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Biomedical subjects

K Howe

Publications and source records attributed to K Howe.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pityriasis rubra pilaris with acantholysis.

Two patients developed a papulosquamous eruption in a widespread distribution which progressed with islands of sparing of uninvolved skin characteristic clinically of adult-onset pityriasis rubra pilaris (PRP). Biopsies from both patients showed multiple areas of nonfollicular and follicular suprabasilar and intra-epidermal acantholysis with minimal dyskeratosis. They also showed the usual histologic features of PRP with a thickened orthokeratosis and parakeratosis, a retained and sometimes thickened granular cell layer, and psoriasiform epidermal hyperplasia with a perivascular lymphohistiocytic infiltrate in the superficial dermis. Two previous patients with PRP have been reported with nonfollicular, focal acantholytic dyskeratosis and both were interpreted as most likely representing an incidental finding. We believe the acantholysis in these two cases is related to the disease process, and in our second patient, was helpful in establishing the diagnosis.

Acantholysis↗
PubMed1996

Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse.

RT-PCR assays used to detect acute promyelocytic leukemia (APL) are generally considered less sensitive than those for other hematological malignancies, such as CGL. Most patients with APL express del(17q)-derived RAR alpha-PML transcripts as well as the putative leukemogenic PML-RAR alpha associated with add(15q). We have found that a nested RT-PCR for RAR alpha-PML affords greater sensitivity than that for PML-RAR alpha, particularly in patients with the commonest breakpoint pattern. Therefore, we have evaluated both assays in parallel to monitor a group of 12 de novo APL patients who relapsed despite treatment with both all-trans retinoic acid (ATRA) and chemotherapy. 5' (bcr 3) breakpoints in PML were over represented among the group and three patients had complex cytogenetic abnormalities suggesting both factors may increase the risk of relapse. The RAR alpha-PML assay changed the PCR status of two patients in morphological remission; in both cases disease contamination of bone marrow harvest specimens was detected. Although parallel assessment of PML-RAR alpha and RAR alpha-PML can enhance minimal residual disease detection in APL, this study demonstrates that treatment strategies involving determination of PCR status post-consolidation, even using RAR alpha-PML in addition to the more conventional PML-RAR alpha assay will fail to identify all patients at risk of relapse. Whether the duration of PCR positivity is a helpful prognostic indicator in those patients who ultimately become PCR negative is being addressed by

Adolescent↗
PubMed1996

Establishing the presence of the t(15;17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial. M.R.C. Adult Leukaemia Working Party.

Detection of the t(15;17) or its molecular consequence, the PML-RAR alpha rearrangement, is critical for meaningful analysis of clinical trials involving patients with suspected acute promyelocytic leukaemia (APL). Its presence remains the best predictor of a favourable response to retinoids, such as ATRA, which in combination with chemotherapy confer significant improvements in disease-free survival. We have evaluated the relative efficacy of RT-PCR, cytogenetics and PML immunofluorescence staining to identify the existence of the translocation in 100 patients entered into the Medical Research Council (M.R.C.) ATRA trial. RT-PCR successfully identified PML-RAR alpha rearrangements in 93/100 patients, including 65 where only peripheral blood or post-induction marrow samples were available for analysis and in 12 patients in whom cytogenetic assessment failed to demonstrate t(15;17) due to poor-quality metaphases (10/12) or as a reflection of cryptic PML-RAR alpha rearrangements (2/12). Parallel employment of the RAR alpha-PML assay confirmed expression of del(17q)-derived transcripts in 81% and permitted determination of the PML breakpoint (a potential independent prognostic variable) in all 93 cases. Sequencing of RT-PCR products derived from 50 patients with 3' PML breakpoints revealed five bcr 2 cases, including a novel exon 5 breakpoint. 35/81 (43%) patients with cytogenetic evidence of t(15;17) possessed additional karyotypic abnormalities. In four patients with available buffy coat smears, lack of cytogenetic or molecular evidence of the t(15;17) was confirmed by a wild-type PML immunofluorescence nuclear staining pattern, in contrast to the characteristic microparticulate distribution detected in 14 patients with RT-PCR evidence of the rearrangement. However, although PML immunofluorescence staining is suitable for rapid determination of patients likely to benefit from ATRA, this approach does not obviate the need for cytogenetic and RT-PCR analysis of all patients entered into APL clinical trials, because both techniques provide additional information which may prove to be of independent prognostic significance.

Adolescent↗
PubMed1995

The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML.

Acute promyelocytic leukaemia (APL) has been ascribed to a chromosomal translocation event which results in a fusion protein comprising the PML protein and the retinoic acid receptor alpha. PML is normally a component of a nuclear multiprotein complex (termed ND10, Kr bodies, nuclear bodies, PML oncogenic domains or PODs) which is disrupted in the APL disease state. PML contains a number of characterized motifs including a Zn2+ binding domain called the RING or C3HC4 finger. Here we describe the solution structure of the PML RING finger as solved by 1H NMR methods at physiological pH with r.m.s. deviations for backbone atoms of 0.88 and 1.39 A for all atoms. Additional biophysical studies including CD and optical spectroscopy, show that the PML RING finger requires Zn2+ for autonomous folding and that cysteines are used in metal ligation. A comparison of the structure with the previously solved equine herpes virus IE110 RING finger, shows significant differences suggesting that the RING motif is structurally diverse. The role of the RING domain in PML nuclear body formation was tested in vivo, by using site-directed mutagenesis and immunofluorescence on transiently transfected NIH 3T3 cells. Independently mutating two pairs of cysteines in each of the Zn2+ binding sites prevents PML nuclear body formation, suggesting that a fully folded RING domain is necessary for this process. These results suggest that the PML RING domain is probably involved in protein-protein interactions, a feature which may be common to other RING finger domains.

Amino Acid Sequence↗
PubMed1994

Molecular analysis of simple variant translocations in acute promyelocytic leukemia.

The primary cytogenetic abnormality in acute promyelocytic leukemia (APL; FAB M3) is a reciprocal translocation, t(15;17)(q22;q12), which serves to fuse the PML gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17. A PML-RARA fusion message transcribed from the der(15) is thought to mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3;15)(q21;q22) and t(X;15)(p11;q22), have previously been reported who lack cytogenetic involvement of chromosome 17, although their breakpoint positions on chromosome 15 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients, in which we wanted to determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the RARA locus has occurred instead. A cryptic involvement of RARA was demonstrated in both patients by a combination of Southern analysis, reverse transcription coupled to PCR (RT-PCR), and fluorescence in situ hybridization. The results indicate an absolute requirement for the rearrangement of the RARA gene in the pathogenesis of APL and underline the importance of RARA during normal myeloid differentiation.

Adolescent↗
PubMed1994

A case of acute monocytic leukemia with t(11;17) involving a rearrangement of MLL-1 and a region proximal to the RARA gene.

A case of acute monocytic leukemia with t(11;17)(123;q11-21) arising in a 4-month-old boy is described. The breakpoint on chromosome 11 could be mapped to an 8-kb BamHI fragment within the MLL-1 gene, as seen in the majority of infant leukemias. In situ hybridization with cosmid probes allowed us to map the breakpoint on 17q proximal to the RARA gene, while Southern and Northern analyses showed that the gene was not disrupted by the translocation.

Chromosomes, Human, Pair 11↗
PubMed1993

Microcystic adnexal carcinoma: in vitro growth characteristics and effect on stromal collagen production.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a locally aggressive cutaneous neoplasm, which is characterized by follicular and sweat gland differentiation and a stroma of dense collagen. METHODS: MAC cells were studied and characterized in vitro through phase microscopy and proliferation assays. Additionally, to delineate a possible role of soluble mediators in bringing about the dense stromal collagen seen in association with these tumors, the effect of conditioned media derived from the tumor cells on the level of collagen production by normal fibroblasts was examined. RESULTS: A significant morphologic difference between the MAC cells and normal keratinocytes was not noted. Proliferation assays demonstrated a significantly slower rate of growth of the MAC cells in comparison to controls. Media conditioned by MAC cells did not induce an increase in collagen synthesis by cultured fibroblasts, but rather, there appeared to be an inhibitory effect on the level of collagen synthesis. CONCLUSIONS: The increased stromal collagen seen in MAC histologically is not the result of growth factors or cytokines produced by the MAC cells.

Carcinoma↗
PubMed1993

Patient-controlled analgesia and postoperative urinary retention after open appendectomy.

We retrospectively studied 279 patients who had undergone uncomplicated open appendectomy for acute appendicitis to determine risk factors for postoperative urinary retention. The gender of the patients, the operating time and the amount of fluid given perioperatively had no influence on the occurrence of retention. The amount of analgesic agent administered postoperatively and the age of the patient were significantly associated with urinary retention (p = 0.01 and p < 0.0001, respectively, after adjustment for potential confounding factors). The use of meperidine hydrochloride as compared with morphine and of patient-controlled analgesia as compared with intramuscular delivery were initially found to be significantly related to retention (p = 0.014 and p < 0.0001, respectively). After the effects of the age of the patient, the drug type and the amount of fluid and analgesic agent administered were controlled for, patient-controlled analgesia remained significantly associated with retention (p < 0.0001), whereas the type of drug given was no longer significant after controlling for potential confounding factors. Because we found that urinary retention was 13 times more likely to occur in the patients who had patient-controlled analgesia, we recommend that the use of this form of analgesia delivery be avoided after open appendectomy.

Adolescent↗
PubMed1992

Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.

Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.

Adenomatous Polyposis Coli↗
PubMed1991

Mycotic aortic aneurysm infected by Clostridium septicum--a case history.

The authors describe a sixty-seven-year-old hypertensive, diabetic man with a mycotic abdominal aortic aneurysm infected with Clostridium septicum. The patient had colonic polyps but no malignant disease. They could find only one other report of a mycotic aneurysm infected with C. septicum. In that case, as in most other cases of C. septicum bacteremia, the patient had gastrointestinal cancer. Their case suggests that treatment for a clostridial infection should be considered in patients with known gastrointestinal disease, signs and symptoms of sepsis, and abdominal pain. Conversely, patients known to have a C. septicum infection should be evaluated for gastrointestinal lesions.

Aged↗
PubMed1991

Using a Full-depth Wound Drainage System to Decrease Wound Infection Rates in the Morbidly Obese.

The morbidly obese surgical patient is at increased risk for wound complications due to mechanical stresses from a deep and heavy subcutaneous tissue layer that create dead spaces in which hematomas and seromas can form. To drain the full depth of this layer, we revised an existing wound drainage system using cut segments of a Davol drain and added a Velcro binder to minimize lateral stress on the wound. We used the full-depth drain for all 384 morbidly obese patients who underwent vertical banded gastroplasty during a 10-year period. No patient developed a wound infection in the hospital; however, three patients had wound abscesses one month postoperatively, an infection rate of 0.78%. We believe that the drain system was an important factor in producing the low infection rate.

Journal Article↗
PubMed1991

Electrode site preparation techniques: a follow-up study.

A posttest-only control group design was used to study the effect of electrode site preparation techniques on reducing electrical potential across a pair of disposable skin electrodes. One hundred twenty healthy volunteers were randomly assigned into one control and three treatment groups of 30 subjects each. The three treatments were One Step Skin Prep used once, ECG Prep Pad used five times, and ECG Prep Pad used once. To control for handedness, the skin preparation site was randomly assigned to either the left or right forearm. One-tailed paired t-test analyses were used to compare differences between treatment arms and control arms within each group (p less than 0.05). Skin preparation done by using One Step Skin Prep or the ECG Prep Pads used once significantly decreased skin potentials by 2.3 mV and 3.3 mV respectively. There was no significant difference in the control group and the group in which ECG Prep Pads were used five times. These findings extend the knowledge of techniques available to reduce the amount of noise (electrical potential) in physiologic measurement using skin electrodes.

Adult↗
PubMed1990

An empirical study of proxy consent for elderly persons.

To investigate empirical assumptions about substituted judgment, three treatment decision scenarios were presented to 43 competent elderly persons and 115 persons related to them. Related subjects who were explicitly asked to make a substituted judgment came significantly closer to the elderly person's preferences than those who were asked to make their best recommendation (p = .005-.067, depending on index used). These results support the use of a substituted judgment approach to proxy decision makers; other results suggest some limitations of durable powers of attorney.

Aged↗