Macrophage function in the elderly and impact on injury repair and cancer.

Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1ß and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-ß1 (TGF-ß1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

A Novel Risk Factor Associated With Colonization by Carbapenemase-Producing Enterobacteriaceae: Use of Proton Pump Inhibitors in Addition to Antimicrobial Treatment.

OBJECTIVE To study the association between gastrointestinal colonization of carbapenemase-producing Enterobacteriaceae (CPE) and proton pump inhibitors (PPIs). METHODS We analyzed 31,526 patients with prospective collection of fecal specimens for CPE screening: upon admission (targeted screening) and during hospitalization (opportunistic screening, safety net screening, and extensive contact tracing), in our healthcare network with 3,200 beds from July 1, 2011, through December 31, 2015. Specimens were collected at least once weekly during hospitalization for CPE carriers and subjected to broth enrichment culture and multiplex polymerase chain reaction. RESULTS Of 66,672 fecal specimens collected, 345 specimens (0.5%) from 100 patients (0.3%) had CPE. The number and prevalence (per 100,000 patient-days) of CPE increased from 2 (0.3) in 2012 to 63 (8.0) in 2015 (P<.001). Male sex (odds ratio, 1.91 [95% CI, 1.15-3.18], P=.013), presence of wound or drain (3.12 [1.70-5.71], P<.001), and use of cephalosporins (3.06 [1.42-6.59], P=.004), carbapenems (2.21 [1.10-4.48], P=.027), and PPIs (2.84 [1.72-4.71], P<.001) in the preceding 6 months were significant risk factors by multivariable analysis. Of 79 patients with serial fecal specimens, spontaneous clearance of CPE was noted in 57 (72.2%), with a median (range) of 30 (3-411) days. Comparing patients without use of antibiotics and PPIs, consumption of both antibiotics and PPIs after CPE identification was associated with later clearance of CPE (hazard ratio, 0.35 [95% CI, 0.17-0.73], P=.005). CONCLUSIONS Concomitant use of antibiotics and PPIs prolonged duration of gastrointestinal colonization by CPE. Infect Control Hosp Epidemiol 2016;1418-1425.

Implementation of directly observed patient hand hygiene for hospitalized patients by hand hygiene ambassadors in Hong Kong.

BACKGROUND: The importance of compliance with hand hygiene by patients is increasingly recognized to prevent health care-associated infections. METHODS: This descriptive study observed the effects of an education campaign, targeted to increase patients' self-initiated hand hygiene, and a hand hygiene ambassador-initiated directly observed hand hygiene program on patients' hand hygiene compliance in a university-affiliated hospital. RESULTS: The overall audited compliance of patients' self-initiated hand hygiene was only 37.5%, with a rate of 26.9% (112/416 episodes) before meals and medications, 27.5% (19/69 episodes) after using a urinal or bedpan, and 89.7% (87/97 episodes) after attending toilet facilities. Patients referred from a residential care home for older adults had significantly lower hand hygiene compliance (P = .007). Comparatively, the overall audited compliance of ambassador-initiated directly observed hand hygiene was 97.3% (428/440 episodes), which was significantly higher than patients' self-initiated hand hygiene via a patient education program (37.5%, 218/582 episodes, P < .001). CONCLUSIONS: Directly observed hand hygiene can play an important role in improving compliance with hand hygiene by hospitalized patients.

Effect of proactive infection control measures on benchmarked rate of hospital outbreaks: An analysis of public hospitals in Hong Kong over 5 years.

BACKGROUND: Hospital outbreaks of epidemiologically important pathogens are usually caused by lapses in infection control measures and result in increased morbidity, mortality, and cost. However, there is no benchmark to compare the occurrence of hospital outbreaks across hospitals. METHODS: We implemented proactive infection control measures with an emphasis on timely education of health care workers and hospitalized patients at Queen Mary Hospital, a teaching hospital. Our benchmarked performance (outbreak episodes per 1 million patient discharges and 1 million patient-days) was compared with those of other regional public hospitals without these additional proactive measures in place between 2010 and 2014. RESULTS: During the study period, Queen Mary Hospital had 1 hospital outbreak resulting in 1.48 and 0.45 outbreak episodes per 1 million patient discharges and patient-days, respectively, values significantly lower than the corresponding overall rates in the 7 acute regional hospitals (24.26 and 6.70 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001) and that of all 42 public hospitals in Hong Kong (41.62 and 8.65 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001). CONCLUSIONS: The results of this large study on benchmarked rate of hospital outbreaks per patient discharges or patient-days suggests that proactive infection control interventions may minimize the risk of hospital outbreaks.

Duchenne muscular dystrophy: focus on pharmaceutical and nutritional interventions.

Duchenne muscular dystrophy is a lethal X-linked muscle disease resulting from a defect in the muscle membrane protein dystrophin. The absence of dystrophin leads to muscle membrane fragility, muscle death (necrosis) and eventual replacement of skeletal muscle by fat and fibrous connective tissue. Extensive muscle wasting and respiratory failure results in premature death often by the early 20s. This short review evaluates drug and nutritional interventions designed to reduce the severity of muscular dystrophy, while awaiting the outcome of research into therapies to correct the fundamental gene defect. Combinations of dietary supplementation with amino-acids such as creatine, specific anti-inflammatory drugs and perhaps drugs that target ion channels might have immediate realistic clinical benefits although rigorous research is required to determine optimal combinations of such interventions.

Consistent repeated M- and H-Wave recording in the hind limb of rats.

Sensory and motor conduction velocities calculated from latencies of H reflexes and M waves in rat hind limbs have been used to assess experimental peripheral neuropathy. Amplitudes and latencies vary with recording location, and are seldom assessed directly. Using subcutaneous electrodes on the foot, we recorded consistent M waves and H reflexes while stimulating the sciatic or tibial nerve. The late wave disappeared when dorsal roots were cut, verifying that it was an H reflex. However, stimulus-response characteristics differed from those in humans: (a) the threshold was often higher than for M waves; (b) stimulus intensity eliciting a maximum H-reflex amplitude (Hmax) was often higher than adequate for a maximum M-wave amplitude; and (c) the amplitudes of H reflexes stimulated with intensities supramaximal for the M wave were over 90% of Hmax. H reflexes and M waves recorded repeatedly in rats can be useful in assessing sensory and motor function in models of neuropathy, using amplitudes as well as conduction velocities.

Axonal transport of neurotrophins by visceral afferent and efferent neurons of the vagus nerve of the rat.

The receptor-mediated axonal transport of [125I]-labeled neurotrophins by afferent and efferent neurons of the vagus nerve was determined to predict the responsiveness of these neurons to neurotrophins in vivo. [125I]-labeled neurotrophins were administered to the proximal stump of the transected cervical vagus nerve of adult rats. Vagal afferent neurons retrogradely transported [125I]neurotrophin-3 (NT-3), [125I]nerve growth factor (NGF), and [125I]neurotrophin-4 (NT-4) to perikarya in the ipsilateral nodose ganglion, and transganglionically transported [125I]NT-3, [125I]NGF, and [125I]NT-4 to the central terminal field, the nucleus tractus solitarius (NTS). Vagal afferent neurons showed minimal accumulation of [125I]brain-derived neurotrophic factor (BDNF). In contrast, efferent (parasympathetic and motor) neurons located in the dorsal motor nucleus of the vagus and nucleus ambiguus retrogradely transported [125I]BDNF, [125I]NT-3, and [125I]NT-4, but not [125I]NGF. The receptor specificity of neurotrophin transport was examined by applying [125I]-labeled neurotrophins with an excess of unlabeled neurotrophins. The retrograde transport of [125I]NT-3 to the nodose ganglion was reduced by NT-3 and by NGF, and the transport of [125I]NGF was reduced only by NGF, whereas the transport of [125I]NT-4 was significantly reduced by each of the neurotrophins. The competition profiles for the transport of NT-3 and NGF are consistent with the presence of TrkA and TrkC and the absence of TrkB in the nodose ganglion, whereas the profile for NT-4 suggests a p75 receptor-mediated transport mechanism. The transport profiles of neurotrophins by efferent vagal neurons in the dorsal motor nucleus of the vagus and nucleus ambiguus are consistent with the presence of TrkB and TrkC, but not TrkA, in these nuclei. These observations describe the unique receptor-mediated axonal transport of neurotrophins in adult vagal afferent and efferent neurons and thus serve as a template to discern the role of specific neurotrophins in the functions of these visceral sensory and motor neurons in vivo.

Physiological characterization of Taxol-induced large-fiber sensory neuropathy in the rat.

The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose-related peripheral neuropathy in humans. We produced a dose-dependent large-fiber sensory neuropathy, without detrimental effects on general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H-wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail-flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol-induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.

Audit of deaths from cervical cancer: proposal for an essential component of the National Screening Programme.

AIMS: To ascertain the type and relative frequency of major factors associated with deaths from cervical cancer. METHODS: Deaths from cervical cancer in Rotherham district for the period 1989-1991 were subjected to multifactorial audit by reviewing laboratory, hospital, and general practitioner records; together with, when appropriate, re-screening of cytology smears. This period represented the three to five years after a computerised National Screening Programme (NSP) had been implemented with a five year recall interval. RESULTS: Thirty six deaths were identified. The average age of death was 59 years with 39% occurring in those over 65. Only 6% of cases presented as a result of a cervical smear, comprising 3% derived from the NSP and 3% by chance. Forty seven per cent of cases in which the patient had died had no record of a previous smear invitation; 22% of patients were under 65 years and 25% 65 or over. Those under 65 had presented before the appropriate age band had been called. A non-response to a cervical smear invitation was identified in 22%. In 25% of cases a true negative smear had been reported one to eight years previously (average 4.8 years). An inappropriate laboratory diagnosis was identified in 17% of cases. Fourteen per cent represented false negative smears and 8% comprised inadequate smears that had been reported as negative. Inappropriate clinical diagnosis or management was identified in 19% of cases. In 22% two or more contributory factors were identified in the same patient. CONCLUSIONS: Areas highlighted by the audit warranting further attention included the targeting of women over 65 with no cytology record; those not responding to smear invitations; laboratory performance; clinical acumen; and the reasons for true negative cervical smears. Multifactorial audit of all deaths from cervical cancer should be advocated nationally to assess and improve the effectiveness of the NSP.