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C Garrett

Publications and source records attributed to C Garrett.

At least 19 recordsLinked to original sources
PubMed2006

Acrosome-reacted human sperm in insemination medium do not bind to the zona pellucida of human oocytes.

In the literature there is still confusion whether acrosome-reacted sperm in medium can initiate primary binding to human zona pellucida (ZP). The ability of acrosome-reacted sperm to bind to ZP in vitro can be deduced by measuring the acrosome reaction (AR) of ZP-bound sperm compared with sperm in medium after incubation under different conditions inhibiting the ZP-induced AR. Motile sperm from fertile men, normospermic men and infertile men diagnosed with disordered ZP-induced AR (DZPIAR) were selected by swim-up (2 x 10(6) in 1 mL medium) and incubated for 1-2 h with four oocytes from failed in vitro fertilization (IVF). The acrosome status of sperm was assessed using pisum sativum agglutinin labelled with fluorescein. The ZP-induced AR was inhibited in experiments using sperm from DZPIAR patients, hyper-osmotic medium (400 mOsm/kg) and medium containing soybean trypsin inhibitor (SBTI; 4 mg/mL). Pre-treatment with calcium ionophore was used to create a sperm population with elevated AR. In all experiments with factors inhibiting the ZP-induced AR, the AR was significantly lower for ZP-bound sperm compared with sperm in medium: DZPIAR patients 4% vs. 15%, hyper-osmotic medium 3% vs. 12%, SBTI 2% vs. 12% and SBTI 3% vs. 23% after treatment with calcium ionophore. In conclusion, acrosome-reacted sperm in vitro have significantly reduced, in fact probably zero ability to bind to the ZP.

Acrosome Reaction↗
PubMed2005

Time course of changes in sperm morphometry and semen variables during testosterone-induced suppression of human spermatogenesis.

BACKGROUND: Quantification of changes in semen may give insight into the testosterone (T)-induced disruption of spermatogenesis in man. METHODS: A model analogous to flushing of sperm from the genital tract after vasectomy was used to quantify the time course of semen changes in subjects participating in male contraceptive trials using 800 mg T-implant (n = 25) or 200 mg weekly intramuscular injection (IM-T; n = 33). A modified exponential decay model allowed for delayed onset and incomplete disruption to spermatogenesis. Semen variables measured weekly during a 91-day period after initial treatment were fitted to the model. RESULTS AND CONCLUSIONS: Sperm concentration, total count, motility and morphometry exhibited similar average decay rates (5 day half-life). The mean delay to onset of decline in concentration was 15 (IM-T) and 18 (T-implant) days. The significantly longer (P < 0.005) delays deduced for the commencement of fall in normal morphology (41 days), normal morphometry (40 days) and sperm viability (43 and 55 days), and the change of morphometry to smaller more compact sperm heads are consistent with sperm being progressively cleared from the genital tract rather than continued shedding of immature or abnormal sperm by the seminiferous epithelium. A significant negative relationship was found between lag time and baseline sperm concentration, consistent with longer sperm-epididymal transit times associated with lower daily production rates.

Adult↗
PubMed2005

Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome.

BACKGROUND: Sotos syndrome is characterised by learning difficulties, overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, encompassing NSD1, are responsible for approximately 10% of non-Japanese cases of Sotos. In contrast, a recurrent approximately 2 Mb microdeletion has been reported as responsible for approximately 50% of Japanese cases of Sotos. METHODS: We screened 471 cases for NSD1 mutations and deletions and identified 23 with 5q35 microdeletions. We investigated the deletion size, parent of origin, and mechanism of generation in these and a further 10 cases identified from published reports. We used "in silico" analyses to investigate whether repetitive elements that could generate microdeletions flank NSD1. RESULTS: Three repetitive elements flanking NSD1, designated REPcen, REPmid, and REPtel, were identified. Up to 18 cases may have the same sized deletion, but at least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In most instances, the microdeletion arose through interchromosomal rearrangements of the paternally inherited chromosome. CONCLUSIONS: Frequency, size, and mechanism of generation of 5q35 microdeletions differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were identified from a large case series with a broad range of phenotypes, suggesting that sample selection variability is unlikely as a sole explanation for these differences and that variation in genomic architecture might be a contributory factor. Non-allelic homologous recombination between REPcen and REPtel may have generated up to 18 microdeletion cases in our series. However, at least 15 cannot be mediated by these repeats, including at least seven deletions of different sizes, implicating multiple mechanisms in the generation of 5q35 microdeletions.

Abnormalities, Multiple↗
PubMed2003

Automated semen analysis: 'zona pellucida preferred' sperm morphometry and straight-line velocity are related to pregnancy rate in subfertile couples.

BACKGROUND: Standard semen analysis has low objectivity and reproducibility and is not closely related to fertility. We assess the prognostic value of automated measurements of sperm motility and morphology. METHODS: During 1997-1999, 1191 infertile couples with no known absolute barrier to conception were assessed by conventional semen analysis, and automated measurements of average straight-line velocity (VSL) and the percentage of sperm with characteristics that conform to those of sperm which bind to the zona pellucida of the human oocyte (%Z). During follow-up to 2001, there were 336 natural pregnancies. RESULTS: Only %Z, VSL and female age were independently significantly related to pregnancy rate by Cox regression analysis. Pregnancy rate was higher with above average %Z and VSL, indicating a continuous rather than a threshold relationship. The likelihood of pregnancy within 12 cycles can be evaluated for specific values of %Z, VSL and female age using the Cox regression model. CONCLUSIONS: The automated semen measures of sperm morphometry (%Z) and velocity (VSL) are related to pregnancy rates in subfertile couples and should assist clinicians in counselling subfertile patients about their prognosis for a natural pregnancy. Objective automated methods should replace the traditional manual assessments of semen quality.

Adult↗
PubMed2003

Low proportions of sperm can bind to the zona pellucida of human oocytes.

BACKGROUND: Sperm binding to the zona pellucida (ZP) is required for human fertilization. Under experimental conditions not limited by ZP binding sites, the cumulative numbers of sperm binding tightly to the ZP will asymptote with time to the total number of sperm in the insemination medium capable of binding. METHODS: Numbers of ZP-bound sperm were counted after groups of 10 oocytes were incubated with 2x10(4) motile sperm in 20 micro l droplets. The time-course of sperm binding was measured in three consecutive 2 h incubation periods using fresh oocytes for each period (n = 12). Using the kinetic theory of gases to model sperm-oocyte collision rates, the time-course results were extrapolated to give the total proportion of motile sperm capable of binding to the ZP. ZP binding of sperm after 4 h incubation was studied in 20 fertile and 20 normozoospermic subfertile men. RESULTS: The percentage of motile sperm capable of binding was for fertile men: mean 14% (range 8-25) and for the subfertile: 4.3% (range 0.1-13, P < 0.001). Sperm morphology correlated with the proportion of ZP-bound sperm. CONCLUSIONS: More than 75% of motile sperm from fertile men have no ability to bind to the ZP. This finding has important implications for improvement of semen analysis.

Case-Control Studies↗
PubMed2003

Genetic linkage analysis of a novel syndrome comprising North Carolina-like macular dystrophy and progressive sensorineural hearing loss.

AIM: To characterise the phenotype and identify the underlying genetic defect in a family with deafness segregating with a North Carolina-like macular dystrophy (NCMD). METHODS: Details of the family were obtained from the Moorfields Eye Hospital genetic clinic database and comprised eight affected, four unaffected members, and two spouses. Pedigree data were collated and leucocyte DNA extracted from venous blood. Positional candidate gene and genetic linkage strategies utilising polymerase chain reaction (PCR) based microsatellite marker genotyping were performed to identify the disease locus. RESULTS: The non-progressive ocular phenotype shared similarities with North Carolina macular dystrophy. Electro-oculography and full field electroretinography were normal. Progressive sensorineural deafness was also present in all affected individuals over the age of 20 years. Hearing was normal in all unaffected relatives. Haplotype analysis indicated that this family is unrelated to previously reported families with NCMD. Genotyping excluded linkage to the MCDR1 locus and suggested a potential novel disease locus on chromosome 14q (Z=2.92 at theta=0 for marker D14S261). CONCLUSION: The combination of anomalies segregating in this family represents a novel phenotype. This molecular analysis indicates the disease is genetically distinct from NCMD.

Adolescent↗
PubMed2002

An anti-actin monoclonal antibody inhibits the zona pellucida-induced acrosome reaction and hyperactivated motility of human sperm.

We report an inhibitory effect of an anti-actin monoclonal antibody (mAb) on the human zona pellucida (ZP)-induced acrosome reaction (AR). Motile sperm were incubated with native human ZP for 2 h in medium containing either the anti-actin mAb, an irrelevant control mAb or cytochalasins B or D (40 micromol/l). Sperm bound to the ZP were recovered and the AR was determined by fluorescein-labelled Pisum Sativum agglutinin. Anti-mouse immunoglobulin G (mIgG) Dynabeads, immunofluorescence and immunogold were used to detect the location of the anti-actin mAb in sperm. The anti-actin mAb significantly inhibited the ZP-induced AR (equivalent to cytochalasins), the ionophore A23187-induced AR and hyperactivation of sperm in medium. After incubation with anti-actin mAb, anti-mIgG beads bound to the head of >50% of sperm recovered after binding to the ZP and 10% of sperm remaining in the medium. The proportion of sperm that bound anti-mIgG beads after recovery from binding to the ZP in the presence of the anti-actin mAb was significantly correlated with the ZP-induced AR in the absence of the antibody. Immunofluorescence and immunogold demonstrated entry of the anti-actin mAb into sperm. This study suggests that the sperm plasma membrane becomes permeable to the anti-actin mAb during capacitation and initiation of the AR.

Acrosome Reaction↗
PubMed2002

Hemifacial microsomia, external auditory canal atresia, deafness and Mullerian anomalies associated with acro-osteolysis: a new autosomal recessive syndrome?

We report the combination of hemifacial microsomia, external auditory canal atresia, deafness and acro-osteolysis in several members of a highly consanguineous Asian family. In addition Mullerian anomalies have been found in two female members of the family. The external auditory canal stenosis and Mullerian anomalies in this family are similar to those reported by Winter et al. [(1968) J Pediatr 72 : 88-93] and overlap with those found in Goldenhar syndrome and Mullerian duct/renal aplasia/cervicothoracic somite dysplasia (MURCS), CHARGE and VATER associations. However, to the authors' knowledge, acro-osteolysis has not been reported in patients with any of these conditions. Overall, the findings in this family appear to be unique and the presence of consanguinity suggests an autosomal recessive condition with variable expression.

Abnormalities, Multiple↗
PubMed2002

Dysplastic cortical hyperostosis (Kozlowski-Tsuruta syndrome): report of a second case.

We report a fetus from a pregnancy that was terminated at 26 weeks gestation for hydrops and short limb skeletal dysplasia. The parents were first cousins. Post mortem examination showed pulmonary hypoplasia and hepatomegaly. The radiographs showed shortening and cortical thickening of all long bones. The cortical thickening was most marked in the long bones, ribs, clavicles and scapulae but spared the skull vault, facial bones and pelvis. There were coronal clefts in the lower lumbar vertebrae. The clinical and radiological features of this fetus conform to those reported in a stillborn male by Kozlowski and Tsuruta in 1989 (Br J Radiol 62:376-378). This is the second reported case of this condition and confirms that it is a distinct and recognisable, lethal skeletal dysplasia. The parental consanguinity in our patient suggests that this condition may be inherited in an autosomal recessive manner.

Aborted Fetus↗
PubMed2001

Ischaemic heart disease may predispose to pseudophakic cystoid macular oedema.

PURPOSE: Pseudophakic macular oedema (PMO) is uncommon following uncomplicated phacoemulsification and lens implantation and the cause of infrequent cases is rarely understood. This study was undertaken to determine whether a relationship exists between ischaemic heart disease (IHD) and PMO. METHODS: Retrospective case note review was carried out of 177 (252 eyes) consecutive patients without pre-existing retinal disease who underwent phacoemulsification and intraocular lens implantation during a 12 month period. Patients with a post-operative best corrected visual acuity < 6/9 underwent slit-lamp biomicroscopy and fluorescein angiography to identify PMO. IHD was defined on clinical and electrocardiographic grounds. The incidence of IHD was compared in patients with and without PMO and statistical analysis performed using the Fisher's exact test. RESULTS: PMO occurred in 4 patients (6 eyes), all of whom had IHD, whereas no PMO occurred in the remaining 173 patients (246 eyes) (p = 0.04). CONCLUSIONS: Pseudophakic macular oedema represents an important complication following modern phacoemulsification and intraocular lens implantation and is associated significantly with ischaemic heart disease.

Aged↗
PubMed2001

Feasibility of surveillance of changes in human fertility and semen quality.

There is concern that male fertility is declining, but this is difficult to study because few men volunteer for studies of semen quality, and recruitment bias may over-represent the subfertile. The Human Reproduction Programme of the World Health Organization developed a protocol for multicentre studies of fertility involving a questionnaire for pregnant women to obtain time to pregnancy (TTP): the number of menstrual cycles taken to conceive. Male characteristics and semen quality will be determined in a subset of the partners. Our aim was to validate the TTP questionnaire, and to examine potential recruitment bias and feasibility of conducting large-scale surveillance of fertility. The questionnaire was administered to 120 pregnant women (16-32 weeks). Validation included internal reliability by consistency of responses, test-re-test reliability by repeat administration (20 women) and accuracy by comparison of gestational age from first antenatal ultrasound and menstrual dates. Internal reliability was high. Agreement between categorical responses on re-testing was very good (k > 0.8). In both the re-test and gestational age analysis, differences in TTP of 1 cycle were found (standard deviation <0.25 cycles). In this small pilot study there was no evidence of recruitment bias. Response rates indicate the feasibility of surveillance of fertility in large maternity centres.

Adult↗
PubMed2001

Frequency of disordered zona pellucida (ZP)-induced acrosome reaction in infertile men with normal semen analysis and normal spermatozoa-ZP binding.

Results of zona pellucida (ZP)-induced acrosome reaction (AR) are reported for 186 normospermic men with unexplained infertility and compared with 34 normal fertile men and 54 patients with disordered ZP-induced AR (DZPIAR) diagnosed after failure of standard IVF. For each ZP-induced AR test, four oocytes that failed to fertilize in IVF were incubated for 2 h with 2x10(6)/ml motile spermatozoa. Spermatozoa tightly bound to the ZP were recovered by aspirating the oocytes with a pipette and the AR assessed using pisum sativum agglutinin labelled with fluorescein. The standard deviation of the difference was 5.2% for repeated tests for ZP-induced AR on different ejaculates from 54 men. The ranges for the ZP-induced AR were 3-98% for normospermic infertile men, 24-95% for fertile men and 0-16% for DZPIAR patients. In the normospermic group, there was a significant correlation between ZP-induced AR and sperm concentration (Spearman r = 0.238, P < 0.001). Using ZP-induced AR < or =16% as the threshold for diagnosis of DZPIAR, the frequency of this condition in normospermic infertile men would be 25%. Thus DZPIAR is common with normospermic idiopathic infertility and this condition should be diagnosed before assisted reproductive technology since it requires intracytoplasmic sperm injection.

Acrosome Reaction↗
PubMed2001

Where genetic algorithms excel.

We analyze the performance of a genetic algorithm (GA) we call Culling, and a variety of other algorithms, on a problem we refer to as the Additive Search Problem (ASP). We show that the problem of learning the Ising perceptron is reducible to a noisy version of ASP. Noisy ASP is the first problem we are aware of where a genetic-type algorithm bests all known competitors. We generalize ASP to k-ASP to study whether GAs will achieve "implicit parallelism" in a problem with many more schemata. GAs fail to achieve this implicit parallelism, but we describe an algorithm we call Explicitly Parallel Search that succeeds. We also compute the optimal culling point for selective breeding, which turns out to be independent of the fitness function or the population distribution. We also analyze a mean field theoretic algorithm performing similarly to Culling on many problems. These results provide insight into when and how GAs can beat competing methods.

Algorithms↗
PubMed2000

Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene.

Acute intermittent porphyria (AIP) is a low-penetrant, autosomal dominant disorder caused by mutations in the HMBS gene. The gene is transcribed from two promoters to produce ubiquitous and erythroid isoforms of porphobilinogen deaminase, which differ only at their NH2 ends. In the classical form of AIP, both isoforms are deficient, but about 5% of families have the non-erythroid variant in which only the ubiquitous isoform is affected. Previously identified mutations in this variant have been within or close to the coding region of exon 1 of the HMBS gene, the only exon that is expressed solely in the ubiquitous isoform. Here, we describe mutations in the ubiquitous promoter (-154delG) and in exon 3 (41delA) that cause the non-erythroid variant. Reporter gene and electrophoretic mobility shift assays show that the G nucleotide at position -154, the most 5' of several transcription-initiation sites in the ubiquitous HMBS promoter, which lies immediately 3' to a transcription-factor IIB binding motif, is essential for normal transcription. The frameshift mutation in exon 3 introduces a stop codon into mRNA for the ubiquitous isoform only. Our investigations identify two new mechanisms for production of the non-erythroid variant of AIP and demonstrate that mutational analysis for diagnosis of this variant needs to include wider regions of the HMBS gene than indicated by previous reports. Furthermore, they show that deletion of one of several transcription initiation sites in the promoter of a housekeeping gene that lacks both TATA and initiator elements can produce disease.

Adolescent↗
PubMed2000

Efficacy and acceptability of testosterone implants, alone or in combination with a 5alpha-reductase inhibitor, for male hormonal contraception.

Testosterone (T) treatment suppresses serum gonadotropins and reduces sperm output sufficiently for contraceptive efficacy in approximately 70% of Caucasian men. In the remaining 30% of men, an increase in 5alpha-reductase activity may maintain testicular androgen activity, thus accounting for the failure of sperm suppression. The form of T therapy is a major consideration in the safety and acceptability of T-based contraception. As compared to T ester injections, T implants provide a more physiological serum T profile and fewer side effects, but have not yet been used in contraceptive efficacy studies. We have used T implants (800-1200 mg every 3 months) in 29 normal men for 3-16 months. T implants produced long-term suppression of sperm densities below 1 million/mL in approximately 70% of men without significant androgenic side effects. No pregnancies occurred in 214 months of exposure. In 16 men failing to suppress within 3 months of T 800 mg, no evidence of enhanced spermatogenic suppression was seen with the co-administration of the type 2 5alpha-reductase inhibitor, finasteride, for 3 months when compared to placebo. We conclude that: 1) T implants provide adequate spermatogenic suppression in approximately 70% of Caucasian men, a rate comparable to intramuscular T injections but with minimal side effects; and, 2) the inclusion of a type 2 5alpha-reductase inhibitor does not enhance spermatogenic suppression.

5-alpha Reductase Inhibitors↗
PubMed2000

Validation of self-reported chronic conditions and health services in a managed care population.

BACKGROUND: Self-reported data are commonly used to estimate the prevalence of health conditions and the use of preventive health services in the population, but the validity of such data is often questioned. METHODS: The Behavioral Risk Factor Survey (BRFS) was admin istered by telephone to a stratified, random sample of health maintenanc e organization (HMO) subscribers in Colorado in 1993, and self-reports w ere compared with HMO medical records for 599 adults aged >21. Sensitivity and specificity were calculated for three chronic conditions and use of six preventive services. RESULTS: Sensitivity was highest for hypertension (83%), moderate for diabetes (73%), and lowest for hypercholesterolemia (59%); specificity was >80% for all three conditions. Sensitivity ranged from 86% to 99% for influenza immunization, clinical breast examination, blood cholesterol screening, mammography, Pap test, and blood pressure screening; specificity was <75% for all preventive services. CONCLUSIONS: Self-reports are reasonably accurate for certain chronic conditions and for routine screening exams and can provide a useful estimate for broad measures of population prevalence.

Adult↗
PubMed2000

Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.

Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial

Adult↗