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Biomedical subjects

G H Smith

Publications and source records attributed to G H Smith.

At least 19 recordsLinked to original sources
PubMed2004

Interventions for primary vesicoureteric reflux.

BACKGROUND: Vesicoureteric reflux (VUR) results in urine passing, in a retrograde manner, up the ureter. Urinary tract infections (UTIs) have been considered to be the main cause of permanent renal parenchymal damage in children with reflux. Therefore management of these children has been directed at preventing infection by antibiotic prophylaxis and/or surgical correction of reflux. However controversy remains as to the optimum strategies for management of children with primary VUR. OBJECTIVES: To evaluate the benefits and harms of the different treatment options for primary VUR. SEARCH STRATEGY: Published and unpublished randomised controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, reference lists of articles and abstracts from conference proceedings. SELECTION CRITERIA: RCTs were included if they compared any treatments of VUR including surgery (open and closed techniques), antibiotic prophylaxis of any duration, non-invasive techniques such as bladder training and any combination of therapies. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched the literature, determined trial eligibility, assessed quality, extracted and entered data. For dichotomous outcomes, results were expressed as relative risk (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model. MAIN RESULTS: Ten trials involving 964 evaluable children comparing long-term antibiotics and surgical correction of VUR with antibiotics (seven trials), antibiotics with no treatment (one trial) and different materials for endoscopic correction of VUR (two trials) were identified. Risk of UTI by 1-2 and 5 years was not significantly different between surgical and medical groups (by 2 years RR 1.07, 95% CI 0.55 to 2.09; by 5 years RR 0.99; 95% CI 0.79 to 1.26). Combined treatment resulted in a 60% reduction in febrile UTI by 5 years (RR 0.43, 95% CI 0.27 to 0.70) but no concomitant significant reduction in risk of new or progressive renal damage at 5 years (RR 1.05, 95% CI 0.85 to 1.29). In one small study no significant differences in risk for UTI or renal damage were found between antibiotic prophylaxis and no treatment. REVIEWERS' CONCLUSIONS: It is uncertain whether the identification and treatment of children with VUR confers clinically important benefit. The additional benefit of surgery over antibiotics alone is small at best. Assuming a UTI rate of 20% for children with VUR on antibiotics for five years, nine reimplantations would be required to prevent one febrile UTI, with no reduction in the number of children developing any UTI or renal damage.

Antibiotic Prophylaxis↗
PubMed2003

Cylinder gratings in conical incidence with applications to woodpile structures.

We use our previous formulation for cylinder gratings in conical incidence to discuss the photonic band gap properties of woodpile structures. We study scattering matrices and Bloch modes of the woodpile, and use these to investigate the dependence of the optical properties on the number of layers. We give data on reflectance, transmittance and absorptance of metallic woodpiles as a function of wavelength and number of layers, using both the measured optical constants of tungsten and using a perfect conductivity idealization to characterize the metal. For semi-infinite metallic woodpiles, we show that polarization of the incident field is important, highlighting the role played by surface effects as opposed to lattice effects.

Journal Article↗
PubMed2002

Cylinder gratings in conical incidence with applications to modes of air-cored photonic crystal fibers.

We develop a formulation for cylinder gratings in conical incidence, using a multipole method. The theory, and its numerical implementation, is applied to two-dimensional photonic crystals consisting of a stack of one-dimensional gratings, each characterized by its plane wave scattering matrix. These matrices are used in combination with Bloch's theorem to determine the band structure of the photonic crystal from the solution of an eigenvalue problem. We show that the theory is well adapted to the difficult task of locating the complete band gaps needed to support air-guided modes in microstructured optical fibers, that is, optical fibers in which the confinement of light in a central air hole is achieved by photonic band-gap effects in a periodic cladding comprising a lattice of air holes in a glass matrix.

Journal Article↗
PubMed2002

Cellular expression of estrogen and progesterone receptors in mammary glands: regulation by hormones, development and aging.

At present, there is an extensive body of literature documenting the participation of estrogen receptors (ER) and progesterone receptors (PR) in mammary gene expression. Yet, the precise roles of these receptors in regulating mammary development, carcinogenesis and the growth of a subset of tumors still remain unclear. Mammary glands are composed of various cell types with different developmental potentials. Further, ultimately, that it is their mutual interactions which dictate the behavior of mammary epithelial cells. Therefore, to resolve the roles of ER and PR in normal mammary growth, differentiation and carcinogenesis, analyses for the expression of these receptors at the level of individual cell types is of paramount importance. Accordingly, in the present studies using immunolocalization techniques, we document the ontogeny and cellular distribution of ER and PR during mammary development and in response to ovarian hormones and aging. In addition, we discuss the potential biological significances of the expression patterns of ER and PR during various physiological states. We believe that the observations reported here should provide a conceptual framework(s) for elucidating the roles of ER and PR in normal and neoplastic mammary tissues.

Aging↗
PubMed2001

Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium.

Functional development of mammary epithelium during pregnancy depends on prolactin signaling. However, the underlying molecular and cellular events are not fully understood. We examined the specific contributions of the prolactin receptor (PrlR) and the signal transducers and activators of transcription 5a and 5b (referred to as Stat5) in the formation and differentiation of mammary alveolar epithelium. PrlR- and Stat5-null mammary epithelia were transplanted into wild-type hosts, and pregnancy-mediated development was investigated at a histological and molecular level. Stat5-null mammary epithelium developed ducts but failed to form alveoli, and no milk protein gene expression was observed. In contrast, PrlR-null epithelium formed alveoli-like structures with small open lumina. Electron microscopy revealed undifferentiated features of organelles and a perturbation of cell-cell contacts in PrlR- and Stat5-null epithelia. Expression of NKCC1, an Na-K-Cl cotransporter characteristic for ductal epithelia, and ZO-1, a protein associated with tight junction, were maintained in the alveoli-like structures of PrlR- and Stat5-null epithelia. In contrast, the Na-Pi cotransporter Npt2b, and the gap junction component connexin 32, usually expressed in secretory epithelia, were undetectable in PrlR- and Stat5-null mice. These data demonstrate that signaling via the PrlR and Stat5 is critical for the proliferation and differentiation of mammary alveoli during pregnancy.

Animals↗
PubMed2001

Evidence for the transforming activity of a truncated Int6 gene, in vitro.

Int6/eIF3-p48 was first identified as a common integration site for MMTV in mouse mammary tumors. In all cases, the MMTV integration event resulted in an interruption of the normal Int6 transcript from one allele leaving the second allele intact and operative. We hypothesize that insertion of MMTV into Int6 results in a mutated allele that encodes a shortened Int6 mRNA and protein (Int6sh), which either modifies normal Int6 function or possesses a new independent function. To confirm the transforming potential of the mutation and its dominant function, we transfected two mammary epithelial cell lines, MCF10A (human), and HC11 (mouse), with Int6sh under the control of the elongation factor-1alpha (eEF1A) promoter. Expression of Int6sh in MCF10A and HC11 mammary epithelial cells leads to anchorage-independent growth in soft agar indicative of a transformed phenotype. Colonies selected from agar exhibited high levels of mutated Int6sh and wild type Int6 RNA transcripts by RT-PCR and Northern blot analysis. In addition, Int6sh transformed MCF10A and HC11 cells formed nodular growths, in vivo, in immune compromised hosts. NIH3T3 cells, mouse embryo fibroblasts, were also transformed to anchorage-independent growth in vitro by Int6sh expression. These observations provide direct evidence that the Int6 mutations observed in MMTV-induced tumors and hyperplasia contribute to the malignant transformation of the mammary epithelial cells.

3T3 Cells↗
PubMed2001

Impairment of mammary lobular development induced by expression of TGFbeta1 under the control of WAP promoter does not suppress tumorigenesis in MMTV-infected transgenic mice.

It has previously been shown that transgenic female mice expressing TGFbeta1 under control of regulatory elements of the whey-acidic protein (WAP) gene were unable to lactate. This was due to the increased apoptosis of the cells committed to the lobular-lactogenic phenotype. Our goal was to determine whether the expression of WAP-TGFbeta1 transgene could inhibit MMTV (mouse mammary tumor virus) tumorigenic activity in the mammary gland. It is well known that the infection with this virus produces focal hyperplastic secretory nodules (HANs) and, some variants can also induce ductal pregnancy-dependent lesions (plaques). In either case, MMTV infection leads ultimately to the appearance of malignant mammary tumors. The results shown herein demonstrate that TGFbeta1 expression in the secretory mammary epithelium does not suppress mammary tumorigenesis in MMTV infected mice. Although MMTV infected WAP-TGFbeta1 transgenic females displayed a strong impairment of lobule-alveolar development, carcinogenesis induced by any of the four MMTV variants used herein proceeded unabated. WAP-TGFbeta1 tumors that showed a strong expression at the WAP promoter, appeared later and grew more slowly than their wild-type counterparts. Transgenic females also had a lower incidence of HANs and plaques. Our study suggests that the epithelial target cells for tumorigenic mutations are probably progenitor cells that are not susceptible to the apoptotic effect of TGFbeta1. Alternatively, their daughters cells that display the secretory phenotype and could be more involved in the formation of premalignant lesions continue to die due to the expression of the transgene.

Animals↗
PubMed2001

Reducing mammary cancer risk through premature stem cell senescence.

The reproductive capacity of the mammary epithelial stem cell is reduced coincident with the number of symmetric divisions it must perform. In a study of FVB/N mice with the transgene, WAP-TGFbeta1, we discovered that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-beta1. To test whether premature aging of mammary epithelial stem cells would have an impact on susceptibility or resistance to mammary cancer, female littermates from FVB/N x WAP-TGF-beta1 mating were injected with mouse mammary tumor virus (MMTV) at 8-10 weeks of age. A total of 44 females were inoculated, maintained as breeders and observed for tumor development for up to 18 months. Only one mammary tumor appeared in 17 TGF-beta1 females while 15 were collected from 29 wild type sisters. Premalignant mammary epithelial cells in infected glands were identified by transplantation of single cell (1 x 10(5)) suspensions into nulliparous hosts and testing for hyperplastic outgrowth. Although the number of positive takes was significantly reduced with TGF-beta1 cells, both MMTV-infected TGF-beta1 and wild type cells produced hyperplastic outgrowths suggesting that premalignant transformation was achieved in each group. The results suggest a positive correlation between the procreative life-span of mammary epithelial stem cells and mammary cancer risk.

Animals↗
PubMed2001

Mammary epithelial stem cells.

It has recently been shown that the progeny from a single cell may comprise the epithelial population of a fully developed lactating mammary outgrowth in mice. Serial transplantation of epithelial fragments from this clonally derived gland demonstrates that the subsequently generated outgrowths are also comprised of progeny from the original antecedent. All epithelial cell types were found to be present within these clonal normal populations including luminal, myoepithelial, ductal, and lobule-committed epithelial progenitors and fully competent mammary epithelial stem cells. These observations demonstrate the presence of multipotent tissue-specific epithelial stem cells among the parenchyma of the murine mammary gland. Similarly, genetic analysis of contiguous portions of individual human mammary ducts within the same breast indicates their clonal derivation. Here, we discuss the properties, location, division-potential, senescence, and plasticity associated with mammary epithelial stem cells and present the developing evidence for their presence in human breast and their important role in the risk for breast cancer development. Further, we review the present morphologic and genetic evidence for the characterization of specific stem cell markers and lineage-limited progenitor cells in human and rodent mammary epithelium. Microsc. Res. Tech. 52:190-203, 2001. Published 2001 Wiley-Liss, Inc.

Animals↗
PubMed2001

Plasmapheresis in the treatment of an acute pancreatitis due to protease inhibitor-induced hypertriglyceridemia.

The use of protease inhibitors such as ritonavir to treat HIV-infected individuals has been associated with lipodystrophy, combined hyperlipidemias, and hypertriglyceridemia-induced pancreatitis. We report here on the treatment by plasmapheresis of a HIV-patient who presented with a rapid onset of severe ritonavir-induced hypertriglyceridemia complicated with an acute pancreatitis. A 35-year-old HIV-1 positive male following 3 weeks of ritonavir treatment presented with nausea, abdominal pain, a distended abdomen, and the following laboratory values: amylase (238 U/L), lipase (864 U/L), total cholesterol (27.1 mmol/L), and triglycerides (62.9 mmol/L). Following two plasmaphereses, the levels of total cholesterol, triglycerides, lipase, and amylase declined drastically and the patient was discharged home after 4 days with lipid and pancreatic enzyme levels within the reference range. To our knowledge, this is the first case of pancreatitis due to a PI-induced hyperlipidemia in a HIV-patient treated with plasmapheresis in an acute setting.

Acute Disease↗
PubMed2001

HOSE: an objective scoring system for evaluating the results of hypospadias surgery.

OBJECTIVE: To determine the accuracy and utility of a scoring system designed to allow an objective appraisal of the outcome of hypospadias repair, based on evaluating meatal location, meatal shape, urinary stream, straightness of erection, and the presence and complexity of any complicating urethral fistula. PATIENTS AND METHODS: Twenty patients (median age 23 months) were randomly selected and reviewed at a median of 8.9 months after their hypospadias repair. Two paediatric surgeons, a nurse and one of the child's parents independently assessed each patient using the "hypospadias objective scoring evaluation" (HOSE) system. The results were collated and the level of interobserver variation assessed using the weighted kappa test. RESULTS: The mean weighted kappa was 0.66, indicating good agreement among observers. The level of agreement was highest between surgeon and nurse at 0.70, but remained good between surgeon and parent, at 0.65. CONCLUSIONS: Interobserver variation using the HOSE system was minimal, supporting its use as an objective outcome measure after hypospadias surgery, and facilitating an impartial evaluation of operations used in correcting hypospadias.

Child↗
PubMed2000

Notch signaling is essential for vascular morphogenesis in mice.

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the Notch4 gene, we generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.

Age Factors↗
PubMed2000

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways.

The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to fix the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary differentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are reflected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

Animals↗
PubMed2000

Clinical review of the 'Snodgrass' hypospadias repair.

BACKGROUND: Snodgrass first described the tubularized, incised plate (TIP) urethroplasty for distal hypospadias repair in 1994 based on the concept of hingeing the incised urethral plate. The use of this technique allows a vertically orientated glanular meatus to be produced. A retrospective review of patients who had this procedure for the primary repair of distal hypospadias at New Children's Hospital was performed to objectively assess the cosmetic and functional outcomes of this technique. METHODS: All patients having a TIP urethroplasty for the primary repair of distal hypospadias between 1996 and 1998 were requested to attend for review in an independent clinic. The parents were interviewed and the patient was examined to determine meatal location, meatal size, glanular configuration, urinary stream, straightness of erections, cosmesis, and the presence or absence of cutaneous sinus tracts or a urethral fistula. RESULTS: Sixty patients were identified. Forty-nine were reviewed in person, 10 were reviewed by telephone and one could not be traced. The median age at surgery was 13 months (range: 6-144 months), with a median follow up of 27 months (range: 2-33 months). A glanular meatus was achieved in 57 patients (97%) and a conical glanular configuration was achieved in 58 patients (98%). The urinary stream and erections were straight in 54 (89%) and 58 patients (98%), respectively. Suture sinus tracts were present in 14 (24%) patients. Six patients (10%) developed a urethral fistula and three (5%) developed meatal stenosis. A good or satisfactory final cosmetic and functional result was achieved in 58 patients (98%). CONCLUSIONS: The results of TIP urethroplasty are satisfactory at New Children's Hospital with the benefit of a cosmetic final outcome similar to a circumcised penis.

Child↗
PubMed2000

The upper range of lumbar spine bone mineral density? An examination of the current world record holder in the squat lift.

Weight-bearing exercise is known to improve bone mineral density, however, excessive forces exerted on the lumbar spine can be pathologic. Cadaveric studies have calculated a hypothetical "critical compression force" at which the lumbar spine would suffer collapse. In addition, recent studies have suggested that bone density correlates with strength. Thus far studies have failed to examine elite power athletes to determine the possible upper range for bone mineral density and critical compression force. Therefore, we recruited the current world record holder in the squat lift, with a record squat lift >469 kg, for an examination of lumbar spine bone mineral density. The subject had dual energy x-ray absorptometry (DEXA) and magnetic resonance imaging (MRI) performed of the lumbar spine. The subject also had serum chemistries, cell blood count and testosterone levels performed. DEXA scan revealed the highest bone mineral density reported to date. MRI revealed normal alignment, no evidence of disc herniation or compressive disc disease. There was no frank or neural foraminal canal stenosis. The estimated compressive force generated on his lumbar spine during the squat lift of > 469 kg doubles the previously reported critical compression force. This case study supports the previously described relationship between strength and bone density and redefines the upper limits of bone density in strength athletes.

Absorptiometry, Photon↗
PubMed2000

Middle cerebral artery blood flow velocity in elite power athletes during maximal weight-lifting.

Cerebral blood flow velocity (CBFV) has been shown to significantly increase during dynamic exercise (running) secondary to increases in cardiac output. Static exercise (weight-lifting) induces supraphysiological arterial pressures up to 450/380 mmHg, and thus may alter CBFV. Catastrophic brain injuries such as stroke, cerebral hemorrhage, subarachnoid hemorrhage, retinal hemorrhage and retinal detachment have been associated with weight-lifting. A recent study has shown that intra-ocular pressure (IOP), which is an indirect measure of intracranial pressure, elevates to pathophysiologic levels during weight-lifting. Recent CBFV studies instituting Valsalva have demonstrated decreases in CBFV from 21%-52%. To date, no studies have examined CBFV during maximal weight-lifting to elucidate the cerebrovascular responses to extreme pressure alterations. We recruited nine elite power athletes, including a multi-world record holder in powerlifting, for a transcranial Doppler study of middle cerebral artery blood flow velocity at rest and during maximal weight-lifting. All subjects' resting blood flow velocities were within normal ranges (mean 64.4 +/- 9.5 cm sec2). Blood flow velocities were significantly (p < 0.0001) decreased in all subjects during maximal lifting (mean 48.4 +/- 10.1 cm sec2). Linear regression analysis demonstrated a significant inverse linear relationship in the net change of blood velocities from rest to maximal lift for each subject (r = 0.8585, p < 0.001). This study demonstrates that blood flow velocities are significantly decreased during heavy resistance training. The drop in CBFV during weight-lifting was significantly less than previous Valsalva studies, which likely reveals the cardiovascular, baroreflex, and cerebrovascular system adaptations occurring in these elite power athletes.

Adult↗
PubMed2000

Effect of the depth and width of the urethral plate on tubularized incised plate urethroplasty.

PURPOSE: We determined the effect of the depth and width of the urethral groove on tubularized incised plate urethroplasty for distal hypospadias. MATERIALS AND METHODS: We retrospectively reviewed the records of 48 patients who underwent tubularized incised plate urethroplasty for distal hypospadias between September 1996 and December 1998 for whom preoperative evaluation of the depth and width of the urethral groove was available. Patients were examined by an independent clinician a median of 28 months after surgery when the neourethra was calibrated and urinary stream assessed. RESULTS: Of the 48 patients 46 were available for clinical examination. The urinary stream was straight in 40 boys and angled in 8, while none sprayed. Urethral fistula developed in 6 patients with a urethral plate of less than 8 mm. wide (p = 0.001). The urethral groove was deep in 13 cases, moderate in 20 and shallow in 15. There were no differences among these 3 groups in regard to urinary stream direction or fistula rate. Of the boys with a shallow urethral groove 6 (40%) have a neourethral caliber of 6Fr or less versus 3 (15%) with a moderate and 0 with a deep groove. This difference was statistically significant (p = 0.028). Each patient in whom meatal stenosis developed had a shallow urethral groove. CONCLUSIONS: Urethral groove depth appears to influence neourethral caliber after tubularized incised plate urethroplasty. A shallow groove predisposes to a narrower neourethra and meatal stenosis subsequently. We observed no evidence that incising the urethral plate increases the final urethral diameter. Urethral fistula after tubularized incised plate urethroplasty was associated with an initially narrow urethral plate.

Adolescent↗