The association between gut microbiome affecting concomitant medication and the effectiveness of immunotherapy in patients with stage IV NSCLC.

Several observational studies suggested that gut microbiome-affecting-medication impairs the effectiveness of immunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC). We postulated that if the effectiveness of immunotherapy is affected by drug-related changes of the microbiome, a stronger association between the use of co-medication and overall survival (OS) will be observed in patients treated with immunotherapy as compared to patients treated with chemotherapy. In a retrospective matched cohort study, immunotherapy patients were matched (1:1) to patients treated with chemotherapy in the pre immunotherapy era. The association between the use of antibiotics, opioids, proton pump inhibitors, metformin and other antidiabetics on OS was assessed with multivariable cox-regression analyses. Interaction tests were applied to investigate whether the association differs between patients treated with immuno- or chemotherapy. A total of 442 patients were studied. The use of antibiotics was associated with worse OS (adjusted Hazard Ratio (aHR) 1.39, p = 0.02) independent of the type of therapy (chemotherapy or immunotherapy). The use of opioids was also associated with worse OS (aHR 1.33, p = 0.01). The other drugs studied showed no association with OS. Interaction term testing showed no effect modification by immuno- or chemotherapy for the association of antibiotics and opioids with OS. The use of antibiotics and opioids is similarly associated with worse outcomes in both chemotherapy and immunotherapy treated NSCLC patients. This suggests that the association is likely to be a consequence of confounding rather than disturbing the composition of the microbiome.

The distracted driver.

A serious health problem is developing from automobile collisions caused by distracted drivers. This is a result of the rapid proliferation of portable cellular telephones and personal organisers used while driving, the development of more sophisticated entertainment systems and instrument panel controls, the advent of navigation and television displays in vehicles and promises of sophisticated wireless e-mail, FAX and Internet services in the vehicle. Preoccupation with electronic gadgets may also degrade human driving performance. Many drivers however, sincerely believe they have the talent to do several things at the same time, such as hold and look at a cellular telephone in one hand and drive with a beverage container in the other hand whilst at the same time, exercise their personal skills. Obviously, they believe that they do not need two hands on the steering wheel and two eyes on the road. This is a unique situation requiring intensive health promotion as distracted or 'offensive driving' may be habit forming and difficult to change, any significant design remedies will be slow to arrive and may be circumvented, and the regulatory laws have proved difficult or impossible to enforce. This special need may require research to determine the most effective techniques for health promotion.

Occupant injury protection in automobile collisions.

Modern technology has produced automotive vehicles that have become both a luxury and a necessity in modern civilization. They have become highly useful, even more varied in form and function, and capable of high speeds on crowded roadways. One unfortunate consequence is the high frequency of accidents and the greater severity of injuries when collisions do occur. In response, modern technology has produced a variety of safety and health features, devices and designs intended for better occupant protection on in high speed vehicles. Injury reduction has become a prime design objective, but there are residual risks, which, as technology evolves, require effective communication to those risk. There can be little risk avoidance behavior without awareness of the hazards and effective communication to the vehicle occupant, as to what could and should be done for self-protection. For example, one out of three drivers apparently fails to understand the function of head restraints, few understand the 'safe zone' posture required for air bags and many believe safety features should be adjusted only for comfort. Some of the current residual injury producing problems in occupant systems are specifically described here in order to illustrate what is needed in terms of both design remedies and health promotion activities.

Effect of prolactin on 2-deoxyglucose uptake in mouse mammary gland explants.

These studies were carried out to explore the possible effect of prolactin (PRL) on glucose uptake into culture mammary gland explants derived from 12- to 14-day pregnant mice. PRL was found to stimulate an increased rate of uptake of a nonmetabolized glucose analogue, 2-[3H]deoxyglucose, into cultured mammary tissues. The onset of this response was 16 h after the addition of PRL, and the response persisted for at least 24 h. A similar temporal response was observed when the PRL stimulation of [14C]glucose oxidation to 14CO2 was determined. The lowest PRL concentration that elicited a stimulation of 2-deoxyglucose uptake was 20 ng/ml, and a maximum response occurred with PRL at a concentration of 250 ng/ml. Ongoing protein synthesis appears to be essential for PRL to express its effect on 2-deoxyglucose transport since cyclohexamide, puromycin, and actinomycin D abolished the PRL response. It is also apparent that the PRL stimulation of 2-deoxyglucose involves activation of a specific carrier-mediated uptake transport system, since the rate of uptake of L-glucose into mouse mammary gland explants was unaffected by PRL.

Oxidative transformations of arachidonic acid in human dispersed lung cells: disparity between the utilization of endogenous and exogenous substrate.

Eicosanoid release from human dispersed lung cells (HDLC) containing ca 5% mast cells was studied before and after cell activation with ionophore A23187 or anti-IgE. Basal release of eicosanoids synthesized from endogenous arachidonate was measured by radioimmunoassay. In descending order of abundance the products were: 5-hydroxyeicosatetraenoic acid (5-HETE) greater than thromboxane B2 (TXB2) greater than prostaglandin F2 alpha (PGF2 alpha) approximately immunoreactive (i)-PGE2 greater than PGD2 greater than 6-keto-PGF1 alpha approximately i-LTC4. Stimulation of HDLC with ionophore A23187 or, after passive sensitization, with anti-IgE resulted in 2-10 fold increases in the generation of individual eicosanoids. In terms of net generation the most abundant products were PGD2 and TXB2 with either stimulus. Activation with A23187 caused net release of i-LTC4 and 5-HETE, but these products were not measured after immunological activation. A more complete profile of lipoxygenase products released from HDLC dispersed from one lung was obtained after separation by high performance liquid chromatography combined with ultra violet spectroscopy and bioassay. The major products released from the cells from this lung with ionophore stimulation were 13-hydroxylinoleic acid greater than LTB4 greater than 5-HETE greater than 12-HETE greater than LTC4 greater than 15-HETE greater than 11-HETE approximately 9-HETE. When the utilization of exogenous [14C]-arachidonic acid for prostanoid biosynthesis was compared to that of endogenous unlabelled arachidonate the formation of TXB2 was consistently underestimated. These results imply compartmentalization of arachidonic acid utilization in Ca2+-activated HDLC. In unstimulated cells the proportional formation of PGD2 was overestimated when exogenous arachidonic acid was substrate. After activation with A23187 the proportions of PGD2 were similar with both substrate sources. The large proportions of PGD2 and TXB2 generated by HDLC further supports the view that these eicosanoids may be important inflammatory mediators in lung tissue.

The separation of leukotrienes and hydroxyeicosatetraenoic acid metabolites of arachidonic acid by high performance liquid chromatography (HPLC).

The following high performance liquid chromatography system was found suitable for separating most lipoxygenase metabolites of arachidonic acid: Techsphere 5-C18 column, eluting solvent methanol:water:acetic acid (65:35:0.06 v/v), pH 5.3. Comparisons with other packing materials and solvent systems are described. The method could be used to identify lipoxygenase products released from mouse macrophage cells stimulated with gamma-hexachlorocyclohexane. Detection limits between 1 and 10 ng were obtained.

Alterations of postural and Valsalva responses in coronary heart disease.

Patients in congestive heart failure are known to have altered autonomic responses to circulatory stress. In this study, two different age groups of male coronary heart disease (CHD) patients, not in failure, as well as normal male subjects, underwent standard 20-min 70 degrees head-up tilt and Valsalva tests. Responses were monitored by noninvasive methods and cardiac output was estamated with a transthoracic impedance method. During tilt, the CHD patients and control subjects had similar heart rate and diastolic pressure responses. However, the CHD patients had a greater decline in pulse pressure during tilt, mainly due to a decrease in systolic pressure. CHD patients had lesser declines in stroke volume and cardiac index and lesser increases in total vascular resistance than did control subjects. In the Valsalva, the heart rate phase increments (and decrements) from control and rate increments (and decrements) between successive phases were less in the coronary patients. The results indicate that coronary patients, not in failure, have diminished circulatory responses to the tilt and Valsalva maneuver and suggest that these tests may be useful functional indices of cardiovascular capability in coronary disease.