VITamin D and OmegA-3 TriaL (VITAL) bone health ancillary study: clinical factors associated with trabecular bone score in women and men.

We investigated the association of clinical variables with TBS at baseline in the bone health sub-cohort of the VITamin D and OmegA-3 TriaL (VITAL). Lower TBS was associated with female sex, aging, BMI ≥ 25 kg/m2, SSRI use, high alcohol intake, and presence of diabetes; there was a trend towards significance between lower TBS and history of fragility fractures. INTRODUCTION: We investigated whether TBS differs by sex, race, body mass index (BMI), and other clinical variables. METHODS: The VITamin D and OmegA-3 TriaL (VITAL) is determining effects of vitamin D3 and/or omega-3 fatty acid (FA) supplements in reducing risks of cancer and cardiovascular disease. In the VITAL: Effects on Bone Structure/Architecture ancillary study, effects of these interventions on bone will be investigated. Here, we examine the associations of clinical risk factors with TBS assessments at baseline in the bone health sub-cohort, comprised of 672 participants (369 men and 303 women), mean (± SD) age 63.5 ± 6.0 years; BMI ≤ 37 kg/m2, no bisphosphonates within 2 years or other bone active medications within 1 year. RESULTS: TBS was greater in men than women (1.311 vs. 1.278, P < 0.001) and lower with elevated BMIs (P < 0.001), higher age (P = 0.004), diabetes (P = 0.008), SSRI use (P = 0.044), and high alcohol intake (P = 0.009). There was a trend for history of fragility fractures (P = 0.072), and lower TBS. TBS did not vary when analyzed by race, smoking, history of falls, and multivitamin or caffeine use. CONCLUSIONS: Lower TBS was associated with female sex, aging, BMI ≥ 25 kg/m2, SSRI use, alcohol use, and presence of diabetes; there was a trend between lower TBS and history of fragility fractures. TBS may be useful clinically to assess structural changes that may be associated with fractures among patients who are overweight or obese, those on SSRIs, or with diabetes. Ongoing follow-up studies will clarify the effects of supplemental vitamin D3 and/or FA's on TBS and other bone health measures. TRIAL REGISTRATION: NCT01747447.

Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression.

Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene-gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression.

Tracheostomy tube occlusion protocol predicts significant tracheal obstruction to air flow in patients requiring prolonged mechanical ventilation.

OBJECTIVE: This study was undertaken to test the hypothesis that a tracheal tube occlusion protocol predicts clinically important obstruction to air flow in patients requiring prolonged mechanical ventilation, making routine bronchoscopy unnecessary. DESIGN: A prospective evaluation of 75 patients who were clinically ready to be decannulated. All patients underwent the tracheal tube occlusion protocol followed by bronchoscopy. SETTING: Three hospitals affiliated with a college of medicine. PATIENTS: Over a 24-month period, 52 males and 23 females were enrolled in the study. Mean age was 55 yrs (range 25 to 85). Mean endotracheal/tracheostomy time was 2.4/8.9 wks (range 1 to 4/5 to 14). All patients were mechanically ventilated for at least 4 wks and were successfully weaned from the mechanical ventilator for at least 48 hrs. During spontaneous breathing, these data were observed: minute ventilation of < 10 L/min; resting respiratory rate of < 18 breaths/min; and arterial oxygen saturation of > 90% on 40% oxygen tracheal collar mask. The tracheal tube occlusion protocol consisted of deflating the cuff on the fenestrated tracheal tube and occluding the tube. INTERVENTIONS: Patients who developed respiratory distress when the tracheal tube was occluded were deemed to have failed the protocol. At bronchoscopy, the patients were asked to cough and hyperventilate in an attempt to forcibly reduce the cross-sectional area of the trachea. A sustained, subjectively assessed decrease of > or = 50% of the effective cross-sectional area of the trachea was considered to be an indication for intervention. MEASUREMENTS AND MAIN RESULTS: Sixty-three (84%) of 75 patients tolerated the tracheal tube occlusion protocol. Twelve (16%) of 75 patients developed signs of respiratory distress and showed decreased oxygen saturation values necessitating uncapping of the tracheal tube. All patients had some degree of tracheal injury. However, those patients who failed to tolerate the tracheal tube occlusion protocol had clinically important tracheal obstruction to air flow. CONCLUSION: A tracheal tube occlusion protocol can predict clinically important obstruction to air flow after prolonged mechanical ventilation.

The FEF25-75% and the clinical diagnosis of asthma.

Nonspecific bronchial provocation testing is clinically useful in the evaluation of patients with symptoms suggestive of asthma. Testing is usually reserved for those with normal or near normal baseline spirometry. Although bronchial provocation testing is safe and widely available, the protocol is time consuming and not without expense. It has been reported that a reduced FEF25-75% in the context of an otherwise normal spirogram suggests that asthma should be considered. To evaluate this suggestion, we compared the baseline FEF25-75% (expressed as percent of predicted) with the results of the subsequent methacholine bronchial provocation test in 205 consecutive patients referred for testing. The mean baseline FEF25-75% in the 112 patients with normally responsive airways (ie, a negative bronchial provocation test) was 95.4 +/- 27.5%. In the 93 patients with a positive bronchial provocation test, the mean FEF25-75% was 77.6 +/- 27.2%. The mean FEF25-75% in those with hyperresponsive airways was significantly lower (t = 4.616, P < .0001). Of those patients with a positive bronchial provocation test, there was no significant correlation, however, between the baseline FEF25-75% and the degree of bronchial hyperresponsiveness as assessed by the PC20FEV1 (r = .154, P = .141). When a significant reduction in FEF25-75% was defined as less than 60% of predicted, the sensitivity of the prediction rule was 25.8%, the specificity was 92.0%, the positive predictive value was 72.7%, and the negative predictive value was 60.0%. From these results, we conclude that the FEF25-75% derived from simple spirometry may be useful in predicting the presence or absence, but not the degree, of bronchial hyperresponsiveness.

Environmental tobacco smoke and lung cancer risk in nonsmoking women.

BACKGROUND: Exposure to environmental tobacco smoke (passive smoking) has been suggested to be a cause of lung cancer, although early epidemiologic studies have produced inconsistent results. PURPOSE: We conducted an epidemiologic case-control study to assess the relationship between exposure to environmental tobacco smoke and lung cancer risk among women who have never smoked (i.e., having smoked for a total of less than 6 months or having smoked less than 100 cigarettes in their lifetimes). METHODS: Case patients (n = 210) were women with histologically confirmed primary carcinomas of the lung who were lifetime nonsmokers. They were identified through hospital tumor registries and the Florida Cancer Data System of the Statewide Cancer Registry. Community-based control women (n = 301) were also lifetime nonsmokers and were identified through random-digit dialing. Details on childhood and adulthood exposures to environmental tobacco smoke were ascertained through interviews with the study participants themselves or with surrogate respondents. Risks were calculated in terms of smoke-years, defined as the sum of the reported years of exposure to cigarette smoke from each smoker in the household. RESULTS: The risk of lung cancer more than doubled for women who reported 40 or more smoke-years of household exposure during adulthood (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.1-5.3) or 22 or more smoke-years of exposure during childhood and adolescence (OR = 2.4; 95% CI = 1.1-5.4). Risks were highest for non-adenocarcinoma lung cancers, although modest elevations in risk were also observed for adenocarcinomas. When a surrogate respondent other than the patient's husband provided information on exposure, the risk estimates were considerably lower. CONCLUSION: These findings suggest that long-term exposure to environmental tobacco smoke increases the risk of lung cancer in women who have never smoked.

Bronchodilator testing "confidence intervals" based on the level of bronchial responsiveness.

"Confidence intervals" based upon inhalation of placebo have been proposed as criteria for defining a significant response to an inhaled bronchodilator. The published intervals were derived from a clinically heterogeneous population. We calculated the difference (delta) between spirometric data before and after placebo in 109 consecutive patients referred for methacholine bronchoprovocation challenge testing. The mean delta, expressed both as a percent change and as actual volume change for both the FVC and FEV1, was not significantly different in patients with bronchial hyperresponsiveness, as compared to subjects with a negative methacholine challenge test; however, the variance of measurements in hyperresponsive subjects was significantly greater than that of the normal population. In addition, as the category of responsiveness increased from mild to moderate to severe hyperresponsiveness, so did the variance within these groups. A negative correlation between the measured PC20FEV1 and the volume and percent change was noted. We conclude that patients with hyperresponsive airways may display increased spirometric variation before and after placebo. This general approach for establishing normal limits for defining a significant response appears to be valid, but the actual values used may vary, depending on the composition of the population tested and the goals of the study. Also, the use of the term, "confidence intervals," in this context is inappropriate; and we propose, instead, the use of percentiles and the simpler terms, upper 90th or 95th percentiles.

Hypervitaminosis A in a cat.

A 10-year-old cat that was kept on a diet consisting largely of raw liver was evaluated because of lethargy, partial anorexia, and weight loss of several months' duration. The cat's head and neck were rigidly extended, and a hard mass was palpable in the ventral cervical region. Cervical and thoracic radiography revealed proliferative bony lesions of the cervical and thoracic vertebrae as well as of the sternum and costal cartilages. Serum vitamin A concentration was 4 times normal. For reasons unrelated to hypervitaminosis A, euthanasia and necropsy were performed 6 months after evaluation. The skull and the cervical and first few thoracic vertebrae were rigidly fused, and the vertebral architecture was altered by deposition of new bone. The sternum and costal cartilages were similarly affected. The historical, physical, radiographic, laboratory, and postmortem findings were consistent with the diagnosis of hypervitaminosis A. On the basis of findings in this cat, hypervitaminosis A should be suspected in any sick cat fed a diet consisting partly or completely of raw liver.

Effect of mild hypoxemia on bronchial responsiveness.

Nonspecific bronchial responsiveness may be influenced by a number of stimuli. A potentially important stimulus with significant clinical implications is hypoxemia. To investigate the effect of hypoxemia on baseline pulmonary function and bronchial responsiveness, 13 subjects (eight with mild asthma and five normal) were tested on two separate days within a 1-week period. Spirometry measured before and after breathing room air through the experimental circuit for ten minutes was not significantly different. Likewise, there was no difference in baseline spirometry during mild hypoxemia (arterial saturation of 90%) compared with air breathing. The eight asthmatic subjects underwent a methacholine bronchoprovocation challenge on each of the two test days. The PC20FEV1 measured on the "hypoxemic" day (3.7 +/- 4.5 mg/mL) was not significantly different from the measured on the "room air" day (2.5 +/- 2.4 mg/mL, P greater than .05). We conclude that mild hypoxemia does not significantly affect baseline spirometry nor bronchial responsiveness.

Intrapleural streptokinase in management of parapneumonic effusions. Report of series and review of literature.

Noncommunicating locules of fluid may develop in the setting of a thoracic empyema or a complicated parapneumonic effusion. When this occurs a single chest tube may not provide adequate drainage. In an effort to promote drainage and thereby obviate the need for further procedures, instillation of streptokinase into the involved pleural space has been advocated. This communication reviews the literature and reports our experience with intrapleural streptokinase. In our retrospective review of nine patients, instillation of streptokinase resulted in an obvious increase in chest tube drainage in six. Of the nine patients, four with improved drainage required no further procedures. Two patients with improved drainage and the three with no change in drainage required an additional chest tube, a decortication procedure, or were lost to follow-up. None of the four patients with an empyema were benefitted. Intrapleural instillation of streptokinase may be a useful adjunct in the treatment of a complicated parapneumonic effusion but appears less likely to be of benefit in the management of an empyema.

Malignant pleural effusions: pleurodesis using a small-bore percutaneous catheter.

This study describes our experience using a percutaneously placed small-bore catheter for drainage of malignant pleural effusions and subsequent instillation of a sclerosing agent to obliterate the pleural space. We treated 15 consecutive patients with known metastatic cancer and a symptomatic pleural effusion. Twelve patients survived for more than four weeks after the procedure; 11 of these 12 patients had a successful objective clinical response. The procedure was well tolerated, with little or no discomfort during catheter placement and the maintenance period. No serious complications were encountered. We conclude that the use of a small-bore percutaneously placed "pneumothorax" catheter in the management of malignant pleural effusions is an effective and more comfortable alternative to large-bore closed-tube thoracostomy.

Echocardiography in planned interruption of the inferior vena cava.

Interruption of the inferior vena cava by the transvenous placement of a filter or umbrella effectively prevents pulmonary embolism by acting primarily as a physical barrier to emboli. Such a device will be effective only if the site of thrombosis is distal to the planned placement site. We have presented two cases in which a preoperative echocardiogram revealed a right atrial embolus, thereby mandating either embolectomy, fibrinolytic therapy, or continued anticoagulation in addition to the filter placement. These cases suggest that an echocardiogram should be included in the evaluation preceding interruption of the inferior vena cava.

Traumatic urethral avulsion at the preputial fornix in a cat.

A cat with pelvic fractures from being hit by a car had voided no urine in 13 hours despite iv administration of fluids. Abdominal radiography had revealed the pelvic fractures and apparently intact urinary bladder. Urine did not flow from a urethral catheter, and contrast radiography revealed the catheter to be extra-urethral within the penis. Intravenous pyelography revealed intact ureters and urinary bladder; celiotomy confirmed intact urinary bladder. Cystotomy and normograde urethral catheterization allowed localization of the ruptured urethra within the deep subcutaneous tissues of the caudal portion of the abdomen. After closure of the cystotomy and celiotomy incisions, perineal urethrostomy was performed.

Clinical use of methacholine bronchial challenge testing.

Whereas the research applications have been well established, the clinical utility of bronchial challenge testing is still being defined. In 19 of 22 patients referred for testing (86%), the results of a methacholine challenge test helped to confirm a clinical suspicion of asthma or to suggest that alternative diagnoses should be investigated. There was a discrepancy between the pretest suspicion of the referring physician and the results of the challenge test in six of these 19 patients (32%). Thus our experience suggests that bronchial challenge testing provides useful information to supplement clinical acumen in the diagnosis of asthma.

Pulmonary disease caused by Mycobacterium malmoense.

Mycobacterium malmoense was isolated from pulmonary material from 4 patients. Two patients had repeatedly positive smears and cultures along with roentgenographic progression of pulmonary disease in the absence of another pathogen. These 2 patients therefore meet the criteria for diagnosis of pulmonary mycobacteriosis. Isolation of the organism may represent colonization in a third patient, and M. malmoense has been isolated from a fourth patient on 2 occasions. It is not yet definite, however, that the pulmonary process is due to mycobacterial disease. Although uncommon, pulmonary disease caused by this organism has been reported from Europe. Only 1 prior case of pulmonary disease caused by M. malmoense, however, has been reported in the United States.

Oral progesterone treatment in chronic obstructive lung disease: failure of voluntary hyperventilation to predict response.

Previous studies have shown that some patients with chronic obstructive lung disease and hypercapnia will respond to medroxyprogesterone with improvement in arterial blood gases. The exact mechanism of this effect is unclear but it is presumed to be a result of ventilatory stimulation. To determine whether the ability to correct arterial blood gas abnormalities by voluntary hyperventilation would predict a subsequent favourable response to progesterone, we studied 11 subjects with chronic obstructive lung disease and chronic hypercapnia. Five subjects had chronic obstructive lung disease of moderate severity with mean (SE) FEV1 1.8 (0.34) 1 maximum voluntary ventilation (MVV) 40.4 (7.16) 1/min-1, arterial oxygen tension (Pao2) 53.8 (2.40 mm Hg, and arterial carbon dioxide tension Paco2) 49.6 (3.91) mm Hg, and were able to normalise their blood gas tensions during voluntary hyperventilation (Pao2 85.4 (8.01) mm Hg; Paco2 32.8 (3.43) mm Hg). Six subjects had severe chronic obstructive lung disease with FEV1 0.77 (0.12) 1, MVV 19 (3.09) 1/min-1, Pao2 60.0 (2.89) mm Hg and Paco2 50.5 (1.38) mm Hg, and they could not significantly alter their blood gases with voluntary hyperventilation (Pao2 62.5 (3.19) mm Hg, Paco2 49.7 (1.84) mm Hg). The groups were similar in age, height, weight, and resting Pao2 and Paco2. Each subject received one month of oral placebo and one month of medroxyprogesterone acetate (Provera). 20 mg orally thrice daily, given in a randomised, double blind fashion. The groups responded similarly with a significantly higher Pao2 and lower Paco2 while having medroxyprogesterone acetate than while having placebo. Two patients with polycythaemia showed a reduction in haemoglobin concentration while taking progesterone. It is concluded that the response to medroxyprogesterone is not predictable from spirometric or blood gas changes after voluntary hyperventilation.

Pulmonary embolism.

PE, a common and serious pulmonary problem, most often results as a complication of DVT in the lower extremities. There are no specific symptoms or signs that allow a clinical diagnosis of PE. The best approach to the diagnosis is controversial and is at least partially dependent on the diagnostic capabilities and expertise available at a given hospital. Pulmonary arteriography is the definitive diagnostic test and should be considered in patients with results of less-than-high probability V-Q scans, those at high risk of bleeding complications with anticoagulation therapy, and those considered candidates for thrombolytic therapy.

Pulmonary exercise testing.

Pulmonary exercise testing can help define the specific cause of exercise-related symptoms. A knowledge of basic respiratory physiology and static pulmonary function studies is necessary to understand and interpret these tests.