn in urine was 1.43 (95% CI 1.26, 1.60). The ratio of the i.v. dose to mean %E in urine (k) was estimated to be 1.60 mg (95% CI 1.43, 1.82). There was no difference in the mean fractional absorption of Zn calculated using the single compared to the dual isotope method: 12.58% (95% CI 2.22, 22.94) vs 12.68% (95% CI 4.52, 20.85), respectively (P=0.89). The correlation coefficient between the two methods was 0.81 (P<0.0001). CONCLUSIONS: The dual isotope method may be replaced by using a constant (k) and a single oral dose of isotopic-enriched Zn to estimate fractional absorption of Zn within a population. SPONSORSHIP: Gerber Products Company, Fremont, MI.

Stabilizing and directional selection on facial paedomorphosis : Averageness or juvenilization?

Averageness is purportedly the result of stabilizing selection maintaining the population mean, whereas facial paedomorphosis is a product of directional selection driving the population mean towards an increasingly juvenile appearance. If selection is predominantly stabilizing, intermediate phenotypes reflect high genetic quality and mathematically average faces should be found attractive. If, on the other hand, directional selection is strong enough, extreme phenotypes reflect high genetic quality and juvenilized faces will be found attractive. To compare the effects of stabilizing and directional selection on facial paedomorphosis (juvenilization), graphic morphing and editing techniques were used to alter the appearance of composite faces to make them appear more or less juvenile. Both facial models and judges of attractiveness were from the CSU-Long Beach campus. Although effect sizes for both preferences were large, the effect for averageness was nearly twice that found for juvenilization, an indication that stabilizing selection influences preferences for facial paedomorphosis more so than directional selection in contemporary humans.

Neuroendocrine aging in the female rat: the changing relationship of hypothalamic gonadotropin-releasing hormone neurons and N-methyl-D-aspartate receptors.

The reproductive axis undergoes alterations during aging, resulting in acyclicity and the loss of reproductive function. In the hypothalamus, changes intrinsic to GnRH neurons may play a critical role in this process, as may changes in inputs to GnRH neurons from neurotransmitters such as glutamate. We investigated the effects of age and reproductive status on neuroendocrine glutamatergic NMDA receptors (NRs), their regulation of GnRH neurons, and their expression on GnRH neurons, in female rats. First, we quantified NR subunit messenger RNAs (mRNAs) in preoptic area-anterior hypothalamus (POA-AH) and medial basal hypothalamus (MBH), the sites of GnRH perikarya and neuroterminals, respectively. In POA-AH, NR1 mRNA levels varied little with age or reproductive status. NR2a and NR2b mRNA levels decreased significantly between cycling and acyclic rats. In MBH, NR mRNAs all increased with aging, particularly in acyclic animals. Second, we tested the effects of N-methyl-D,L-aspartate (NMA) on GnRH mRNA levels in POA-AH of aging rats. NMA elevated GnRH mRNA levels in young rats, but decreased them in middle-aged rats. Third, we quantified expression of the NR1 subunit on GnRH perikarya in aging rats using double label immunocytochemistry. NR1 expression on GnRH cell bodies varied with age and reproductive status, with 30%, 19%, and 46% of GnRH somata double labeled with NR1 in young proestrous, middle-aged proestrous, and middle-aged persistent estrous rats, respectively. Thus, 1) the expression of hypothalamic NR subunit mRNAs correlates with reproductive status; 2) changes in NR subunit mRNA levels, if reflected by changes in protein levels, may result in alterations in the stoichiometry of the NR during aging, with possible physiological consequences; 3) the effects of NR activation on GnRH mRNA switches from stimulatory to inhibitory during reproductive aging; and 4) expression of the NR1 subunit on GnRH perikarya changes with reproductive status. These molecular, physiological, and cellular neuroendocrine changes are proposed to be involved in the transition to acyclicity in aging female rats.

CD39L2, a gene encoding a human nucleoside diphosphatase, predominantly expressed in the heart.

E-NTPDases are extracellular enzymes that hydrolyze nucleotides. The human E-NTPDase gene family currently consists of five reported members (CD39, CD39L1, CD39L2, CD39L3, and CD39L4). Both membrane-bound and secreted family members have been predicted by encoded transmembrane and leader peptide motifs. In this report, we demonstrate that the human CD39L2 gene is expressed predominantly in the heart. In situ hybridization results from heart indicate that the CD39L2 message is expressed in muscle and capillary endothelial cells. We also show that the CD39L2 gene encodes an extracellular E-NTPDase. Flow cytometric experiments show that transiently expressed CD39L2 is present on the surface of COS-7 cells. Transfected cells also produce recombinant glycosylated protein in the medium, and this process can be blocked by brefeldin A, an inhibitor of the mammalian secretory pathway. The enzymology of CD39L2 shows characteristic features of a typical E-NTPDase, but with a much higher degree of specificity for NDPs over NTPs as enzymatic substrates. The kinetics of the ADPase activity exhibit positive cooperativity. The predominance of CD39L2 expression in the heart supports a functional role in regulating platelet activation and recruitment in this organ.

Biochemical characterization of CD39L4.

Nucleotides are involved in regulating a number of important processes ranging from inflammation to platelet aggregation. Enzymes that can modulate levels of nucleotides in the blood therefore represent important regulatory components in these physiological systems. CD39L4 is a soluble E-nucleoside triphosphate dephosphohydrolase (E-NTPDase) with specificity for nucleotide diphosphates (NDPs). In this study, stable mammalian and insect cell lines were generated expressing CD39L4 protein to purify and characterize the recombinant protein. We demonstrate that recombinant CD39L4 protein expressed in human embryonic carcinoma 293 cells is glycosylated by comparing the molecular masses before and after glycosidase treatment. Activity measurements of CD39L4 isolated from tunicamycin-treated, transiently transfected COS-7 cells indicate that glycosylation is not required for full ADPase activity. Recombinant human CD39L4 protein isolated from stable insect cells was glycosylated differently, but also demonstrated relative activity comparable to that of the mammalian protein. When denatured by SDS under nonreducing conditions, a fraction of the CD39L4 protein migrates as a 110 kDa disulfide-linked dimer. We determined that the monomer is the most active form of CD39L4 by measuring the activity of sucrose density gradient fractions of monomers and partially purified dimers. The physiological significance of the biochemical and enzymatic characterization is discussed.

Adaptation of post-traumatic angiogenesis in the rabbit knee by apposition of torn ligament ends.

Apposition of torn ligament ends has been shown to have a beneficial effect on healing of the medial collateral ligament; however, the mechanism underlying this improved recovery is unclear. Excessive post-traumatic angiogenesis, an inherent component of soft-tissue regeneration, may be functionally detrimental in relatively hypovascular tissues such as ligaments. The present study therefore examined the relationship between contact of transected ligament ends and vascular remodeling. Female New Zealand White rabbits were subjected to a gap injury, Z-plasty apposition, or sham operation to the midsubstance of the medial collateral ligament. Six weeks after treatment, the volume of vessels supplying the healing zone of the medial collateral ligament, as well as the ipsilateral lateral collateral ligament, posterior cruciate ligament. menisci, and medial capsule, was quantified by carmine red vascular casting. The volume of vessels supplying the neoligamentous scar formed by gap injury to the medial collateral ligament was found to be twice that of ligaments that had undergone the sham operation, and lateral collateral ligament and meniscal vascularity was also augmented in the injured joint. The medial collateral ligaments that underwent Z-plasty apposition exhibited a level of vascularity comparable with that of the control ligaments that had undergone the sham procedure, whereas meniscal and lateral collateral ligament vascularities remained elevated in this group. Capsular and posterior cruciate ligament vascularities were unaffected by gap injury or Z-plasty to the ipsilateral medial collateral ligament. These findings indicate that injury to the medial collateral ligament not only stimulates angiogenesis in the healing ligament, but other ipsilateral soft tissues also undergo vascular remodeling. Furthermore, apposition of an injured medial collateral ligament modifies these pro-angiogenic events, and this may partly explain why contact of torn ligament ends is beneficial for post-traumatic recovery of an injured joint.

Efficacy of meat and iron-fortified commercial cereal to prevent iron depletion in cow milk-fed infants 6 to 12 months of age: a randomized controlled trial.

OBJECTIVE: To determine whether utilization of iron from infant cereal and pureed meat was sufficient to prevent iron depletion and/or anaemia in infants 6 to 12 months old fed whole cow milk (WCM) as their primary milk source. DESIGN: Six-month-old infants were randomized into a treatment group (n = 43) receiving iron-fortified infant cereal (10.2 mg iron), pureed meat (0.75-1.7 mg iron) and WCM for six months or a control group (n = 54) receiving no dietary intervention. Haemoglobin < 110 g/L or ferritin < 10 micrograms/L (measured bi-monthly), confirmed in a second blood sample, defined end-points. RESULTS: Proportion reaching end-point was similar between the treatment (3/43) and control infants (5/54) (p = 0.66). Infants not complying with the protocol were at greater risk of reaching end-point (p = 0.0002). Change in haemoglobin and ferritin across age was similar in both groups. CONCLUSIONS: Iron deficiency is not a concern in WCM-fed infants after six months of age if iron-containing complementary foods are concurrently ingested.

A role for calcitonin gene-related peptide in rabbit knee joint ligament healing.

Knee joint ligament healing has been shown to be improved when the torn ligament ends remain in contact, however, the rationale for these effects is unknown. The sensory neuropeptide calcitonin gene related peptide (CGRP) has potent trophic and vasodilatatory properties and as such is thought to be advantageous in wound repair. In ascertaining a role for CGRP in rabbit medial collateral ligament healing, the present study examined changes in CGRP-like immunoreactivity (CGRP-LI) and CGRP-mediated vasomotor responses in gap injured (non-contact), Z-plasty apposed (contact), and sham operated control medial collateral ligaments. At 6 weeks post-trauma, CGRP-LI decreased in the healing zone of gap injured and Z-plasty apposed medial collateral ligaments compared with controls, and non-contact ligament nerve fibres exhibited an abnormal morphology. Topical administration of CGRP (10(-13) to 10(-9) mol) caused a dose-dependent increase in ligament perfusion in each experimental group of knees. The CGRP-mediated vasodilatation associated with gap injured ligaments was not significantly different from controls (P = 0.06), whereas apposed medial collateral ligaments showed an augmented response to the peptide (P < 0.0005). These findings indicate that the beneficial effects of ligament interposition post-trauma may be related to an enhanced responsiveness to CGRP in conjunction with a more typical re-innervation profile. Conversely, the aberrant characteristics of CGRP-LI nerves occurring in gap injured tissue is suggestive of impaired CGRP release which may explain the poor functional recovery associated with these ligaments.

Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R superoxide dismutase transgenic mice.

In recent years, several mouse models of amyotrophic lateral sclerosis (ALS) have been developed. One, caused by a G86R mutation in the superoxide dismutase-1 (SOD-1) gene associated with familial ALS, has been subjected to extensive quantitative analyses in the spinal cord. However, the human form of ALS includes pathology elsewhere in the nervous system. In the present study, analyses were extended to three motor nuclei in the brainstem. Mutant mice and control littermates were evaluated daily, and mutants, along with their littermate controls, were killed when they were severely affected. Brains were removed after perfusion and processed for Nissl staining, the samples were randomized, and the investigators were blinded to their genetic status. Stereologic methods were used to estimate the number of neurons, mean neuronal volumes, and nuclear volume in three brainstem motor nuclei known to be differentially involved in the human form of the disease, the oculomotor, facial, and hypoglossal nuclei. In the facial nucleus, neuron number consistently declined (48%), an effect that was correlated with disease severity. The nuclear volume of the facial nucleus was smaller in the SOD-1 mutant mice (45.7% difference from control mice) and correlated significantly with neuron number. The oculomotor and hypoglossal nuclei showed less extreme involvement (<10% neuronal loss overall), with a trend toward fewer neurons in the hypoglossal nucleus of animals with severe facial nucleus involvement. In the oculomotor nucleus, neuronal loss was seen only once in five mice, associated with very severe disease. There was no significant change in the volume of individual neurons in any of these three nuclei in any transgenic mouse. These results suggest that different brainstem motor nuclei are differentially affected in this SOD-1 mutant model of ALS. The relatively moderate and late involvement of the hypoglossal nucleus indicates that, although the general patterns of neuronal pathology match closely those seen in ALS patients, some differences exist in this transgenic model compared with the progression of the disease in humans. However, these patterns of cellular vulnerability may provide clues for understanding the differential susceptibility of neural structures in ALS and other neurodegenerative diseases.

Cloning of a novel epidermal growth factor repeat containing gene EGFL6: expressed in tumor and fetal tissues.

The epidermal growth factor (EGF) repeat superfamily of genes often encodes proteins that govern cellular proliferative responses. Using a high-throughput screening by hybridization approach, a novel human EGF repeat superfamily member that maps to human chromosome X was identified. Termed EGFL6, the gene encodes a predicted signal peptide, suggesting that it is secreted. Other predicted features include four and one-half EGF-like repeat domains, two N-linked glycosylation sites, an integrin association motif (RGD), and a tyrosine phosphorylation site. Importantly, its transcripts are expressed in brain and lung tumor and fetal tissues, but are generally absent from normal adult tissues. Implications with respect to cell cycle regulation and oncogenesis are discussed.