Changes in myopic refractive error with nine months' extended wear of hydrogel lenses with high and low oxygen permeability.
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Contact Lenses, Extended-Wear↗
Biomedical subjects
S Patel
Publications and source records attributed to S Patel.
A study to evaluate serum and urinary hormone levels following short and long term administration of two regimens of progesterone cream in postmenopausal women.
OBJECTIVE: To determine the pharmacokinetics of a progesterone cream following short and long term dermal administration. DESIGN: Single-centre, randomised, multiple-dose, open-label study. SETTING: Reproductive Medicine Trust, London. POPULATION: Twenty-four healthy postmenopausal women aged between 40 and 65 years were recruited through an advertisement in a local newspaper. METHODS: The women were randomly allocated to progesterone cream 40 mg daily or 20 mg, twice daily, for 42 days. MAIN OUTCOME MEASURES: The concentration of progesterone in the serum was measured on days 1 and 42 before the morning dose, and at 2, 4, 6, 12 and 24 hours after the morning dose. Serum follicle stimulating hormone, oestradiol, testosterone and urinary pregnanediol-3-glucuronide were also measured on days 1 and 42. RESULTS: Three subjects dropped out before using the cream and two more dropped out after the first treatment leaving a reportable sample of 19 women. There was a rise in the mean progesterone concentration at each sampling time between days 1 and 42. There was evidence of a rise in pregnanediol-3-glucuronide over the course of the study. There was no change in follicle stimulating hormone, oestradiol or testosterone. There was no difference between the two regimens. CONCLUSIONS: Transdermal progesterone (40 mg) per day for 42 days causes a small increase in serum progesterone concentration, although there is wide variation. Whether such levels are of clinical benefit remains to be seen.
Administration, Topical↗
Mutations at arg486 and glu571 in human topoisomerase IIalpha confer resistance to amsacrine: relevance for antitumor drug resistance in human cells.
Human topoisomerase II, a nuclear protein involved in chromosome segregation, is the target of amsacrine and other clinically important anticancer drugs. The enzyme is expressed as alpha and beta isoforms whose mutation/down-regulation has been implicated in drug resistance. To understand the role of target mutations in cellular drug resistance, we have used yeast to select and characterize plasmid-borne human topoisomerase IIalpha mutants resistant to amsacrine. Single point changes of Glu571 to Lys (E571K) or Arg486 to Lys (R486K) in the conserved PLRGK motif, both of which reside in the GyrB homology domain of human topoisomerase IIalpha, were frequently selected and could be shown in vivo to confer >25-fold and >100-fold resistance, respectively, to amsacrine and approximately 3-fold cross-resistance to etoposide. Highly purified E571K and R486K human topoisomerase IIalpha proteins required 100-fold higher levels of amsacrine to induce DNA cleavage similar to that of wild-type protein, consistent with a resistance mechanism involving reduced cleavable complex formation. Our functional studies of the R486K mutation, previously identified in two amsacrine-resistant human cell lines and in human biopsy material, establish unequivocally that it confers resistance, and suggest mechanisms for its phenotypic expression in vivo. These results differ significantly from previous work using yeast topoisomerase II as a model system: introduction of the equivalent mutation to R486K (R476K) into the yeast enzyme did not give amsacrine resistance. We conclude that species-specific differences in topoisomerase II enzymes can affect the drug resistance phenotype of particular mutations and highlight the need to study the relevant human homolog.
Amsacrine↗
Probing the interaction of the cytotoxic bisdioxopiperazine ICRF-193 with the closed enzyme clamp of human topoisomerase IIalpha.
Topoisomerase II is an ATP-operated protein clamp that captures a DNA helix and transports it through another DNA duplex, allowing chromosome segregation at mitosis. A number of cytotoxic bisdioxopiperazines such as ICRF-193 target topoisomerase II by binding and trapping the closed enzyme clamp. To investigate this unusual mode of action, we have used yeast to select plasmid-borne human topoisomerase IIalpha alleles resistant to ICRF-193. Mutations in topoisomerase IIalpha of Leu-169 to Phe (L169F) (in the N-terminal ATPase domain) and Ala-648 to Pro (A648P) (in the core domain) were identified as conferring >50-fold and 5-fold resistance to ICRF-193 in vivo, respectively. The L169F mutation, located next to the Walker A box ATP-binding sequence, resulted in a mutant enzyme displaying ICRF-193-resistant topoisomerase and ATPase activities and whose closed clamp was refractory to ICRF-193-mediated trapping as an annulus on closed circular DNA. These data imply that the mutation interferes directly with ICRF-193 binding to the N-terminal ATPase gate. In contrast, the A648P enzyme displayed topoisomerase activities exhibiting wild-type sensitivity to ICRF-193. We suggest that the inefficient trapping of the A648P closed clamp results either from the observed increased ATP requirement, or more likely, from lowered salt stability, perhaps involving destabilization of ICRF-193 interactions with the B'-B' interface in the core domain. These results provide evidence for at least two different phenotypic classes of ICRF-193 resistance mutations and suggest that bisdioxopiperazine action involves the interplay of both the ATPase and core domains of topoisomerase IIalpha.
Adenosine Triphosphatases↗
Factors influencing the frequency of fluorescence transients as markers of peri-infarct depolarizations in focal cerebral ischemia.
BACKGROUND AND PURPOSE: Peri-infarct depolarizations (PIDs) that occur in ischemic boundary zones of the cerebral cortex of experimental animals have been shown to promote rather than simply to indicate the evolution of the lesion and are especially prominent in the rat. To study the influence of one factor, species, on PID incidence, we compared the frequency of PIDs in a primate species, the squirrel monkey, with that in the cat after middle cerebral artery occlusion. Plasma glucose was reviewed as a possible cause of interexperiment variability in the cat experiments. METHODS: In open-skull experiments under chloralose anesthesia, changes in cortical fluorescence believed to indicate NADH/NAD(+) redox state, as markers of PIDs, were recorded by serial imaging of the cortical surface in vivo for 4 hours after middle cerebral artery occlusion. RESULTS: Fluorescence transients occurred in squirrel monkeys at a frequency (mean+/-SD) of 0.7+/-0.8 hours(-1) (n=5), which was not significantly less than in that observed in cats (1.3+/-1.6 hours(-1), n=8). Data from the cat experiments indicated a relationship between number of transients (dependent) and plasma glucose, with a striking increase in PID frequency in association with values of mean postocclusion plasma glucose <4.1 mmol/L (Mann-Whitney U=15.0, P=0.034); this observation agrees well with other published findings. CONCLUSIONS: Transient changes in fluorescence strongly suggestive of peri-infarct depolarizations, either transient or terminal, occur and propagate in the ischemic cerebral cortex of a nonhuman primate. The results also suggest that the relationship of frequency of peri-infarct depolarizations with plasma glucose requires further examination, to confirm the finding and to determine a safe lower limit for a target range for control of plasma glucose if insulin is used in the management of patients with cerebral ischemia.
Action Potentials↗
Mitochondrial DNA sequence diversity in bipolar affective disorder.
OBJECTIVE: Point mutations in mitochondrial DNA (mtDNA) are one mechanism that could explain the apparent excess maternal transmission of bipolar affective disorder observed in some families. The authors sequenced the mtDNA from probands with bipolar disorder and tested nucleotide variants for association with the disorder. METHOD: The entire 16.5 kilobase mitochondrial genome was sequenced in nine unrelated probands selected from large pedigrees with exclusively maternal transmission of bipolar affective disorder. Compared to a reference sequence, variants were detected at 107 nucleotide positions. Fifteen variants of possible pathogenic significance were selected for further study. These variants were assayed in 93 unrelated probands with bipolar I, bipolar II, or schizoaffective-manic disorder and 63 comparison subjects, all of whom were classified into the major groups comprising the European mtDNA haplotype structure (haplogroups). RESULTS: The major European haplogroups were represented at the expected frequencies among both probands and comparison subjects. There was no significant difference between probands and comparison subjects in the frequency of any variant, although odds ratios >2 or <0.5 were observed for four variants. Frequencies of these four variants were similar in probands and haplogroup-matched comparison subjects. The results of all comparisons were essentially unchanged when probands from families with an apparently paternal transmission pattern were excluded. CONCLUSIONS: The results demonstrate that bipolar affective disorder occurs across all of the major European mtDNA haplogroups but do not reveal any point mutations that explain excess maternal transmission of the disorder.
Adolescent↗
Multidrug-resistant typhoid fever.
One hundred children (consecutive) with positive blood culture for Salmonella typhi were studied for clinical profile and complications. The common clinical features were fever (100%), vomiting (58%), abdominal pain (48%), cough (22%) and loose stools (14%) and the Widal test was positive in 75% patients. Eighty per cent of the salmonella isolates were resistant to amoxycillin, chloramphenicol and co-trimoxazole drugs, but all were sensitive to ciprofloxacin and ceftriaxone. Forty patients developed complications: encephalopathy (18), melaena (12), haematemesis (10), epistaxis (4), hepatitis (4), acalculous cholecystitis (4), bowel perforation (3) and nephritis (2). Complications were more frequent in children with multidrug-resistant typhoid. The final antibiotic required to render the children afebrile included ciprofloxacin (80), ceftriaxone, amoxycillin (4), chloramphenicol (4), amoxycillin and gentamicin (4), amoxycillin with chloramphenicol (2), and furazolidone (2). The defervesence time was least with ceftriaxone and greatest with amoxycillin. All the affected children made a complete recovery.
Anti-Bacterial Agents↗
In vitro proliferation and differentiation of megakaryocytic progenitors in patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria, and the myelodysplastic syndromes.
It has previously been shown that patients with aplastic anemia (AA) have a stem cell defect both of proliferation and differentiation. This has been shown by long-term bone marrow (BM) culture, long-term initiating cell assays, and committed progenitor assays. We present, for the first time, data on megakaryocyte (Mk) colony formation from purified BM CD34(+) cells from patients with AA. The results are compared with those from normal controls and from patients with paroxysmal nocturnal hemoglobinuria (PNH) and the myelodysplastic syndromes (MDSs). Those treated for AA had previously received immunosuppression (antithymocyte globulin and/or cyclosporin). No patients had received bone marrow transplantation. A total of 13 AA patients (five untreated, eight treated), six PNH, six MDS, and 13 normal donors were studied. BM CD34(+) cells were purified by indirect labeling and then cultured in a collagen-based Mk assay kit (MegaCult-C, StemCell Technologies). The cultures were fixed on day 12, and the Mk colonies were identified by the alkaline phosphatase anti-alkaline phosphatase technique using the monoclonal antibody CD41 (GP IIb/IIIa). The slides were scored for Mk colony-forming units (CFU-Mks) (3-20 and >20 cells), Mk burst-forming units (BFU-Mks) (>50 cells), and mixed colonies. The results show that total Mk colony formation in AA was significantly lower than in normal donors (p<0.0001), both in untreated patients/nonresponders to treatment (p = 0.0001) and in complete/partial responders (p<0.002). There was no significant difference in Mk colony formation in treated and untreated patients (p = 0.05). Patients with AA had a lower total colony formation than PNH patients (p = 0.0002). PNH patients exhibited lower colony formation than normal controls (p = 0.03), as shown by MDS patients, although the considerable number of variables resulted in a lack of statistically significant difference from normal controls (p = 0.2). We have now shown that Mk colony formation from purified BM CD34(+) cells is significantly reduced, supporting previous evidence that AA results from a stem cell defect.
Anemia, Aplastic↗
Radiographic and aerodynamic measures of velopharyngeal anatomy and function following Furlow Z-plasty.
Recent studies have shown that the Furlow double-opposing Z-plasty has several advantages that make it an attractive procedure for cleft palate repair and treatment of velopharyngeal insufficiency in selected cases. The anatomic changes associated with this procedure have never been documented prospectively. The purpose of this study was to describe radiographic dimensions of the velopharynx and aerodynamic measures of velopharyngeal function in a group of patients before and after Furlow Z-plasty for the treatment of velopharyngeal insufficiency. Twelve consecutive patients with cleft palate and velopharyngeal insufficiency, ranging in age from 3 to 19 years, were selected as candidates for Furlow Z-plasty based on perceptual, endoscopic, and radiographic findings. Eight patients had repaired cleft palate with a residual muscle diastasis and four patients had unrepaired submucous cleft palate. Subjects received aerodynamic and cephalometric assessments before and after Z-plasty. Cephalometric x-rays were measured for velar length, thickness, and pharyngeal depth. Mean nasal airflow during pressure consonants (Vn) was calculated from pressure/flow studies, and patients were categorized as having complete closure (<10 cc/sec Vn) or incomplete closure (>10 cc/ sec Vn). After Z-plasty, there was a significant increase in velar length (p = 0.002) and velar thickness (p = 0.001). After surgery, patients with complete velopharyngeal closure had significantly greater velar length than the incomplete closure group (p = 0.05) with nearly twice the increase in length. Similarly, following surgery, the complete closure group had significantly greater thickness than the incomplete closure group (p = 0.01), with a greater postoperative increase in velar thickness (p = 0.005). Finally, there was a significant negative correlation between percent increase in length and percent increase in thickness for patients in the complete closure group (r = -0.91, p = 0.03). Findings demonstrate that following Furlow Z-plasty, patients with cleft palate and velopharyngeal insufficiency obtained significant increases in velar length and thickness. Greater velar length and greater velar thickness both were associated with complete velopharyngeal closure. Patients in the complete closure group tended to demonstrate large percent gains in either length or thickness or moderate gains in both. Patients in the incomplete closure group tended to demonstrate relatively small percent gains in both dimensions. Results suggest there may be important anatomic features (such as pharyngeal depth/velar length ratio) that can be evaluated before surgery to predict which patients may be most likely to benefit from Furlow Z-plasty as a form of treatment for velopharyngeal insufficiency.
Adolescent↗
Routine referral for radiography of patients presenting with low back pain: is patients' outcome influenced by GPs' referral for plain radiography?
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Adolescent↗
Extremes of white blood cell count do not independently predict outcome among surgical patients with infection.
Historically patients with severely depressed or elevated white blood cell (WBC) counts during infection were felt to have worse outcomes. To test this assumption we prospectively analyzed all infections on the surgical services at the University of Virginia hospital between December 1, 1996 and April 1, 1999. Among 1737 infectious episodes 59 presented with leukopenia (WBC count < or = 3,000 cells/microL) whereas 66 presented with leukemoid responses (WBC count > or = 30,000 cells/microL). Compared with other infected patients leukopenic patients had higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (18+/-0.9 vs 12+/-0.2, P < 0.0001) and mortality (23.7% vs 11.4%, P = 0.004). Patients with leukemoid responses also had higher APACHE II scores (21+/-1.0 vs 12+/-0.2, P < 0.0001) and mortality (30.3% vs 11.4%, P < 0.0001). Compared with a control group randomly matched (2:1) by age and APACHE II score, however, there was no significant difference in mortality associated with leukopenia or a leukemoid response. Furthermore logistic regression did not reveal leukopenia or leukemoid responses to be independent predictors of mortality (odds ratio for death with leukopenia = 1.57, 95% confidence interval = 0.63-3.91, P = 0.33; odds ratio for death with leukemoid response = 1.19, 95% confidence interval = 0.70-2.02, P = 0.53). Although very low or very high WBC counts may represent markers of severe illness in infected surgical patients they do not appear to be significant contributors to a worsened outcome.
APACHE↗
Implementation of revised strategy of filaria control-baseline clinico-parasitological survey.
A clinico-epidemiological study of filariasis was carried out in Varanasi District in October and November, 1997 to generate baseline data for assessing the impact of Mass Drug Administration (MDA) in the district. Disease rate was found to be 6.6% (9.9% in males and 3.0% in females) and microfilaria rate was 5.3% (5.2% in males and 5.5% in females). Mean microfilaria density was found to be 9.86 per 20 Cu.mm blood. Genital manifestations (77.5%) outnumbered all other forms of clinical manifestations. Vector infectivity rate was found to be 0.93%.
Adolescent↗
Transoesophageal echocardiography: its role in the management of patients in a district general hospital.
The aim of this study was to assess the value of a transoesophageal echocardiography (TOE) service in a district general hospital (DGH). A series of 151 consecutive cases was analysed retrospectively to determine the relative additional benefit of TOE over transthoracic echocardiography (TTE) in establishing diagnoses and making therapeutic decisions. Of the 151 cases, 140 were suitable for the two procedures to be compared. In 56%, TOE provided useful information for patient management. This consisted of the detection of new major findings (33%) and the exclusion of significant abnormalities (23%), suspected either clinically or by TTE. TOE made a minor clinical contribution in 8% of cases, while in 30% there was concordance between the two studies. Finally, in 6% both examinations were inconclusive. We conclude that TOE has a significant complementary role to TTE in terms of clinical diagnosis and patient management in the DGH setting.
Adolescent↗
Antibiotic use and risk of myocardial infarction.
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4-Quinolones↗
Occult metastases in the sentinel lymph nodes of patients with early stage breast carcinoma: A preliminary study.
BACKGROUND: Thirty percent of lymph node negative patients with operable breast carcinoma experience disease recurrence within 10 years. Retrospective serial sectioning of axillary lymph nodes has revealed undetected metastases in 9-30% of these patients. These occult metastases have been shown to have an adverse effect on survival. Serial sectioning (SS) is impractical for all axillary lymph nodes harvested from Levels I and II, but it is feasible if applied only to sentinel lymph nodes. METHODS: Sentinel lymph nodes from 52 patients with invasive breast carcinoma were cut at 2 mm intervals, fixed in 10% formalin, and embedded in paraffin. Sections were taken from the blocks, stained with hematoxylin and eosin (H & E), and compared with cytokeratin-stained sections taken at 0.25 mm intervals throughout the entire blocks. RESULTS: Tumor metastases were found in 6 patients (12%) when the sentinel lymph nodes were sectioned at 2 mm intervals and stained with H & E, compared with 30 patients (58%) when the same lymph nodes were serially sectioned at 0.25 mm intervals and stained with cytokeratin. Of 24 patients whose metastases were detected by SS and cytokeratin staining, 12 had isolated tumor cells and 12 had colonies of several thousand malignant cells. CONCLUSIONS: Routine histologic examination of axillary lymph nodes, including sentinel lymph nodes, in cases of breast carcinoma significantly underestimates lymph node metastases. This deficiency may be overcome by SS of the entire lymph nodes and staining with a specific monoclonal antibody. The percentage of patients found to have colonies of cells that were missed by routine sectioning corresponds closely to the percentage of "lymph node negative" patients who would be expected to relapse. The true clinical significance of these occult metastases will be determined by long term follow-up. [See editorial on pages 905-7, this issue.]
Adult↗
Orexin A activates locus coeruleus cell firing and increases arousal in the rat.
The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.
Animals↗
APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif.
We have identified a novel member of the calcium-dependent (C-type) lectin family. This molecule, designated DCIR (for dendritic cell (DC) immunoreceptor), is a type II membrane glycoprotein of 237 aa with a single carbohydrate recognition domain (CRD), closest in homology to those of the macrophage lectin and hepatic asialoglycoprotein receptors. The intracellular domain of DCIR contains a consensus immunoreceptor tyrosine-based inhibitory motif. A mouse cDNA, encoding a homologous protein has been identified. Northern blot analysis showed DCIR mRNA to be predominantly transcribed in hematopoietic tissues. The gene encoding human DCIR was localized to chromosome 12p13, in a region close to the NK gene complex. Unlike members of this complex, DCIR displays a typical lectin CRD rather than an NK cell type extracellular domain, and was expressed on DC, monocytes, macrophages, B lymphocytes, and granulocytes, but not detected on NK and T cells. DCIR was strongly expressed by DC derived from blood monocytes cultured with GM-CSF and IL-4. DCIR was mostly expressed by monocyte-related rather than Langerhans cell related DC obtained from CD34+ progenitor cells. Finally, DCIR expression was down-regulated by signals inducing DC maturation such as CD40 ligand, LPS, or TNF-alpha. Thus, DCIR is differentially expressed on DC depending on their origin and stage of maturation/activation. DCIR represents a novel surface molecule expressed by Ag presenting cells, and of potential importance in regulation of DC function.
Amino Acid Sequence↗