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.

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.

Daily spirometric variability: normal subjects and subjects with chronic bronchitis with and without airflow obstruction.

To determine the daily variability of spirometry, we performed spirometry on five consecutive days on 15 normal subjects and on 24 patients with chronic bronchitis. The patients with chronic bronchitis were divided into the following two groups: 13 with chronic airflow obstruction (forced expiratory volume in 1 s [FEV1] 80%, FEV1/forced vital capacity [FVC] ratio less than 75%) and 11 without airflow obstruction (FEV1 and FVC greater than 80%0. We attempted to control most of the factors known to affect spirometric variability. Our results indicate that the day-to-day FEV1 has to change by 17% and the FCV by 15% in patients with airflow obstruction before the change should be considered significant. In patients with nonobstructive chronic bronchitis or in normal subjects, a greater than 5% change should occur in FEV1 and FVC before considering the change to be significant.

The determination of resectability of lung cancer by fiberoptic bronchoscopy.

The usefulness of flexible fiberoptic bronchoscopy (FFB) in determining resectability of lung cancer in 152 patients was evaluated. Based on clinical and routine chest roentgenographic examinations, 66 patients (43%) had what were considered to be operable lesions greater than 3 cm in diameter or tumors associated with atelectasis or obstructive pneumonitis (but less than an entire lung), without evidence of pleural effusion or chest wall, mediastinal, or extrathoracic involvement. Forty-eight (73%) of the 66 patients were eventually found to have unresectable conditions. With FFB alone, the conditions of 32 (67%) of these 48 patients were staged as unresectable, so that more invasive procedures, eg, mediastinoscopy or thoracotomy, were required in only 12 and four patients, respectively. Early FFB should be done in potentially resectable cases in which these roentgenographic criteria are met. This procedure is easy, safe, and economical and would allow many patients with lung cancer to have the stage of their disease determined and be treated entirely as outpatients.

Postural hypoxemia in quadriplegic patients.

Quadriplegic patients frequently undergo unusual positional changes, including head-down tilt. To determine if hypoxemia develops in this position and whether it is related to the duration of quadriplegia, five patients were studied within 1 year of injury (group A) and five after 1 year from injury (group B). Arterial blood gases were obtained in the seated and 45-degree head-down position. Group A patients had a decrease in arterial partial pressure of oxygen in the head-down position (p less than 0.025), while group B patients did not (p greater than 0.4). This study demonstrated that quadriplegic patients have positional hypoxemia early in their course. This probably results from relative hypoventilation of the upper lung fields caused by flaccid paralysis of the intercostal muscles. The positional hypoxemia disappears with time, presumably because of the change from flaccid to spastic paralysis of the intercostal muscles.

Bilateral diaphragmatic paralysis complicating local cardiac hypothermia during open heart surgery.

Filling the pericardial sac with ice and saline during open heart surgery protects the myocardium during periods of ischemic arrest. Bilateral diaphragmatic paralysis complicated intense local hypothermia in five patients undergoing coronary artery bypass surgery. All complained of severe orthopnea, exertional dyspnea, insomnia, and excessive daytime somnolence. All exhibited paradoxic inward movement of the abdominal wall with inspiration. The diagnosis of bilateral diaphragmatic paralysis was confirmed with upright and supine spirometry and, in one patient, with transdiaphragmatic pressure measurements. Although paralysis has resolved in four patients, all experienced months of disabling impairment. One patient required four months of mechanical ventilatory support prior to her recovery. Alternative methods of intraoperative myocardial preservation that avoid this complication should be developed.

Carboxyhemoglobin levels in primary and secondary cigar and pipe smokers.

This study of 130 subjects was performed to obtain more data about the smoking habits and levels of carboxyhemoglobin in various types of pipe and cigar smokers. These smokers may be divided by history into primary or secondary smokers and also into current inhalers and noninhalers. Prior studies of carboxyhemoglobin levels have yielded conflicting results, presumably due to differences in current habits of inhalation, which were often not taken into account. Cigarette, primary pipe, and secondary pipe inhalers had similar carboxyhemoglobin levels that were significantly higher than nonsmokers (5.6, 5.0, 5.4, and 1.0 percent, respectively). Cigar inhalers had markedly elevated concentrations of carboxyhemoglobin (13.8 and 11.8 percent in primary and secondary inhalers, respectively). Most secondary cigar and pipe smokers inhaled, whereas most primary smokers did not. Intentional inhalation, rather than past smoking history, is the most important factor in determining the carboxyhemoglobin level for each type of smoke.

Hyperacute radiation pneumonitis.

We present a patient who developed radiation pneumonitis only eight days after beginning therapy. The pneumonitis responded dramatically to prednisone on four occasions, which was a helpful point in the differential diagnosis.

Use of lateral position test and perfusion lung scan in predicting mediastinal metastases.

The lateral position test (LPT) accurately measures differential ventilation of the lungs when the mediastinum is mobile. The quantitative perfusion lung scan (PLS) also correlates well with differential ventilation but is not dependent on mediastinal movement. If tumor metastasis to mediastinal lymph nodes (MLN) inhibits mediastinal movement, then the PLS may give discordant values for differential ventilation from that of the LPT. Before mediastinoscopy or thoracotomy or both, 14 cases of lung cancer were prospectively evaluated by comparing the relative ventilation of the involved lung as determined by LPT and PLS. Seven patients who had no evidence of MLN involvement had nearly equal ventilation by the two techniques (r = .94), and the absolute difference was always less than 12 percent (mean, 4.4 percent). Seven patients with MLN involvement had unequal ventilation as determined by LPT and PLS (r = 0.07), and between the two techniques there was a difference of at least 13 percent (mean, 27.3 percent). We conclude that the LPT used in combination with the PLS is an accurate, economical, and noninvasive technique for suggesting MLN metastasis and, thus, tentatively staging carcinoma of the lung. Those patients with discordant values should probably undergo mediastinoscopy before thoracotomy.

Effectiveness of oxygen therapy in hypoxic polycythemic smokers.

Eleven hypoxic (arterial oxygen pressure [PaO2] less than or equal to 61 mm Hg), polycythemic (hematocrit reading greater than or equal to 54 percent) patients were studied to determine the effect of the carboxyhemoglobin level on their response to therapy with supplemental oxygen. Five nonsmokers with a mean carboxyhemoglobin level of 2.8 percent showed an excellent response to therapy with supplemental oxygen, with a decrease in hematocrit reading from 57 percent to 48 percent (P less than 0.0025) as the PaO2 increased from 53 mm Hg to 69 mm Hg (P less than 0.01) and the arterial oxygen saturation (SaO2) increased from 86 percent to 94 percent (P less than 0.0025). Six smokers with a mean carboxyhemoglobin level of 13 percent showed an incomplete response to therapy with supplemental oxygen, with a decrease in hematocrit reading from 62 percent to 57 percent (P less than 0.0025) as the PaO2 increased from 53 mm Hg to 69 mm Hg (P less than 0.0025) and the SaO2 increased from 82 percent to 88 percent (P less than 0.001). In spite of similar values for the PaO2, the smokers had higher hematocrit readings before and during therapy with oxygen (P less than 0.01), presumably due to superimposed desaturation by carboxyhemoglobin. We concluded that polycythemia in hypoxic smokers is due to additive effects of hypoxia and a high carboxyhemoglobin level. The former is responsive to therapy with oxygen, while the latter is not. To achieve a "complete" response to therapy with supplemental oxygen, hypoxic polycythemic smokers should quit smoking.

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.

Biopsy of the main carina; staging lung cancer with the fiberoptic bronchoscope.

The efficacy of main carinal biopsy through the fiberoptic bronchoscope for evaluating resectability has not been determined. Forty-eight patients with carcinoma, but without gross neoplastic involvement of the main carina, underwent biopsy. Five (10 percent) had abnormal results on biopsy of the main carina. Three of the five patients were initially considered candidates for surgery. There were no complications from the procedure. Biopsy of the main carina through the fiberoptic bronchoscope is a valuable staging procedure in selected patients because of its simplicity and yield and the significance of abnormal findings.

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.

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.

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.

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.

Respiratory abnormalities in hypothyroidism.

While the respiratory and oxygen transport systems are complex, they are orderly, so that they can be studied logically and systematically. There are many interactions and potential abnormalities at various levels that may combine to give the ultimate defect of inadequate oxygen supply at the tissue level. An understanding of these many factors using hypothyroidism as a model should enable the clinician to approach the problem rationally and manage if effectively.