Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults

It is well established that many continuously distributed traits have a heritable component. However, it is often difficult to communicate to the general public the meaning of quantitative estimates of heritability. To address this problem, the present paper introduces a heuristic for communicating heritability to nonscientific audiences. This heuristic involves adopting an extremely simplified model of inheritance and artificially (and somewhat arbitrarily) defining a cutoffs of "low environmental risk" and "affectation status." Using body weight and obesity as an example, we present a table which gives estimates of the proportion of obese persons who are "genetically obese" assuming varying levels of "environmental risk" for obesity and relative body weight scores for defining obesity. The resulting statistic may prove useful for lay audiences in understanding a heritability estimate.     

Clostridium difficile-associated diarrhea: epidemiology, risk factors, and infection control

OBJECTIVES: To evaluate the effectiveness of specific infection control measures on the incidence of Clostridium difficile-associated diarrhea (CDAD) and to identify risk factors for its development. SETTING: 370-bed, tertiary-care teaching hospital with approximately 12,000 to 15,000 admissions per year. METHODS: Several infection control measures were implemented in 1991 and 1992, and the attack rates of CDAD were calculated quarterly. Antibiotic use for 1988 through 1993 was analyzed. A case-control study was conducted from January 1992 to December 1992 to identify risk factors for acquisition of CDAD. RESULTS: From 1989 to 1992, the attack rate of CDAD increased from 0.49% to 2.25%. An increase in antibiotic use preceded the rise in the incidence of CDAD in 1991. Despite implementation of various infection control measures, the attack rate decreased to 1.32% in 1993, but did not return to baseline. Ninety-two cases and 78 controls (patients with diarrhea but with negative toxin assay) were studied. By univariate analysis, history of prior respiratory tract infections (odds ratio [OR], 3.6; 95% confidence interval [CI95], 1.2-10.4), the number of antibiotics, and the duration of exposure to second-generation cephalosporins (OR, 3.55; CI95, 1.47-9.41) and to ciprofloxacin (OR, 7.27; CI95, 1.13-166.0) were related significantly to the development of CDAD. By stepwise logistic regression analysis, only exposure to antibiotics and prior respiratory tract infections (P = .0001 and .0203, respectively) were found to be significant. CONCLUSION: Antibiotic pressure might have contributed to failure of infection control measures to reduce the incidence of CDAD to baseline.     

Protein phosphorylation in snail cardiocytes stimulated with molluscan peptide SCPb

Dissociated muscle cells prepared from hearts of the pulmonate snail Helix aspersa were used to study signal transduction induced by molluscan cardioactive peptides. The effects of SCPb on the cAMP levels of whole hearts and the cell preparation were compared. The cells responded to SCPb with a dose-dependent increase in cAMP that had the same structure-activity relations as seen in the intact tissue. SCPb increased the phosphorylation of a 53 kDa protein in a dose dependent manner; threshold was 10(-9) M. The SCPb-induced phosphorylation was mimicked by forskolin and 8-CPT-cAMP. FMRFamide stimulation had no effect on the phosphorylation of this protein.     

Immunoglobulin G responses against human papillomavirus type 16 virus-like particles in a prospective nonintervention cohort study of women with cervical intraepithelial neoplasia

BACKGROUND: Infection with cancer-linked human papillomavirus (HPV) types such as HPV type 16 (HPV16) is the most important risk factor in the development of cervical cancer. It has been shown that immunoglobulin G (IgG) antibody responses against HPV16 virus-like particles (VLPs) are specifically associated with genital HPV16 infection. PURPOSE: The aim of this study was to determine the temporal relationships between the presence of HPV16 VLP-specific IgGs, HPV16 infection patterns, and the course of premalignant cervical disease. METHODS: Plasma samples from 133 women who had been diagnosed originally with mild to moderate cervical dyskaryosis and enrolled in a prospective non-intervention cohort study conducted in Amsterdam, The Netherlands, from 1991 through 1996 were analyzed for the presence of HPV16 VLP-specific IgGs by use of an enzyme-linked immunosorbent assay. A detailed analysis was performed on 43 women with different HPV16 infection patterns during a follow-up period of 10-34 months. Progression or regression of cervical intraepithelial neoplasia (CIN) lesions was monitored by cytologic and colposcopic testing at intervals of 3-4 months. HPV typing in cervical smears was performed by use of a polymerase chain reaction-based assay. Statistical analysis of the serologic data was performed by use of the Mann-Whitney U test or 2 x 2 table analyses. RESULTS: The presence of HPV16 VLP-specific IgGs in the plasma of the patients was found to be associated with the presence of HPV16 DNA in the cervical smear. Significantly higher proportions of patients with persistent HPV16 infections (i.e., who were polymerase chain reaction positive in three to 11 consecutive tests) than of patients with cleared HPV16 infections were found to be positive for the presence of HPV16 VLP-specific IgGs (18 [69.2%] of 26 versus nine [28.1%] of 32, respectively; P = .003). HPV16 VLP-specific IgGs were consistently detected in all women (n = 11) who were persistently HPV16 DNA positive during follow-up and whose disease ultimately progressed to CIN III (histologically diagnosed severe dysplasia or carcinoma in situ). CONCLUSION: HPV16 VLP-specific IgG responses are present in the plasma of a majority of patients with persistent HPV16 infections and histologically confirmed high-grade lesions but only in a smaller subset of patients with cleared HPV16 infections and either normal cervical histology or low-grade CIN lesions. IMPLICATIONS: These results suggest that HPV16 VLP-specific antibodies are not responsible for the clearance of virally induced CIN lesions but that they might, in patients with persistent HPV16 infections, be indicative of an increased cervical cancer risk.     

Leptospirosis: an ignored cause of acute renal failure in Taiwan

Leptospirosis, caused by a spirochete, is the most common zoonosis in domestic or wild animals. Animals excrete infected urine in soil or water and may cause human infections through abrased wound, mucosa, conjunctiva, or by swallowing contaminated water. Clinical presentations of leptospirosis are mostly subclinical. Five to ten percent of leptospirosis are fatal, causing fever, hemorrhage, jaundice, and acute renal failure (Weil's syndrome). Leptospirosis has been ignored as a cause of acute renal failure in Taiwan. We report two patients with leptospirosis who presented with high fever, abdominal pain, jaundice, and acute renal failure. Patient 1 died on day 12 of admission of multiple organ failure associated with pancytopenia, hypogammaglobulinemia, and reactive hemophagocytosis. Leptospirosis was recognized after death. Patient 2 was admitted with similar presentations 2 weeks later. Penicillin and doxycycline were given early in the course, and azotemia, jaundice, respiratory failure, and aseptic meningitis gradually improved. Renal biopsy showed interstitial nephritis. Several tubular clearance tests showed proximal tubular defect with severe bicarbonate wasting (FeHCO3- 20.9%) and incomplete type II renal tubular acidosis without affecting the distal nephron. After 80 days of treatment, this patient was discharged with recovery of conscious level and renal function. This is the first leptospirosis patient with detailed tubular functional and morphological studies of the kidney. Diagnosis of leptospirosis was made by microscopic agglutination test (MAT) for antibody to leptospira and by polymerase chain reaction (PCR) for leptospira DNA in blood and urine (interrogans serogroup australis in case 1 and Leptospira borgpetersenii serogroup ballum in case 2). Because active surveillance has resulted in 13 cases diagnosed as leptospirosis islandwide thereafter, underestimation and ignorance of leptospirosis as a cause of acute renal failure may occur in Taiwan. Therefore, an area with a low leptospirosis incidence may actually have a very high incidence. Leptospirosis should be suspected in febrile patients with jaundice and renal failure when pathogens cannot be identified by traditional culture for microorganisms.     

Mutations in purine nucleoside phosphorylase deficiency

PURPOSE: The aim of this study was to investigate the incidence of unexpected malignant uveal melanoma in the age of ultrasound diagnostics and to highlight the reasons for misdiagnosis. PATIENTS AND METHODS: All eyes were surgically removed and histologic examination was performed between 1981 and 1995. The eyes were investigated for the incidence of uveal melanoma, and the history of the unexpected malignant melanoma of the uvea or ciliary body highlighted. RESULTS: 225 (18.7%) eyes with malignant melanoma out of 2583 enucleated eyes were found. Eight (3.6%) of 225 were clinically unexpected. The clinical misdiagnoses were secondary angle closure or open angle glaucoma (6), retinal detachment (5), iritis (1), scleritis (1), cataract (4) and an intraocular mass that was believed to be a metastasis of a colon carcinoma. Seven of eight eyes were blind, and one eye had light perception only. The longest follow up before enucleation was 13 years. On three eyes diagnostic ultrasound was reportedly performed without specific diagnosis of uveal melanoma. Surgery was performed on four eyes for reasons of uncontrollable intraocular pressure or retinal detachment up to five years before enucleation. Histologic diagnoses were 3 epitheloid-type, 2 spindel-type and 3 necrotic melanoma of the uvea. Four eyes showed scleral invasion by tumor cells and one eye an invasion into the episcleral space. CONCLUSIONS: Even today the rate of unexpected uveal melanoma, according to our study is 3.6%. Therefore, all blind eyes without visualisation of the posterior pole should be examined with ultrasound in order to diagnose an uveal melanoma prior to enucleation.     

Immunoreactive pinopsin in pineal and retinal photoreceptors of various vertebrates

Studies of severe hypoxemic events, defined as an arterial oxygen saturation < 80% greater than 4 s in spontaneously breathing infants, have been limited. The purpose of our study was to examine the distribution of respiratory events that lead to a fall in oximetrically measured oxygen saturation by using breathing patterns, heart rate, and validated pulse oximetry analysis. A total of 161 hypoxemic events were detected in 18 of 30 premature infants studied. Using an inductive plethysmographic based monitor, a total of 460 h of cardiorespiratory monitor recordings were analyzed. Hypoxemic events were categorized as being the direct result of apnea (duration longer than 15 s) or pauses (duration 4-14 s) with either unchanged or lower end-expiratory lung volumes compared with the preevent breaths. The breaths in the preevent period were analyzed for volume, timing, and thoracoabdominal coordination indices. Forty of the 161 events (25%) were associated with apnea of which 80% (31/40) had a mixed/obstructive basis. Ninety-four of the 161 severe hypoxemic events (58%) were associated with pauses with unchanged end-expiratory lung volume. Twenty-two of the 161 events (14%) showed pauses with lower end-expiratory lung volume. There were 5/161 events (3%) with severe hypoxemia in which no pause was observed. Comparison of the preevent periods in each category showed significant differences for only percent tidal volume from initial calibration and arterial oxygen saturation. Sixty-two percent (100/161) of severe hypoxemic events were preceded by hypopneic values of percent tidal volume. Seventy-five percent (40/161) of these hypoxemic events and their etiology would have gone undetected using respiratory monitoring from impedance pneumograms and ECGs. The varied basis for these events underscores the importance of analyzing detailed respiratory wave forms along with movement-free signal of arterial oxygen saturation and ECG, to formulate appropriate intervention strategies.     

The role of the active site cysteine in catalysis by type 1 iodothyronine deiodinase

Type 1 iodothyronine deiodinase (deiodinase 1) is a selenoenzyme that converts the prohormone T4 to the active thyroid hormone T3 by outer ring deiodination or to the inactive metabolite rT3 by inner ring deiodination. Although selenocysteine has been demonstrated to be essential for the biochemical profile of deiodinase 1, the role of a highly conserved, active site cysteine (C124 in rat deiodinase 1) has not been defined. The present studies examined the effects of a Cys124Ala mutation on rat deiodinase 1 enzymatic function and substrate affinity. At a constant 10-mM concentration of dithiothreitol (DTT), the C124A mutant demonstrated a 2-fold lower apparent maximal velocity (Vmax) and Km for rT3 (KmrT3) than the wild type for outer ring deiodination, whereas the Vmax/Km ratio was unchanged. Similarly, the apparent Vmax and KmT3 sulfate for inner ring deiodination were 2-fold lower in the C124A mutant relative to those in the wild type, with no change in the Vmax/Km ratio. The C124A mutant exhibited ping-pong kinetics in the presence of DTT, and substitution of the active site cysteine increased the KmDTT by 14-fold relative to that of the wild-type enzyme, with no significant effects on KmrT3 or Vmax. The C124A mutant was inhibited by propylthiouracil in an uncompetitive fashion and exhibited a 2-fold increase in K(i)propylthiouracil compared with that of the wild type. KmrT3 was also reduced for the C124A mutant when 5 mM reduced glutathione, a potential physiological monothiol cosubstrate, was used in outer ring deiodination assays. These results demonstrate that thiol cosubstrate interactions with C124 in type 1 deiodinase play an important role in enhancing catalytic efficiency for both outer and inner ring deiodination.     

Giant cell arteritis in Lugo, Spain, is associated with low longterm mortality

OBJECTIVE: To assess the longterm survival of patients with giant cell arteritis (GCA) in a well defined area in Northwestern Spain. METHODS: A followup study of consecutive biopsy proven patients with GCA diagnosed in Lugo, Spain January 1, 1982-March 31, 1996 was performed. Patients were followed from time of diagnosis until either their death or October 1, 1996. Time and cause of death were reviewed. Statistical methods included standardized mortality ratio (SMR), and Kaplan-Meier product-limit survival analysis. Cox proportional hazard models were used to identify clinical features and laboratory findings associated with survival. RESULTS: By October 1, 1996, full information about 109 biopsy proven patients with GCA (59 men/50 women) was available. The mean age +/- SD at the time of diagnosis was 73.9 +/- 7.3 years for women and 74.1 +/- 5.8 for men (p = NS). After a median followup of 54 months, 22 patients (20.2%) had died. Three died within the first month after diagnosis due to either vascular complications related to GCA or therapy complications. Apart from a history of severe underlying diseases (comorbid condition unrelated to GCA), neither sex nor any clinical features of GCA were significantly associated with an increase in mortality. As in the general population of the same age in Lugo, the majority of deaths were due to cardiovascular and cerebrovascular complications. SMR was 0.80 (95% CI 0.47-1.13). One, 2, 5, and 10 year survival rates were 95, 91, 81, and 62%, respectively. Hazard function was 1.8% at Day 30 after diagnosis and remained low until the end of the first year of treatment. Thereafter, mortality increased slightly. As this function was constant, we applied an exponential model. The estimated risk of death with this model was 5.3% per year. CONCLUSION: Longterm mortality of GCA in our area is low. However, it may be possible to further lower the mortality rate through early diagnosis and careful followup.