Michael B. Goldberg

Bacterial biogeography of the human digestive tract

We present bacterial biogeography as sampled from the human gastrointestinal tract of four healthy subjects. This study generated >32 million paired-end sequences of bacterial 16S rRNA genes (V3 region) representing >95,000 unique operational taxonomic units (OTUs; 97% similarity clusters), with >99% Goods coverage for all samples. The highest OTU richness and phylogenetic diversity was found in the mouth samples. The microbial communities of multiple biopsy sites within the colon were highly similar within individuals and largely distinct from those in stool. Within an individual, OTU overlap among broad site definitions (mouth, stomach/duodenum, colon and stool) ranged from 32–110 OTUs, 25 of which were common to all individuals and included OTUs affiliated with Faecalibacterium prasnitzii and the TM7 phylum. This first comprehensive characterization of the abundant and rare microflora found along the healthy human digestive tract represents essential groundwork to investigate further how the human microbiome relates to health and disease.

Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination.

Rumination is a form of thought characterized by repetitive focus on discomforting emotions or stimuli. In chronic pain disorders, rumination can impede treatment efficacy. The brain mechanisms underlying rumination about chronic pain are not understood. Interestingly, a link between rumination and functional connectivity (FC) of the brains default mode network (DMN) has been identified within the context of mood disorders. We, and others, have also found DMN dysfunction in chronic pain populations. The medial prefrontal cortex (mPFC) is a key node of the DMN that is anatomically connected with the descending pain modulatory system. Therefore, we tested the hypothesis that in patients with chronic pain, the mPFC exhibits abnormal FC related to the patients degree of rumination about their pain. Seventeen patients with idiopathic temporomandibular disorder (TMD) and 17 age- and sex-matched healthy controls underwent resting state functional MRI, and rumination about pain was assessed through the rumination subscale of the Pain Catastrophizing Scale. Compared with healthy controls, we found that TMD patients exhibited enhanced mPFC FC with other DMN regions, including the posterior cingulate cortex (PCC)/precuneus (PCu) and retrosplenial cortex. We also found that individual differences in pain rumination in the chronic pain patients (but not in healthy controls) were positively correlated to mPFC FC with the PCC/PCu, retrosplenial cortex, medial thalamus, and periaqueductal/periventricular gray. These data implicate communication within the DMN and of the DMN with the descending modulatory system as a mechanism underlying the degree to which patients ruminate about their chronic pain.

Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.

Cortical plasticity is thought to occur following continuous barrage of nociceptive afferent signals to the brain. Hence, chronic pain is presumed to induce anatomical and physiological changes in the brain over time. Inherent factors, some pre-dating the onset of chronic pain, may also contribute to brain abnormalities present in patients. In this study we used structural MRI to examine whether patients with chronic temporomandibular (TMD) pain have abnormalities in gray matter (GM) within brain areas implicated in pain, modulation and sensorimotor function. We found that patients with TMD have cortical thickening in the primary somatosensory cortex (S1), frontal polar and the ventrolateral prefrontal cortex (PFC). These findings provide a structural basis for previous findings of TMD pain and cognitive sluggishness in TMD. We then examined the contribution of TMD characteristics to GM abnormalities. We found that 1) GM in the sensory thalamus positively correlated to TMD duration, 2) cortical thickness in the primary motor (M1) and the anterior mid-cingulate cortices (aMCC) were negatively correlated to pain intensity, and 3) pain unpleasantness was negatively correlated to cortical thickness in the orbitofrontal cortex (OFC). These findings suggest that an individuals TMD pain history contributes to GM in the brain. Lastly, we examined the contribution of a potential pre-existing vulnerability due to neuroticism. In the TMD patients, we found that there was an abnormal positive correlation between neuroticism and OFC thickness, in contrast to the negative correlation found in the healthy controls. Therefore, neuroticism may contribute to TMD pathophysiology. In sum, our data suggest that GM in the brain of patients with chronic TMD pain can be shaped by both personality and pain characteristics.

The Effect of Photodynamic Therapy for Periodontitis: A Systematic Review and Meta-Analysis

BACKGROUND The purpose of this review was to evaluate the effectiveness of photodynamic therapy (PDT) for periodontitis in adults as a primary mode of treatment or as an adjunct to non-surgical treatment of scaling and root planing (SRP) compared to a conventional non-surgical SRP treatment. METHODS MEDLINE, EMBASE, CINAHL, other relevant databases, and the International Pharmaceutical Abstracts were searched from their inception until May 2009 for randomized controlled trials of PDT compared to a placebo, no intervention, or non-surgical treatment in an adult population. Data on changes in clinical attachment level (CAL), probing depth, gingival recession, and full-mouth plaque or bleeding scores were extracted and meta-analyzed, and the pooled mean difference (MD) was reported. RESULTS Five studies were included in this review. These studies had a small sample size for some of the performed analysis with a moderate to high risk of biases. There were clinical heterogeneities among included studies. PDT as an independent treatment or as an adjunct to SRP versus a control group of SRP did not demonstrate statistically or clinically significant advantages. Combined therapy of PDT + SRP indicated a probable efficacy in CAL gain (MD: 0.34; 95% confidence interval [CI]: 0.05 to 0.63) or probing depth reduction (MD: 0.25 mm; 95% CI: 0.04 to 0.45 mm). CONCLUSIONS PDT as an independent treatment or as an adjunct to SRP was not superior to control treatment of SRP. Therefore, the routine use of PDT for clinical management of periodontitis cannot be recommended. Well-designed clinical trials are needed for proper evaluation of this therapy.

White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.

Summary Temporomandibular disorder patients have white matter abnormalities along the trigeminal nerve and pain‐related brain pathways, and abnormal connectivity of cognitive‐affective brain regions. ABSTRACT Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion tensor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisotropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractography, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data provide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD.

Abnormal gray matter aging in chronic pain patients

Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid- and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed age-related cortical thinning, whereas the controls had age-related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes.

Refractory Periodontitis Population Characterized by a Hyperactive Oral Neutrophil Phenotype

BACKGROUND Neutrophils, in addition to being the primary protective component of the innate immune system, also contribute to periodontal destruction through production of reactive oxygen species (ROS), which cause damage to connective tissues and extracellular matrix after neutrophil activation. We have previously shown that hyperactive neutrophils are present in peripheral blood samples of patients diagnosed with refractory periodontitis. To test the hypothesis that oral neutrophil hyperactivity is related to periodontal disease severity, we used a flow cytometric approach to isolate and analyze oral neutrophil ROS (oROS) production in a refractory periodontal disease patient population. METHODS Oral rinse samples and venous blood were obtained from 13 patients diagnosed with refractory periodontitis. After isolation of neutrophils from both samples, dihydrorhodamine 123 was used as a fluorescent probe for phorbol 12-myristate 13-acetate-mediated ROS production as assessed through flow cytometry. For each patient, oROS production levels were expressed as a percentage of their baseline to maximal peripheral blood neutrophil ROS production range. RESULTS Two distinct groups of refractory patients were identified based on levels of phorbol 12-myristate 13-acetate-stimulated oROS production. The patient group with high oROS production had significantly more clinical attachment loss (AL) compared to the patient group with low oROS production. CONCLUSIONS Our findings demonstrate that a group of refractory patients with increased clinical AL present a hyperactive oral neutrophil phenotype characterized by increased potential for ROS production. Identification of this exaggerated oral neutrophil phenotype could allow clinicians to identify which patients are more susceptible to rapid disease progression.

Differentiation of rhabdomyosarcoma cell lines using retinoic acid

Rhabdomyosarcoma (RMS) is the most frequent sporadic soft tissue sarcoma of childhood and adolescence. The overall 5‐year survival rate for patients with RMS is 70% with the use of surgery, radiation, and chemotherapy. Novel therapeutic approaches are necessary to improve on these outcomes particularly among the more aggressive alveolar RMS (ARMS) and late stages of disease, where 5‐year survival is less than 20%. Retinoids have been successfully used in the treatment of acute promyelocytic leukemia (APML) and neuroblastoma.

Bacterial community composition of chronic periodontitis and novel oral sampling sites for detecting disease indicators

BackgroundPeriodontitis is an infectious and inflammatory disease of polymicrobial etiology that can lead to the destruction of bones and tissues that support the teeth. The management of chronic periodontitis (CP) relies heavily on elimination or at least control of known pathogenic consortia associated with the disease. Until now, microbial plaque obtained from the subgingival (SubG) sites has been the primary focus for bacterial community analysis using deep sequencing. In addition to the use of SubG plaque, here, we investigated whether plaque obtained from supragingival (SupG) and tongue dorsum sites can serve as alternatives for monitoring CP-associated bacterial biomarkers.ResultsUsing SubG, SupG, and tongue plaque DNA from 11 healthy and 13 diseased subjects, we sequenced V3 regions (approximately 200 bases) of the 16S rRNA gene using Illumina sequencing. After quality filtering, approximately 4.1 million sequences were collapsed into operational taxonomic units (OTUs; sequence identity cutoff of >97%) that were classified to a total of 19 phyla spanning 114 genera. Bacterial community diversity and overall composition was not affected by health or disease, and multiresponse permutation procedure (MRPP) on Bray-Curtis distance measures only supported weakly distinct bacterial communities in SubG and tongue plaque depending on health or disease status (P < 0.05). Nonetheless, in SubG and tongue sites, the relative abundance of Firmicutes was increased significantly from health to disease and members of Synergistetes were found in higher abundance across all sites in disease. Taxa indicative of CP were identified in all three locations (for example, Treponema denticola, Porphyromonas gingivalis, Synergistes oral taxa 362 and 363).ConclusionsFor the first time, this study demonstrates that SupG and tongue dorsum plaque can serve as alternative sources for detecting and enumerating known and novel bacterial biomarkers of CP. This finding is clinically important because, in contrast with SubG sampling that requires trained professionals, obtaining plaque from SupG and tongue sites is convenient and minimally-invasive and offers a novel means to track CP-biomarker organisms during treatment outcome monitoring.

Perceived helplessness is associated with individual differences in the central motor output system

Learned helplessness is a maladaptive response to uncontrollable stress characterized by impaired motor escape responses, reduced motivation and learning deficits. There are important individual differences in the likelihood of becoming helpless following exposure to uncontrollable stress but little is known about the neural mechanisms underlying these individual differences. Here we used structural MRI to measure gray and white matter in individuals with chronic pain, a population at high risk for helplessness due to prolonged exposure to a poorly controlled stressor (pain). Given that self‐reported helplessness is predictive of treatment outcomes in chronic pain, understanding such differences might provide valuable clinical insight. We found that the magnitude of self‐reported helplessness correlated with cortical thickness in the supplementary motor area (SMA) and midcingulate cortex, regions implicated in cognitive aspects of motor behavior. We then examined the white matter connectivity of these regions and found that fractional anisotropy of connected white matter tracts along the corticospinal tract was associated with helplessness and mediated the relationship between SMA cortical thickness and helplessness. These data provide novel evidence that links individual differences in the motor output pathway with perceived helplessness over a chronic and poorly controlled stressor.