Biomedical subjects
J W Kelly
Publications and source records attributed to J W Kelly.
Factitious infections in orthopedic patients.
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Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro.
Amyloid diseases are caused by the self-assembly of a given protein into an insoluble cross-beta-sheet quaternary structural form which is pathogenic. An understanding of the biochemical mechanism of amyloid fibril formation should prove useful in understanding amyloid disease. Toward this end, a procedure for the conversion of the amyloidogenic protein transthyretin into amyloid fibrils under conditions which mimic the acidic environment of a lysosome has been developed. Association of a structured transthyretin denaturation intermediate is sufficient for amyloid fibril formation in vitro. The rate of fibril formation is pH dependent with significant rates being observed at pHs accessible within the lysosome (3.6-4.8). Far-UV CD spectroscopic studies suggest that transthyretin retains its secondary structural features at pHs where fibrils are formed. Near-UV CD studies demonstrate that transthyretin has retained the majority of its tertiary structure during fibril formation as well. Near-UV CD analysis in combination with glutaraldehyde cross-linking studies suggests that a pH-mediated tetramer to monomer transition is operative in the pH range where fibril formation occurs. The rate of fibril formation decreases markedly at pHs below pH 3.6, consistent with denaturation to a monomeric TTR intermediate which has lost its native tertiary structure and capability to form fibrils. It is difficult to specify with certainty which quaternary structural form of transthyretin is the amyloidogenic intermediate at this time. These difficulties arise because the maximal rate of fibril formation occurs at pH 3.6 where tetramer, traces of dimer, and significant amounts of monomer are observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Effective treatment of cerebral toxoplasmosis with doxycycline.
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A severe, unusual reaction to trimethoprim-sulfamethoxazole in patients infected with human immunodeficiency virus.
The clinical features of three patients with a life-threatening reaction to trimethoprim-sulfamethoxazole (TMP-SMZ) are presented along with seven other cases from the literature. All patients developed sudden fever and hypotension immediately after the administration of TMP-SMZ; usually this reaction occurred within approximately 2 weeks of completion of a previous course of the drug. All but one patient had a rash. Most patients were hypoxemic and developed diffuse pulmonary infiltrates. All patients responded rapidly to supportive care, while bacterial cultures remained negative. The presence, absence, or character of previous adverse reactions to TMP-SMZ did not predict subsequent severe reactions. Although its mechanism remains unclear, this reaction has features of both IgE-mediated anaphylaxis and cytokine (tumor necrosis factor)-mediated effects. We advise extreme caution, with close observation, when this drug is first readministered to patients who have experienced any TMP-SMZ-associated toxicity within the previous 6-8 weeks.
Beta-sheet rearrangements: serpins and beyond.
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Serum angiotensin-converting enzyme level is elevated in patients with human immunodeficiency virus infection.
BACKGROUND: Serum angiotensin-converting enzyme (ACE) level is elevated in a number of disease states and medical conditions. Based on review of the medical literature, we postulated that serum ACE level elevation may occur during infection with the human immunodeficiency virus (HIV). METHODS: In a prospective, controlled study, serum ACE levels of HIV-positive patients were compared with those of an HIV-negative control population. RESULTS: Serum ACE levels were significantly elevated in patients with the acquired immunodeficiency syndrome (55.4 +/- 11.4 U/L) and in patients with an intermediate stage of HIV infection (57.2 +/- 25.3 U/L) when compared with levels in controls (31.9 +/- 14.0 U/L). CONCLUSIONS: Elevated serum ACE levels occur in HIV infection and may be an important marker for this disease.
Gastric acid secretion in HIV-1 infection.
It has been suggested that AIDS patients may have reduced gastric acid output. This is of concern because gastric acid may be required for absorption of oral antifungal agents that are important in AIDS management. The cause as well as the progression of reduced gastric acid output in AIDS patients is unclear. This study investigated gastric acid output in relation to the stage of non-AIDS HIV-1-infected patients. No statistical difference was found between nine control and 26 male HIV-infected subjects in basal acid output, maximal acid output, peak acid output, or fasting serum gastrin, regardless of stage. Likewise, no relationship between stage of HIV infection and gastric acid output was determined. We conclude that there is no impairment in basal and maximally stimulated gastric acid secretion in non-AIDS HIV-1-infected males. In addition, the clinical stage of non-AIDS HIV-1 infection has no effect on gastric acid secretion.
Following lentigo maligna may not prevent the development of life-threatening melanoma.
BACKGROUND: Management of lentigo maligna (Hutchinson's melanotic freckle, in situ lentigo maligna melanoma) by regular observation relies on the detection of invasive melanoma before it has developed significant life-threatening potential. Recent studies indicate that lentigo maligna melanoma does not have a better prognosis than other forms of melanoma. OBSERVATIONS: A case is reported of an amelanotic lentigo maligna that evolved from a macular lesion to a deeply invasive, amelanotic, lentigo maligna melanoma within 6 months. The melanoma was Clark level IV and measured 3.0 mm in maximum tumor thickness. CONCLUSIONS: Observation of lentigo maligna at 6-month intervals would not seem to be sufficiently reliable in detecting the development of invasive lentigo maligna melanoma before it becomes a life-threatening disease. Early surgical excision is the treatment of choice.
Retinoids to prevent skin cancer in organ transplant recipients.
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T-cell subsets with a naive phenotype are selectively decreased in the peripheral blood of patients with mycosis fungoides.
Peripheral blood lymphocytes of 33 patients with histopathologic confirmation of mycosis fungoides and 27 healthy controls matched for age and sex were analyzed with a panel of monoclonal antibodies using both single and dual color immunofluorescence. Patients with mycosis fungoides had a significant reduction in the percentage of circulating T cells with a naive phenotype (i.e., CD4+2H4+ and CD4+Leu8+), as well as a significant reduction in the absolute numbers of circulating lymphocytes with the phenotype CD8+Leu8+ compared to the control cohort. The reduction in circulating naive T cells was found to occur irrespective of stage of disease, duration of disease, or mode of treatment. The depletion of circulating naive T cells may reflect increased conversion to memory T cells in the peripheral blood or skin.
Safety and efficacy of mometasone furoate cream in the treatment of steroid responsive dermatoses.
The safety and efficacy of once daily application of mometasone furoate cream 0.1% was determined by comparison with twice daily applications of betamethasone dipropionate cream 0.05% in a single blind, dual centre, randomized study in patients with a variety of steroid-responsive inflammatory dermatoses, the most common of which was psoriasis. Morning plasma cortisol levels revealed little adrenal suppression in either of the two study groups and there was no significant difference between the two groups. Routine laboratory investigations showed no trends in values outside the normal ranges that were of clinical significance. Less skin atrophy was seen in the group treated with mometasone furoate. In comparison to the betamethasone dipropionate treated group, those treated with mometasone furoate exhibited only slight evidence of skin atrophy, and this was not observed before four to twelve weeks of treatment. Eighteen percent of patients using mometasone reported adverse reactions but all were of limited duration and did not persist despite continued application of the drug. Nine percent of patients using betamethasone dipropionate reported adverse effects. Both drugs were found to be highly effective with no significant difference between the two groups at the termination of the treatment period. Of importance is the fact that whilst mometasone furoate is found to be a highly effective treatment for a variety of steroid-responsive dermatoses, this drug has only a limited potential for production of local and systemic side effects. Thus, a high margin of safety can be expected for patients using this drug.
Serum interleukin-2 receptor levels and cutaneous T-cell lymphoma.
The serum of twenty-four patients with histopathological confirmation of cutaneous T-cell lymphoma, including three with Sezary's syndrome, and twenty age matched controls was examined for soluble interleukin-2 receptor using a commercially available ELISA kit. Whilst there was no significant difference in the mean concentration of the interleukin-2 receptor between patients with mycosis fungoides and controls, six of twenty-one patients had interleukin-2 receptor levels outside the mean plus two standard deviations of the age matched cohort. Patients with Sezary's syndrome had markedly elevated levels of this receptor. Our data support a previous report suggesting serum levels of soluble interleukin-2 receptor increase with advancing age, highlighting the need for age matched controls when studying soluble interleukin-2 receptor levels in disease states.
The lack of utility of the latex agglutination test for detection of Candida antigen in the diagnosis of systemic candidiasis.
The Ramco latex agglutination test in the diagnosis of systemic candidiasis was utilized for 11 serum samples from 10 patients with systemic candidiasis, 21 serum samples from patients colonized with Candida species, and 20 control serum samples from patients with stable medical problems and no evidence of Candida albicans infection. This study was double-blind and the results of the latex agglutination test did not influence the decision for antifungal therapy. Nine of 10 patients with systemic candidiasis had positive titers (greater than or equal to 1:4); however, these were determined only 1 to 5 days before culture positivity. Nine of 21 (43%) of colonized patients were falsely positive (greater than or equal to 1:4) and all of the control samples were negative. The Ramco latex agglutination test was unreliable and inconsistent in this small sample group to establish an early diagnosis of systemic candidiasis.
Incidence of colonization, nosocomial pneumonia, and mortality in critically ill patients using a Trach Care closed-suction system versus an open-suction system: prospective, randomized study.
Eighty-four intubated, mechanically ventilated patients were prospectively evaluated for incidences of colonization and nosocomial pneumonias dependent on whether they received endotracheal suctioning by an "open" suction method vs. "closed" suction (Trach Care Closed Suction System) method. Results show that closed suctioning is associated with a significant (67% vs. 39% p less than .02) increase in colonization compared with open suctioning. However, difference in the incidence of nosocomial pneumonia was not significantly (26% vs. 29%) different between closed and open suctioning. Differences in severity of illness (Acute Physiology and Chronic Health Evaluation II and Therapeutic Intervention Scoring System), age, sex, presence of NG tubes, use of H2 antagonists or antacids, use of antibiotics, and history of smoking were all nonsignificant. Survival analysis demonstrated that the probability of survival without developing nosocomial pneumonia was greater among closed-suctioning patients vs. open-suctioned patients (p less than .03). This study shows that suctioning performed via the Trach Care closed-suction system increases the incidence of colonization but not the incidence of nosocomial pneumonia, and may actually decrease mortality when compared with open-suction systems.
The management of early skin cancer in the 90s.
Skin cancer has become a major source of illness and death in Australia. Recent advances in the early detection of skin cancer and in its treatment have significantly altered management, particularly of melanoma. Evidence that a high proportion of all skin cancers and most life-threatening skin cancers arise on the normally protected areas of the trunk and limbs has underlined the need for complete skin examination as a part of the care of long term patients in general practice.
Peptide and protein synthesis by segment synthesis-condensation.
The chemical synthesis of biologically active peptides and polypeptides can be achieved by using a convergent strategy of condensing protected peptide segments to form the desired molecule. An oxime support increases the ease with which intermediate protected peptides can be synthesized and makes this approach useful for the synthesis of peptides in which secondary structural elements have been redesigned. The extension of these methods to large peptides and proteins, for which folding of secondary structures into functional tertiary structures is critical, is discussed. Models of apolipoproteins, the homeo domain from the developmental protein encoded by the Antennapedia gene of Drosophila, a part of the Cro repressor, and the enzyme ribonuclease T1 and a structural analog have been synthesized with this method.
The distribution of melanocytic naevi in melanoma patients and control subjects.
A study of 121 melanoma patients and 139 control subjects was conducted among whites to examine and compare the distribution of non-dysplastic and dysplastic naevi and other pigmented lesions in each group. Melanoma patients had a mean of 97 melanocytic naevi which were greater than 2 mm in diameter and controls had a mean of 36 such naevi, while the medians were 58 and 22 respectively (p less than 0.0001). 55% of melanoma patients and 17% of controls had at least one clinically determined dysplastic naevus, and 26% of melanoma patients and 6% of controls had at least 5 dysplastic naevi. Men were found to have more naevi on the trunk than women in both melanoma cases (p = 0.01), and controls (p = 0.005). Dysplastic naevi were most often found on the trunk and were present at this location in 51% of cases and 17% of controls. Melanoma patients and control subjects with dysplastic naevi, when compared to those without these lesions, had larger number of non-dysplastic naevi. Lentigines were more common among melanoma patients that among control subjects (p = 0.02). There were no differences in the number of non-dysplastic naevi among cases with light and dark hair and eyes, or among controls with these characteristics. There also was little variation in the number of naevi according to number of blistering sunburns.