A comparison of high vs standard tidal volumes in ventilator weaning for individuals with sub-acute spinal cord injuries: a site-specific randomized clinical trial.

STUDY DESIGN: Prospective, randomized, controlled parallel group trial with single-blinded data analysis. OBJECTIVES: To determine the safety and efficacy of higher (20 ml kg(-1) ideal body weight (IBW)) vs standard (10 ml kg(-1) IBW) tidal volumes (Vt) for patients with sub-acute traumatic tetraplegia during ventilator weaning using a 14-day (minimum) weaning protocol. SETTING: United States regional spinal cord injury treatment center. METHODS: Thirty-three ventilator requiring inpatients were randomized to either the higher (Group 1) or the standard (Group 2) Vt protocol. Initially, all patients were ventilated at 10 ml kg(-1) IBW Vt and 5 cm H(2)O [corrected] of PEEP for 72 h. For Group 1, Vt was raised 100 ml kg(-1) until reaching target Vt of 20 ml kg(-1) IBW. Group 2 was maintained at Vt of 10 ml kg(-1) IBW. Plateau pressures were kept at or below 30 cm H(2)O. [corrected]. Safety outcomes included incidence of adverse events. RESULTS: Because of smaller than expected enrollment, evaluation of efficacy was not possible. Therefore, we report the safety outcomes of 33 study participants. The 16 patients in Group 1 and 17 patients in Group 2 were demographically similar at baseline, except for age. The average age was 39.3 years in Group 1 and 27.2 years in Group 2, (P=0.002). There was no difference in median days to wean: 14.5 days in Group 1 and 14 days in Group 2. The incidence of adverse pulmonary events was similar between groups. CONCLUSION: Higher tidal volumes can be safely utilized during weaning of patients with tetraplegia from mechanical ventilation using a 14-day weaning protocol.

CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3).

In vivo, apoptotic cells are efficiently removed by professional or nonprofessional phagocytes, a process thought to be essential for tissue remodeling and resolution of inflammation. Macrophages recognize apoptotic cells by several mechanisms, including recognition of exposed phosphatidylserine (PS); however, PS recognition on apoptotic cells has not been identified as a feature of human macrophages. The purpose of this study was to determine whether human monocyte-derived macrophages could be stimulated to recognize PS, defined as inhibition of phagocytosis by PS-containing liposomes. We also assessed the potential roles for scavenger receptors, CD14, and lectins. Uptake of apoptotic neutrophils into unstimulated macrophages was blocked about 50% by Arg-Gly-Asp-Ser and anti-alpha(v), and up to 20% by oxidized low density lipoprotein and N-acetylglucosamine, implying a major role for integrin and minor roles for scavenger and lectin receptors. Uptake into macrophages stimulated with beta-1,3-glucan was blocked 50% by PS liposomes and 40% by oxidized low density lipoprotein, suggesting that the macrophages had switched from using integrin to recognition of PS. MEM-18 and 61D3 (anti-CD14 mAbs) were poor inhibitors of apoptotic neutrophil uptake, but good inhibitors of apoptotic lymphocyte uptake. The switch to PS recognition was accompanied by down-regulation of alpha(v)beta3 expression and function. Anti-CD36 blocked uptake into unstimulated or stimulated macrophages, suggesting CD36 involvement not only with the alpha(v)beta3 integrin mechanism (as previously reported) but also with PS recognition. A maximum of 70% inhibition was achieved by combining anti-CD36 with either anti-a(v) or PS liposomes.

Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent hemorrhage from the sites of vascular lesions. Two genes have been identified for HHT. Endoglin, a TGF-beta binding protein which maps to chromosome 9q3, is the gene for HHT1. The type and location of most of the previously described mutations in the endoglin (ENG) gene suggested a dominant-negative model of receptor-complex dysfunction for the molecular basis of this disorder. In this article we describe 11 novel ENG mutations in HHT kindreds, which include missense and splice-site mutations. Two identical missense mutations in unrelated families disrupt the start codon of the gene. In addition, some frameshift and nonsense mutations lead to very low or undetectable levels of transcript from the mutant allele. These combined data suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.

The role of phosphatidylserine in recognition of apoptotic cells by phagocytes.

Exposure of phosphatidylserine on the outer leaflet of the plasma membrane is a surface change common to many apoptotic cells. Normally restricted to the inner leaflet, phosphatidylserine appears as a result of decreased aminophospholipid translocase activity and activation of a calcium-dependent scramblase. Phosphatidylserine exposure has several potential biological consequences, one of which is recognition and removal of the apoptotic cell by phagocytes. It is still not clear which receptors mediate PS recognition on apoptotic cells; however, several interesting candidates have been proposed. These include the Class B scavenger and thrombospondin receptor CD36, an oxLDL receptor (CD68), CD14, annexins, beta2 glycoprotein I, gas-6 and a novel activity expressed on macrophages stimulated with digestible particles such as beta-glucan. Whether PS is the sole ligand recognized by phagocytes or whether it associated with other molecules to form a complex ligand remains to be determined.

Epidemiology of endometriosis.

This article summarizes present knowledge about the epidemiology of endometriosis. Surprisingly, little is known about the prevalence or risk factors of endometriosis, given the medical care and employment costs. Knowledge about the epidemiology of endometriosis is hampered by the inability to diagnose this disease in the general population. Based on a single cohort study, it is estimated that there is a 10% prevalence of endometriosis in the general population. Age is the only sociodemographic characteristic for which a consistent positive relationship has been observed. In general, the risk of endometriosis appears to increase for reproductive health factors that may relate to increased exposure to menstruation (i.e., shorter cycle length, longer duration of flow, or reduced parity). The risk appears to decrease for personal habits that may relate to decreased estrogen levels (i.e., smoking, exercise).

Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome.

Diffuse alveolar hemorrhage (DAH) complicating systemic lupus erythematosus (SLE) remains a devastating pulmonary complication of this systemic disease. We conducted this study to review the clinicopathologic presentation and the effects of prior treatment, presence of infection, and current treatment on the survival and outcome of patients with DAH and SLE. We reviewed the records of 15 SLE patients who experienced 19 episodes of DAH over a 10-year period in a single tertiary care hospital. These patients were compared with 57 previously reported cases. The 19 episodes of DAH represented 3.7% of the 510 admissions occasioned by various complications of SLE. As previously reported, the majority (66%) were women with a median age of 27 years. The onset was often abrupt: < 3 days in 12 of the episodes. In 3 patients (20%), DAH was the initial manifestation of SLE, compared with 11% in the literature series. In the other patients in the present series, DAH appeared a median of 31 months following the diagnosis of SLE, versus 35 months in the literature series. In only 42% of the episodes in the present series, compared with 66% in the literature series, was hemoptysis present at the time of admission. However, hemoptysis eventually appeared in all 19 episodes. Temperature elevation (> 38 degrees C) was another inconsistent finding, found in only 5 episodes (26%) in the present series. The most constant concurrent systemic finding was lupus nephritis (14/15 patients). This represents a significant increase when compared with the literature series (29/48 patients). In 8 of 10 patients in whom lung tissue was available, pulmonary capillaritis accompanied the DAH. This represents a marked difference in the underlying histologic pattern when compared with the literature series. In those patients, 72% (31/43 patients) had bland pulmonary hemorrhage, and capillaritis was described in only 6 patients. The overall patient mortality rate was 53% in the current series and 50% in the literature series. Factors associated with an increased mortality in the present series include the following: mechanical ventilation (62%) versus no mechanical ventilation (0%); infection (78%) versus no infection (20%); and cyclophosphamide therapy for the acute DAH episode (70%) versus no cyclophosphamide therapy (20%). The incidence of infection in DAH and SLE (9/19 episodes) is far greater than previously reported (7/ 57 episodes). One possible explanation for this difference is the increased use of outpatient immunosuppressive therapy with monthly intravenous cyclophosphamide therapy for lupus nephritis. Eighteen DAH episodes in the present series were treated with intravenous methylprednisolone. When one combines both the current and literature series experience (16 episodes), the use of plasmapheresis does not improve survival. Of the 7 patients in the present series who survived all episodes of DAH, 6 remain alive a median of 50 months post episode and without recurrence of DAH. Diffuse alveolar hemorrhage is an uncommon but lethal complication of SLE. The survival rate remains unchanged from previous reports. The absence of hemoptysis should not exclude this diagnosis, particularly in those patients who experience an acute pulmonary syndrome with new radiographic infiltrates accompanied by falling hematocrit and the presence of a hemorrhagic bronchoalveolar lavage. Evidence for lupus nephritis is present in the great majority of cases. Most cases demonstrate the histologic pattern of pulmonary capillaritis. The mortality is adversely affected by the need for mechanical ventilation, either the presence of infection at the time of admission or the development of infection in the hospital, and the use of cyclophosphamide for treatment of the acute event.

Hantavirus serologies in patients hospitalized with community-acquired pneumonia.

In many patients, the etiology of community-acquired pneumonia is not known but may be caused by previously undescribed pathogens in some cases. The recently identified hantavirus Sin Nombre (SN) causes hantavirus pulmonary syndrome. Because sporadic cases have occurred outside the range of its reservoir (the deer mouse Peromyscus maniculatus), an investigation sought to determine whether hantaviruses contributed to cases of community-acquired pneumonia in a large Baltimore hospital. Acute-phase sera from 385 hospitalized patients with pneumonia were examined using an IgG ELISA technique with antigens prepared from several hantaviruses: prototype Hantaan (HTN), Seoul (SEO), Puumala (PUU), Convict Creek (HN107), and SN. Of 385 sera, 8 (2.1%) showed some reactivity with one or more HTN, SEO, or PUU antigens but none had detectable specific IgM antibodies. No sera were reactive with SN or HN107 antigens. Thus, hantaviruses are an uncommon cause of community-acquired pneumonia in the Baltimore area.

Use of the fluorescent micronucleus assay to detect the genotoxic effects of radiation and arsenic exposure in exfoliated human epithelial cells.

The exfoliated cell micronucleus (MN) assay using fluorescent in situ hybridization (FISH) with a centromeric probe is a rapid method for determining the mechanism of MN formation in epithelial tissues exposed to carcinogenic agents. Here, we describe the use of this assay to detect the presence or absence of centromeric DNA in MN induced in vivo by radiation therapy and chronic arsenic (As) ingestion. We examined the buccal cells of an individual receiving 6,500 rads of photon radiation to the head and neck. Exfoliated cells were collected before, during, and after treatment. After radiation exposure a 16.6-fold increase in buccal cell MN frequency was seen. All induced MN were centromere negative (MN-) resulting from chromosome breakage. This finding is consistent with the clastogenic action of radiation and confirmed the reliability of the method. Three weeks post-therapy, MN frequencies returned to baseline. We also applied the assay to exfoliated bladder cells of 18 people chronically exposed to high levels of inorganic arsenic (In-As) in drinking water (average level, 1,312 micrograms As/L) and 18 matched controls (average level, 16 micrograms As/L). The combined increase in MN frequency was 1.8-fold (P = 0.001, Fisher's exact test). Frequencies of micronuclei containing acentric fragments (MN-) and those containing whole chromosomes (MN+) both increased (1.65-fold, P = 0.07, and 1.37-fold, P = 0.15, respectively), suggesting that arsenic may have both clastogenic and weak aneuploidogenic properties in vivo. After stratification on sex, the effect was stronger in male than in female bladder cells. In males the MN- frequency increased 2.06-fold (P = 0.07) while the frequency of MN+ increased 1.86-fold (P = 0.08). In addition, the frequencies of MN- and MN+ were positively associated with urinary arsenic and its metabolites. However, the association was stronger for micronuclei containing acentric fragments. By using FISH with centromeric probes, the mechanism of chemically induced genotoxicity can now be determined in epithelial tissues.

Community-acquired pneumonia: impact of immune status.

This cross-sectional and prospective one year study evaluated adults admitted to an inner city hospital with community-acquired pneumonia. The study used extensive diagnostic methods to evaluate the etiologies of community-acquired pneumonia in hospitalized patients with differing immunologic status. Of 385 study patients, concurrent problems associated with immunosuppression were noted in 221 (57%) patients, 180 of whom were human immunodeficiency virus (HIV)-infected. The five most common causes of community-acquired pneumonia were: Streptococcus pneumoniae, Pneumocystis carinii, aspiration, Hemophilus influenzae, and gram-negative bacilli. Only 8.3% of patients had either Legionella, Chlamydia pneumoniae or Mycoplasma pneumoniae. Despite use of state-of-the-art diagnostic techniques, no diagnosis was made in 46 of 180 (25.6%) HIV-infected patients, 56 of 164 (34.1%) immunocompetent patients, and 20 of 41 (48.8%) non-HIV-infected immunosuppressed patients. The diagnostic yield of pre-antibiotic sputum culture for conventional bacteria was 99/155 (63.9%) compared to 52 of 169 patients (32.7%) with adequate post-antibiotic sputum culture (p < 0.0001). Although S. pneumonia continues to be the most commonly identified etiologic agent of community-acquired pneumonia, it is surpassed by P. carinii in the HIV-infected patient population. The apparent decline in the frequency of S. pneumoniae in our series presumably reflects administration of antibiotics prior to procurement of sputum culture. The paucity of atypical agents in this study support the current American Thoracic Society guidelines for selective use of macrolide therapy in immunocompetent adults hospitalized with community-acquired pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased micronuclei in exfoliated bladder cells of individuals who chronically ingest arsenic-contaminated water in Nevada.

It is well established that inorganic arsenic is causally associated with lung cancer via inhalation and skin cancer via ingestion. Epidemiological evidence based on studies in Taiwan suggests that ingestion of inorganic arsenic may also cause other more fatal internal cancers, with the highest relative risks reported for bladder cancer. Here, we have used a biological marker of response, the micronucleus assay in exfoliated bladder cells, to evaluate the possible genotoxic effects of chronic arsenic ingestion on the bladder. The overall objective of this study was to compare the frequency of micronucleated cells in exfoliated bladder and buccal cells between a group of 18 individuals in Nevada who chronically ingested high levels of inorganic arsenic from their well water (average level, 1,312 micrograms/liter) and an individually matched control group with low exposure to arsenic (average level, 16 micrograms/liter). A 1.8-fold increase (90% confidence interval, 1.06-2.99) was observed in the weighted mean frequency of micronucleated bladder cells in the exposed group (2.79 per 1000 cells) compared with the unexposed group (1.57 per 1000 cells). In addition, the frequency of micronucleated bladder cells was positively associated with the urinary concentration of inorganic arsenic plus its methylated metabolites (Spearman correlation = 0.33; P = 0.03). In contrast, there was no increase in micronucleated buccal cells associated with arsenic ingestion (frequency ratio = 1.0; 90% confidence interval, 0.65-1.53). The results of this study provide evidence that chronic ingestion of high levels of inorganic arsenic in drinking water is associated with an increased frequency of micronucleated bladder cells. These findings are consistent with a genotoxic effect of arsenic on bladder cells, but a larger study is needed to confirm them.

Diagnosis of Chlamydia pneumoniae infection in patients with community-acquired pneumonia by polymerase chain reaction enzyme immunoassay.

We conducted a prospective study of 385 patients who had community-acquired pneumonia with use of a modified polymerase chain reaction (PCR) assay that detects amplified DNA by enzyme immunoassay (EIA). We used PCR-EIA to improve detection of Chlamydia pneumoniae infection and to differentiate C. pneumoniae infection from other chlamydial infections. Cultures of throat swab specimens from four patients yielded Chlamydia species (C. pneumoniae, one patient; Chlamydia species, two patients; and C. psittaci, one patient). C. pneumoniae was repeatedly detected by PCR-EIA for thirteen (3.4%) of these 385 patients. Six of these 13 patients were infected with the human immunodeficiency virus. Ten (76.9%) of the patients who were positive by PCR-EIA had IgG titers of > or = 1:16, and two (15.4%) of the 13 patients had IgG titers of < 1:16; no sera was available in one case. Other pathogens were recovered in eight (61.5%) of the 13 cases in which C. pneumoniae was detected by PCR-EIA. In addition, for 46 (11.9%) of the 385 patients the titers of antibody were considered diagnostic of C. pneumoniae infection; however, as 36 of the 46 patients were infected with the human immunodeficiency virus (which may have affected their serological response to C. pneumoniae), interpretation of these titers was problematic. As PCR-EIA was more sensitive than was culture for detecting C. pneumoniae infection in this study, this method may be a valuable tool for the prompt diagnosis of this infection.

Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution.

BACKGROUND: Women generally regard their hair loss as socially unacceptable and go to great measures to conceal their problem. In some cases, the negative self-image brought about by hair loss may be the basis of psychiatric illness. The purpose of this study was to evaluate a 2% topical minoxidil solution (Rogaine/Regaine, The Upjohn Co, Kalamazoo, Mich) for the treatment of female androgenetic alopecia. A 32-week, double-blind, placebo-controlled trial was conducted in 11 US centers. Three hundred eight women with androgenetic alopecia were enrolled. Two hundred fifty-six of these women completed the trial. A refined photographic technique was used to objectively determine the number of nonvellus hairs regrown. RESULTS: After 32 weeks of treatment, the number of nonvellus hairs in a 1-cm2 evaluation site was increased by an average of 23 hairs in the 2% minoxidil group and by an average of 11 hairs in the placebo group. The 95% confidence interval for the difference in mean hair count change between the treatment groups was 5.9 to 17.5 hairs. The investigators determined that 13% in the minoxidil-treated group had moderate growth and 50% had minimal growth. This compared with 6% and 33%, respectively, in the placebo-treated group. Similarly, 60% of the patients in the 2% minoxidil group reported that they had new hair growth (20% moderate, 40% minimal) compared with 40% (7% moderate, 33% minimal) of the patients in the placebo group. No evaluations of dense hair growth were reported for either treatment group. No clinically significant changes in vital signs were observed and no serious or unexpected medical events were reported. CONCLUSIONS: Topical minoxidil was significantly more effective than placebo in the treatment of female androgenetic alopecia.

Use of topical minoxidil therapy for androgenetic alopecia in women.

BACKGROUND: Androgenetic alopecia is the most common cause of hair loss in men and women. Androgenetic alopecia in women begins as a diffuse and progressive thinning of the frontoparietal area of the scalp. In women, hair loss at any age is socially unacceptable and may be the basis of psychiatric illness. METHODS: A 32-week, double-blind, placebo-controlled trial was conducted in 10 European centers to assess the efficacy and safety of 2% topical minoxidil solution for the treatment of androgenetic alopecia in women. Two hundred ninety-four of the 346 women enrolled (85%) completed the 32-week trial. Photographic and computer imaging techniques were used at each visit to determine objectively the number of nonvellus hairs present in a 1-cm2 area selected as the target evaluation site. RESULTS: In the 2% minoxidil group, the mean increase in nonvellus hair count was 33 hairs, which was significantly greater than that of 19 hairs in the placebo group (P = 0.0001). The investigators observed that 44% of the patients in the 2% minoxidil group achieved new hair growth compared with 29% in the placebo group. When asked to evaluate their own hair growth, 55% of the women in the 2% minoxidil group compared to 41% of the women in the placebo group believed that they had achieved new hair growth. No clinically significant changes in vital signs were observed during the study and no serious or unexpected medical events were reported. CONCLUSION: Topical minoxidil solution was significantly more effective than placebo in the treatment of androgenetic alopecia in women.

The hospital treatment of alcoholism and drug addiction.

Inpatient treatment of alcoholism is an option indicated by certain clinical criteria. The American Society of Addiction Medicine suggests four levels of care, and six assessment dimensions determine which level of care is indicated. An addiction medicine physician can consult with the primary care physician to recommend appropriate placement in difficult cases. Abstinence is a primary goal of treatment; for without abstinence, no other recovery will be possible. The remaining goals of recovery are detoxification, medical evaluation, stabilization of life-threatening emotional issues, education, identification of barriers to recovery, readjustment of behavior toward recovery, and orientation and membership in a self-help group. Successful family contributions can make the difference between success or failure of treatment goals; the role the family plays in recovery is discussed. Treatment for family members is important; the physical, emotional, and spiritual effects on family members can be just as profound on them as they are on the alcoholic. Continuing care maintains the link between the patient and the professional recovery community after discharge and is appropriate for all patients. Extended care allows for structured support of sobriety and often further progress through psychosocial issues identified during the initial treatment phase (i.e., abuse, molestation, unresolved grief). Extended care is indicated for patients requiring further structured assistance in early recovery. A large variety of treatment options are available once the decision has been made to hospitalize the patient.

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses.

BACKGROUND: The phenoxyherbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) has been widely used by professional pesticide applicators in New Zealand since before 1950. Epidemiologic studies of the risk of cancer and birth defects have been conducted in this group of workers, but little is known about the extent of their exposure to the 2,4,5-T contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent carcinogen in animals. PURPOSE: The objective of this study was to determine whether the blood serum levels of TCDD in a group of professional 2,4,5-T applicators in New Zealand were greater than those of a matched control group not involved in 2,4,5-T spraying. METHODS: Of 548 men employed as professional pesticide applicators in New Zealand from 1979 through 1982, nine were selected who had sprayed pesticides, although not necessarily 2,4,5-T, for at least 180 months. These applicators had sprayed 2,4,5-T for a range of 83-372 months. We measured the blood serum levels of polychlorinated dibenzo-p-dioxins and dibenzofurans, which were substituted with chlorine at the 2,3,7,8 position, in the nine pesticide applicators and in a matched group of nine control subjects. RESULTS: The average serum level of TCDD for applicators was almost 10 times that for the matched control subjects, while the average levels of all other congeners and isomers measured in the two groups did not differ substantially. TCDD levels in eight of the nine applicators were higher than those in the control subjects (mean difference, 47.7 parts per trilion). The variation in TCDD levels among the applicators was related to their duration of work exposure to 2,4,5-T. CONCLUSIONS: On the basis of our findings in these subjects in New Zealand, we conclude that increased risks of cancer from brief exposure to phenoxyherbicides reported in other countries are probably not attributable to the TCDD that contaminates 2,4,5-T. We cannot determine from these results, however, whether TCDD exposure from prolonged use of 2,4,5-T poses significant health risks.

Positive and negative symptoms and social competence in adolescents at risk for schizophrenia and affective disorder.

The authors compared adolescents at risk for schizophrenia and affective disorder and normal adolescents. The subjects at risk for schizophrenia had significantly poorer social competence, and formal thought disorder was greater in both high-risk groups. There were no group differences in negative symptoms.

Role of insulin and branched-chain amino acids in regulating protein metabolism during fasting.

This study examines the independent effects of insulin and amino acids on protein metabolism after a 12-h and 4-day fast in healthy volunteers. Leucine (Leu) kinetics were examined during sequential insulin infusions of 0 (group I) or 0.0125 (groups II and III), 1.2, and 10 mU.kg-1.min-1. Plasma Leu was maintained at 12-h fasted levels in groups I and II and at 84-h fasted levels in group III. Four-day fast (vs. 1 day, P less than 0.01) was associated with a 79% drop in plasma insulin and elevations in plasma Leu (122%), Leu rates of appearance (Ra) (21%), and Leu oxidation (56%), and no change in nonoxidative rates of disappearance (Rd). Insulin resulted in a dose-dependent suppression of endogenous Leu Ra with group III = I greater than II. Leu oxidation rose 1.7-fold in group III at the highest insulin dose but remained stable in the two other groups. In conclusion, 4-day fasting is associated with enhanced proteolysis and Leu oxidation with no change in nonoxidative Rd (protein synthesis). Elevated branched-chain (and other) amino acids were required to restore tissue sensitivity and specificity to the effects of insulin on protein metabolism after 4 days of fasting.