Approach to the patient with pulmonary disease

The approach to the HIV-infected patient with pulmonary disease is summarized by the algorithms in Figures 3 and 4. These are not intended to be followed in a rigid step-wise fashion. Rather, the practitioner's knowledge of the patient with his or her accompanying medical risks influences the path taken, including the depth and the speed of the evaluation. For example, the patient with cough who is afebrile and breathing at 18 breaths a minute, with a normal chest radiograph and a CD4 count of 350 cells/mm3, is reasonably treated with a macrolide or cephalosporin for bacterial bronchitis and clinical follow-up while awaiting cultures (see Fig. 4). A febrile patient with a cough productive of thin mucus, but known to have a CD4 count of 60 cells/mm3 should be started on anti-PCP therapy while being evaluated for PCP with an induced sputum and if nondiagnostic, a bronchoscope despite a normal chest radiograph. Screening can be as simple as placing an oximeter on the patient's finger in the clinic. If the oxygen saturation of a patient with a normal chest radiograph is low, then the patient should be hospitalized and begun on treatment for PCP while diagnostic evaluation is initiated. If the oxygen saturation is normal, the patient can be exercised to elicit desaturation. If there is no desaturation, PCP is unlikely. If the results are equivocal (i.e., a decrease in saturation, but less than 3%), rest and exercise arterial blood gases can be performed, along with a Dlco-Gallium scanning can be done in patients known to have abnormal Dlco or those who cannot exercise. Patients with focal infiltrates who have acute onset of symptoms (see Fig. 4) commonly have bacterial infections, but the possibility of PCP or TB should not be dismissed. Induced sputum should be examined if TB or PCP is suspected. Patients who are severely ill might go quickly to bronchoscopy without awaiting improvement on empiric therapy. The patient with diffuse infiltrates (see Fig. 4) needs no screening because the presence of disease is apparent from the radiograph. The diagnostic part quickly leads to bronchoscopy for these patients and the initiation of therapy for PCP when suspected. In patients with known pulmonary KS, gallium scanning can be helpful to rule out acute infection, but bronchoscopy is warranted if the patient is severely ill, or at high risk for PCP. This approach should avoid unnecessary procedures in patients with simple bacterial infections, without missing opportunistic infections and tumors.     

Filtration of diaspirin crosslinked hemoglobin into lung and soft tissue lymph

Diaspirin crosslinked hemoglobin (DCHb) is a new blood substitute manufactured from human blood. To evaluate its microvascular filtration properties, we infused DCLHb into unanesthetized sheep (10%, 20 ml/kg) and measured the flow and composition of lung and soft tissue lymph. For comparison, we also infused human serum albumin (HSA; 10%, 20 ml/kg). DCLHb raised systemic and pulmonary arterial pressures from baseline values of 83 +/- 7 and 13 +/- 2 mm Hg, respectively, to peak values of 113 +/- 9 and 26 +/- 3 mm Hg (p < 0.05 versus baseline). These increases were significantly greater than those associated with HSA, which raised systemic and pulmonary arterial pressures from baseline values of 86 +/- 4 and 13 +/- 2 mm Hg, respectively, to peak values of 97 +/- 3 and 21 +/- 7 mm Hg (p <= 0.05 versus baseline and versus DCLHb). These differences reflect the known pressor properties of DCLHb. Accordingly, DCLHb raised lung and soft tissue lymph flows to peak values of 12.2 +/- 3.8 and 1.6 +/- 0.7 ml/30 min, respectively, while HSA raised lung and soft tissue lymph flows to peak values of 7.5 +/- 4.8 and 4.6 +/- 1.9 ml/30 min, respectively (p <= 0.05 versus DCLHb). The half-times of DCLHb equilibration from plasma into lung and soft tissue lymph of 1. 0 +/- 0.3 and 2.1 +/- 1.1 h, respectively, were significantly faster than HSA equilibration half-times of 3.1 +/- 0.2 and 3.8 +/- 0.9 h. Filtration differences between DCLHb and HSA appear to be due to the pressor properties DCLHb.     

Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer

OBJECTIVE: Endoscopic surveillance of Barrett's esophagus is commonly practiced to detect malignancy in an early and curable stage. However, the cost-effectiveness of this practice has been questioned. To clarify this issue, we undertook a cost analysis of endoscopic surveillance to detect adenocarcinoma in Barrett's esophagus compared with mammography used to detect occult carcinoma of the breast, a widely accepted cancer surveillance technique. METHODS: The rate of esophageal adenocarcinoma detected by endoscopic surveillance was calculated for Duluth Clinic patients with Barrett's esophagus seen from 1980 to 1995 and compared with published rates. The rate of occult breast cancer detection was calculated for all women undergoing surveillance mammography at the Duluth Clinic for the year 1994 and compared with published rates. Costs for screening studies and therapy for cancer treatment for both cancers were calculated based on clinical results and assumptions regarding outcomes derived from published reports, and the costs were compared. RESULTS: Endoscopic surveillance of 149 patients with benign Barrett's esophagus was performed for a total of 510 patient-yr, during which time seven patients developed adenocarcinoma, an incidence of one case per 73 patient-yr of follow-up. Occult breast cancer was detected in 50 of 12,537 mammograms, a detection rate of 0.4%. The incidences in both cases were comparable to published figures. The costs of detecting a case of adenocarcinoma in Barrett's esophagus and occult breast cancer were $37,928 and $54,513, respectively, and those for treatment resulting in cure were $83,340 and $83,292. Cost per life-yr saved was $4,151 for adenocarcinoma in Barrett's esophagus and $57,926 for breast cancer. CONCLUSION: Endoscopic surveillance of patients with Barrett's esophagus compares favorably with the common practice of surveillance mammography to detect early breast cancer, and should therefore be considered to be as cost-effective as surveillance mammography.     

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.     

Inputs to directionally selective simple cells in macaque striate cortex

It is clear that the initial analysis of visual motion takes place in the striate cortex, where directionally selective cells are found that respond to local motion in one direction but not in the opposite direction. Widely accepted motion models postulate as inputs to directional units two or more cells whose spatio-temporal receptive fields (RFs) are approximately 90 degrees out of phase (quadrature) in space and in time. Simple cells in macaque striate cortex differ in their spatial phases, but evidence is lacking for the varying time delays required for two inputs to be in temporal quadrature. We examined the space-time RF structure of cells in macaque striate cortex and found two subpopulations of (nondirectional) simple cells, some that show strongly biphasic temporal responses, and others that are weakly biphasic if at all. The temporal impulse responses of these two classes of cells are very close to 90 degrees apart, with the strongly biphasic cells having a shorter latency than the weakly biphasic cells. A principal component analysis of the spatio-temporal RFs of directionally selective simple cells shows that their RFs could be produced by a linear combination of two components; these two components correspond closely in their respective latencies and biphasic characters to those of strongly biphasic and weakly biphasic nondirectional simple cells, respectively. This finding suggests that the motion system might acquire the requisite temporal quadrature by combining inputs from these two classes of nondirectional cells (or from their respective lateral geniculate inputs, which appear to be from magno and parvo lateral geniculate cells, respectively).     

Preweaning growth traits for Senepol, Hereford, and reciprocal crossbred calves and feedlot performance and carcass characteristics of steers

We conducted a multiyear study in two phases to determine preweaning performance traits of Senepol (S x S), Hereford (H x H), and reciprocal (S x H and H x S) F1 crossbred calves and feedlot performance and carcass characteristics of steers. In Phase I, from 1985 to 1989, data from S x S (n = 194), H x H (n = 383), and S x H (n = 120) calves were used. Numbers of S x S cows were increased during Phase I so that data from H x S (n = 74) calves could be included in Phase II (1990 to 1992) in addition to S x S (n = 118), H x H (n = 130), and S x H (n = 56) calves. Also during Phase II, feedlot performance and carcass characteristics were determined for S x S (n = 30), H x H (n = 26), H x S (n = 36), and S x H (n = 26) steers. In Phase I, S x S calves had heavier (P < .01) birth weights and heavier (P < .01) 205-d adjusted weaning weights than H x H calves. Birth weights of S x H calves were heavier (P < .01) than the mean of the purebred calves, but 205-d adjusted weaning weights did not differ (P > .10). In phase II, direct heterosis was 3.5% for birth weight (P < .05) and 5.1% for 205-d adjusted weaning weight (P < .01). Senepol maternal breed effects were 1.9 kg for birth weight (P < .10) and 37.9 kg for 205-d adjusted weaning weight (P < .01). Levels of direct heterosis, Senepol maternal breed effects, and Hereford direct breed effects were significant for most feedlot performance traits of steer calves that were fed to a common end point. Breeds did not differ (P > .10) for USDA yield and quality grades, and direct heterosis was not significant for Warner-Bratzler shear force. These results demonstrate significant levels of heterosis in preweaning performance between S x S and H x H calves and in feedlot performance of steers. Levels of heterosis were smaller and nonsignificant for most carcass traits including meat tenderness, which did not differ between S x S and H x H steers in this study.     

Liposomes containing lipid A serve as an adjuvant for induction of antibody and cytotoxic T-cell responses against RTS,S malaria antigen

Encapsulation of soluble protein antigens in liposomes was previously shown to result in processing of antigen via the major histocompatibility complex class I pathway, as evidenced by costaining of the trans-Golgi region of murine bone marrow-derived macrophages (BMs) by fluorophore-labeled liposomal antigen and by a trans-Golgi-specific fluorescent lipid. Evidence is presented here that free or liposome-encapsulated RTS,S, a particulate malaria antigen consisting of hepatitis B particles coexpressed with epitopes from the Plasmodium falciparum circumsporozoite protein, also was localized in the trans-Golgi after incubation with BMs, suggesting processing by the class I pathway. An in vivo cytotoxic T-lymphocyte (CTL) response was detected, however, only after immunization with RTS,S encapsulated in liposomes containing lipid A and not after immunization with free RTS,S or with RTS,S encapsulated in liposomes lacking lipid A. Therefore, intracellular delivery of antigen containing CTL epitopes to the Golgi of BMs does not necessarily result in a CTL response in vivo unless an additional adjuvant, such as liposomes containing lipid A, is utilized. Encapsulation of RTS,S in liposomes containing monophosphoryl lipid A (MPL) resulted in a dose-dependent enhancement of the NANP-specific immunoglobulin G (IgG) antibody response compared to that of free RTS,S. The IgG1 and IgG2a subclasses predominated after immunization with RTS,S encapsulated in liposomes containing MPL. These results demonstrate that encapsulation of a lipid-containing particulate antigen, such as RTS, S, in liposomes containing lipid A can enhance both humoral and cellular immune responses.     

Effect of pulmonary artery stenoses on the cardiopulmonary response to exercise following repair of tetralogy of Fallot

Data from exercise tests, echocardiograms, and lung perfusion scans were analyzed to determine whether the excessive minute ventilation (VE) often encountered among patients with tetralogy of Fallot is due to ventilation-perfusion mismatch secondary to branch pulmonary artery stenoses. Patients with branch PA stenoses had lower peak oxygen consumptions and higher VE during exercise than did patients without stenoses, and a strong correlation existed between the degree of pulmonary blood flow maldistribution on lung perfusion scan and the amount of excessive VE during exercise.