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Biomedical subjects

K Howell

Publications and source records attributed to K Howell.

At least 19 recordsLinked to original sources
PubMed2004

B-cell subsets in blood and lymphoid organs in Macaca fascicularis.

BACKGROUND: Cynomolgus monkeys (Macaca fascicularis) are widely used animal models in biomedical research. However, the phenotypic characteristics of cynomolgus monkey (CM) B cells in peripheral blood (PB) and lymphoid organs are poorly understood. METHODS: FACS analyses of PB-, spleen-, lymph node (LN)-, and bone marrow (BM)-derived B cells were performed. RESULTS: CM peripheral blood B cells have a smaller fraction of CD27(-) (naive) cells ( approximately 40%), as compared to human blood samples ( approximately 70%). Similar to humans, an early activation marker, CD23, is expressed more on CD27(-) CM naive B cells, as compared to CD27(+) B cells. The mean fraction of B cells exhibiting a memory phenotype is similar to that seen in human blood. Unlike humans, CM blood contains a subset of CD20(++)CD80(+)CD21(-)IgM(+/-)CD27(+)CD19(+)FSC(++)BAFF-R(low) B cells that are likely of germinal center origin. Thus, CM blood contains (i) a higher percentage of B cells that express the co-stimulatory molecule CD80, and (ii) a lower fraction of B cells that are CD21(+), as compared to human blood. Due to the relative paucity of information on B-cell subsets in organs of healthy humans, a direct comparison between human and CM lymphoid organ data is limited. The fraction of CD27(+) and CD23(+) B cells appears to be similar, while the fraction of CD80(+) B cells appears to be higher than that seen in human lymphoid organs. CM spleens and to some extent lymph nodes have a distinct subset of CD21(++) cells that are also CD80(+/-)CD23(low)IgM(++)CD27(+/-)FSC(++). This subset is phenotypically similar to the marginal zone B cells present in human spleen and LN samples. We also provide detailed analyses on the fraction of lymphoid organ B cells that express CD21, CD23, CD32, and/or CD80 B-cell markers. CONCLUSIONS: In general, cynomolgus monkey B-cell subsets are similar to those seen in humans, as well as to those seen in other nonhuman primates. However, there are some clear differences between human and cynomolgus monkey B-cell subsets. These findings have direct implications for a variety of in vivo studies in cynomolgus monkeys, ranging from basic research on primate B-cell differentiation to models of infectious diseases and trials of new B-cell targeting therapeutic agents.

Animals↗
PubMed2003

X-chromosome-linked immune-deficient mice have B-1b cells.

The B lymphocyte subsets of X-chromosome-linked immune-deficient (XID) mice were examined by flow cytometric analyses of spleen and peritoneal cells. As shown in prior studies, young adult XID mice had reduced representation of the CD5+ (B-1a) subset in their peritoneal cavity. However, the CD11b+ (B-1b) B-cell subset was present and exhibited the IgM(hi) CD45(lo) CD23- phenotype characteristic of most B-1 cells. Although present at a lower frequency than that found in their normal counterparts, B-1b cells were evident in CBA/N and (XD2J)F1 male mice. With increasing age, B-1b cell number increased and in the oldest XID mice were present as B-cell chronic lymphocytic leukaemia. These results show that XID mice do have B-1 cells, particularly the B-1b subset.

Aging↗
PubMed2001

The use of portable radiometry to assess Raynaud's phenomenon: a practical alternative to thermal imaging.

OBJECTIVES: To compare the performance of a portable radiometer with thermal imaging and to assess the potential for radiometry to provide a practical alternative for assessing vascular responsiveness in Raynaud's phenomenon (RP). METHODS: Subjects comprised 18 patients with diagnosed RP and 19 non-RP subjects. A thermal imager (Starsight) and a portable radiometer (Cyclops) measured digital temperature at baseline and the subsequent drop and rise in temperature following a cold challenge test. RESULTS: The intra-class correlations between the two instruments for all three measures exceeded 80%. The overall performance of each instrument was almost the same, the Starsight thermal imager correctly classifying 84% of subjects as RP or non-RP and the Cyclops portable radiometer correctly classifying 86% of subjects. The sensitivity of the thermal imager was 83%, compared with 89% for the portable radiometer; the specificity of both instruments was 84%. The positive and negative predictive values of the thermal imager were 83 and 84% respectively, and those for the portable radiometer were 84 and 89%. CONCLUSIONS: The two instruments performed equally well and the differences between them in their absolute measurements did not influence their ability to detect RP. Portable radiometry provides a practical, cheap, accurate and reliable alternative to thermal imaging and has the potential to be used in range of clinical and epidemiological settings.

Adolescent↗
PubMed2001

Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibitor fluoxetine.

OBJECTIVE: To compare fluoxetine, a selective serotonin reuptake inhibitor, with nifedipine as treatment for primary or secondary Raynaud's phenomenon. METHODS: Twenty-six patients with primary and 27 patients with secondary Raynaud's phenomenon were assigned randomly to receive 6 weeks of treatment with fluoxetine (20 mg daily) or nifedipine (40 mg daily). Following a 2-week washout period, each group was crossed over to the other treatment arm. The primary outcome variable was the frequency of attacks of Raynaud's phenomenon. Self-reported attack severity, thermographic recovery from cold challenge and plasma levels of von Willebrand factor and soluble P-selectin were also measured. RESULTS: There was a reduction in attack frequency and severity of Raynaud's phenomenon in patients treated with either fluoxetine or nifedipine, but the effect was statistically significant only in the fluoxetine-treated group (P=0.0002 for attack severity and P=0.003 for attack frequency). Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud's phenomenon. A significant improvement in the thermographic response to cold challenge was also seen in female patients with primary Raynaud's phenomenon treated with fluoxetine but not in those treated with nifedipine. There was no significant treatment effect on von Willebrand factor or soluble P-selectin. No significant adverse effects occurred in the fluoxetine-treated group. CONCLUSION: This pilot study confirms the tolerability of fluoxetine and suggests that it would be effective as a novel treatment for Raynaud's phenomenon. Larger and placebo-controlled trials are warranted to assess fluoxetine's therapeutic potential further in this vasospastic condition.

Adult↗
PubMed2000

Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling.

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O(2) fraction (FI(O(2))) = 0.10], chronic hypercapnia (inspiratory CO(2) fraction = 0.10), hypoxia-hypercapnia (FI(O(2)) = 0.10, inspiratory CO(2) fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone (P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk (P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 +/- 1.8 mmHg) was significantly (P < 0.01, ANOVA) elevated compared with control conditions (12.1 +/- 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 +/- 0.9 mmHg) or hypercapnia (11.8 +/- 1.3 mmHg). HPV (FI(O(2)) = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control (P < 0.05, ANOVA). Addition of N(omega)-nitro-L-arginine methyl ester (10(-4) M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.

Animals↗
PubMed1999

Clinical observations of axillary involvement for tubular, lobular, and ductal carcinomas of the breast.

BACKGROUND AND OBJECTIVES: Recently, there has been much interest in identifying primary breast cancer characteristics which have predictive value for axillary metastases. We studied breast cancer patients to determine variables associated with the incidence/extent of axillary involvement and to construct a modeled analysis. METHODS: Patients with invasive ductal, lobular, and tubular breast cancer (group 1, n = 15,719) were analyzed by tumor size and histology for the probability/extent of axillary metastases. A subgroup of patients was analyzed separately for any association of axillary involvement and other variables (group 2). RESULTS: In group 1, the incidence and extent (number of positive lymph nodes) of axillary metastases correlated significantly with histology and increasing tumor size of ductal and lobular histologies. Significant associations for < or = 10% axillary involvement in group 2 were age and S phase for tubular histology and differentiation for ductal histology. In a multivariate analysis, increasing tumor size was the only statistically significant correlate for axillary involvement (group 2) and for increasing number of positive nodes (group 1). CONCLUSIONS: A multivariate model of tumor size and age combined with staging techniques can successfully confirm or assess extent of axillary metastases in breast carcinoma.

Adenocarcinoma↗
PubMed1999

Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial.

OBJECTIVE: To compare the efficacy and tolerability of losartan, an antagonist of angiotensin II receptor type 1, with nifedipine for the treatment of primary and secondary Raynaud's phenomenon (RP) in a pilot study. METHODS: In a randomized, parallel-group, controlled trial, patients with primary RP (n = 25) or RP secondary to systemic sclerosis (SSc [scleroderma]; n = 27) were allocated to receive 12 weeks' treatment with either losartan (50 mg/day) or nifedipine (40 mg/day). Primary outcome variables were the severity and frequency of RP episodes and findings on vascular measurements, including thermography and laser Doppler flowmetry. Serum levels of soluble adhesion molecules, endothelin 1, fibrinogen, von Willebrand factor, and procollagen type I N-terminal propeptide (PINP) were also measured. RESULTS: There was a reduction in the severity of RP episodes following treatment with losartan and with nifedipine, but this effect was greater in the losartan arm of the study (P<0.05): episode frequency was reduced only in the losartan group (P<0.01 versus baseline). Symptomatic improvement was associated with a significant reduction in soluble vascular cell adhesion molecule 1 and PINP (P<0.01). Subgroup analysis suggested that although these biochemical changes occurred mainly in SSc patients, the clinical benefit was greater in the primary RP group. CONCLUSION: This study confirms the tolerability of short-term treatment of RP with losartan, and our data suggest its clinical benefit. Further evaluation of this drug as a long-term treatment for SSc-associated RP should be considered, since it may have additional disease-modifying potential.

Adult↗
PubMed1999

Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud's phenomenon.

OBJECTIVE: Reactive oxygen species have been implicated in the pathogenesis of inflammatory and vascular disease. We have undertaken a controlled trial to evaluate probucol, a synthetic antioxidant, as a potential therapy for Raynaud's phenomenon. METHODS: The study cohort included patients with systemic sclerosis (SSc; n = 20), primary Raynaud's phenomenon (n = 15) or 'autoimmune Raynaud's' (n = 5). Patients were allocated to receive either probucol (500 mg daily) or nifedipine (20 mg daily) for 12 weeks. Clinical and biochemical variables at baseline were compared with those at completion of treatment. Evaluation included assessment of Raynaud's attack frequency and severity by visual analogue scale, measurement of low-density lipoprotein (LDL) oxidation lag time, and plasma concentrations of cholesterol, triglyceride, vitamin E and vitamin C. RESULTS: There was a significant reduction of both the frequency and severity of Raynaud's attacks in the patients who received probucol, but not in the control group. LDL oxidation lag time, reflecting in vitro susceptibility to oxidation, was also increased by probucol therapy and serum cholesterol levels were significantly reduced. Similar changes were observed in both SSc- and non-SSc-associated Raynaud's cases. CONCLUSION: These data suggest that probucol may be useful for the symptomatic treatment of Raynaud's phenomenon and also reduces LDL oxidation susceptibility. Since oxidized lipoproteins may mediate vascular damage in SSc, the use of probucol could have additional disease-modifying benefits. Based upon the results of this pilot study, further evaluation of this novel form of therapy is warranted.

Anticholesteremic Agents↗
PubMed1997

Pathways to orthodontic care.

BACKGROUND: The research described in this paper arose out of the need to address the growing waiting list for orthodontic treatment in Northamptonshire. Although the prevalence of dento-facial anomalies is the same across time, sex, race and socio-economic class, studies in the United States and this country suggest that certain groups are over-represented among patients who receive orthodontic treatment. The introduction of valid and reliable indices of therapeutic need such as the index of Orthodontic Treatment Need (IOTN) will allow improved focusing of services. The aim of the study was to determine the variables affecting access to orthodontic care, and the extent to which services were delivered according to objective measures of need. METHODS: Analyses were undertaken for speed, appropriateness, timing of referral, duration and complexity of the pathway for new referrals to specialist orthodontic care. possible explanations for the length of pathway were examined, including socio-demographic factors, location of residence and the IOTN. RESULTS: A total of 405 patients were approached, of whom 400 (99 per cent) agreed to participate. There was an over-representation among socio-economic groups I and V among patients referred to orthodontic treatment. By contrast, those of male sex and from socio-economic class IV were under-represented. This appeared to be the case irrespective of treatment setting. There was also a wide range of waiting times to treatment and complexity of pathway. Over a quarter of the sample had been inappropriately referred, and objective need as measured by the IOTN was not a determinant in the speed of access to specialist treatment. Adult patients waited longer for treatment. CONCLUSIONS: These results suggest that the delivery of care is neither based on objective need nor equitably distributed. More appropriate directing of resources is required, using the IOTN and agreed protocols, so that referrals are made to the most suitable provider.

Adolescent↗
PubMed1995

Does administration of chemotherapy before radiotherapy in breast cancer patients treated with conservative surgery negatively impact local control?

PURPOSE: To determine if a delay of irradiation to the intact breast for administration of adjuvant chemotherapy results in increased local recurrence in breast cancer. PATIENTS AND METHODS: The records of 262 women with 264 cases of breast cancer were reviewed. Group I contained 105 patients treated with conservative surgery, chemotherapy, and radiotherapy. Group II contained 157 patients (used as a concurrent control) treated with conservative surgery and radiotherapy only. Eighty-nine percent of subjects in group I received all chemotherapy before radiotherapy. Fifty-eight percent of patients received hormone therapy. Seventy-one percent of patients had negative surgical margins, and 74% had negative lymph nodes. For group I, conservative surgery-radiotherapy intervals in months were less than 1 (five, 5%), > or = 1 to less than 3 (10, 9%), > or = 1 to less 6 (48, 46%), and > or = 6 (42, 40%), mean of 5. For group II, the intervals were less than 1 (20, 13%), > or = 1 to less than 3 (123, 79%), > or = 3 to less than 6 (11, 7%), and > or = 6 (two, 1%), mean of 1.5. RESULTS: Thirty patients (11.5%) have disease recurrence (19 distant [6%] and 12 local [5%]). There were no significant differences in local recurrence (group I, four [4%]; group II, eight [5%]; difference not significant). There were no significant differences in local recurrence in any surgery-radiotherapy interval within each group. Although we found marginal increases in the percentage of local recurrences in group I patients (with prolonged surgery-radiotherapy intervals) who had positive margins, positive lymph nodes, and tumor size more than 2 cm versus group II (without prolonged surgery-radiotherapy intervals), these results were not significant. CONCLUSION: We could not identify any surgery-radiotherapy interval that resulted in increased local recurrence if radiotherapy was delayed for administration of adjuvant chemotherapy in breast cancer patients. Because of the heterogenous population of breast cancer patients, our results also support the need for further study to determine the optimum integration of radiotherapy and chemotherapy in the management of the conservatively treated breast.

Adult↗
PubMed1994

Comparison of laser Doppler perfusion imaging, laser Doppler flowmetry, and thermographic imaging for assessment of blood flow in human skin.

In this study we compared three non-invasive methods of measuring skin perfusion, thermographic imaging (TI), laser Doppler flowmetry (LDF) and the new technique of laser Doppler imaging (LDI). Seven normal volunteers were studied in a temperature-controlled room with an ambient temperature of 22 +/- 1 degree C. Images of the left hand were recorded using LDI followed by TI. LDF was then used on two standard locations on the fingers and back of the hand. The measurements were then repeated for a hot (37 degrees C) and then a cold (10 degrees C) challenge. A significant linear correlation (r = 0.960, p < 0.01, with 95% confidence limit of 0.35-0.77, n = 38) was found between LDF and LDI. However, LDF and LDI did not correlate well with TI (r = 0.577, p < 0.01, with 95% confidence limit of 0.32-0.76, n = 38). The LDI method was found to be highly reproducible (mean +/- 1 SD; 625 +/- 30, with coefficient of variation 5%). The blood flow and temperature distribution of skin of the hand was then recorded using TI and LDI in 10 patients (mean age +/- SD, 41.7 +/- 9.9) with scleroderma and eight normal volunteers (mean age +/- SD, 30.6 +/- 6.5). The overall mean blood flow and temperature in the hands of patients with scleroderma (mean +/- SD 444 +/- 265 flux, 29.3 +/- 3.3 degrees C) was significantly (p < 0.0001) lower compared with the normal volunteers (mean +/- SD, 912 +/- 390 flux, 34.0 +/- 3.2 degrees).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗