A Critical Role for IFN-ß Signaling for IFN-κ Induction in Keratinocytes.

Background/Purpose: Cutaneous lupus erythematosus (CLE) affects up to 70% of patients with systemic lupus erythematosus (SLE), and type I interferons (IFNs) are important promoters of SLE and CLE. Our previous work identified IFN-kappa (IFN-κ), a keratinocyte-produced type I IFN, as upregulated in non-lesional and lesional lupus skin and as a critical regulator for enhanced UVB-mediated cell death in SLE keratinocytes. Importantly, the molecular mechanisms governing regulation of IFN-κ expression have been relatively unexplored. Thus, this study sought to identify critical regulators of IFN-κ and identified a novel role for IFN-beta (IFN-ß). Methods: Human N/TERT keratinocytes were treated with the RNA mimic poly (I:C) or 50 mJ/cm2 ultraviolet B (UVB), followed by mRNA expression quantification by RT-qPCR in the presence or absence neutralizing antibody to the type I IFN receptor (IFNAR). IFNB and STAT1 knockout (KO) keratinocytes were generated using CRISPR/Cas9. Results: Time courses of poly(I:C) and UVB treatment revealed a differential expression of IFNB, which was upregulated between 3-6 hours and IFNK, which was upregulated 24 hours after stimulation. Intriguingly, only IFNK expression was substantially abrogated by neutralizing antibodies to IFNAR, suggesting that IFNK upregulation required type I IFN signaling for induction. Indeed, deletion of IFNB abrogated IFNK expression. Further exploration confirmed a role for type I IFN-triggered STAT1 activation. Conclusion: Collectively, our work describes a novel mechanistic paradigm in keratinocytes in which initial IFN-κ induction in response to poly(I:C) and UVB is IFNß1-dependent, thus describing IFNK as both an IFN gene and an interferon-stimulated gene.

Rapid response to dupilumab in an adult patient with eosinophilic esophagitis and allergic asthma.

BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus that belongs to the spectrum of Th2-mediated diseases. It is often associated with atopic comorbidities such as allergic asthma (AA) and poses a therapeutic challenge. CASE REPORT: We report on a 43-year-old patient with EoE and AA who did not show sufficient therapeutic control despite standard therapy. We started treatment with dupilumab, whereupon both EoE and AA rapidly improved and complete symptom resolution could be documented. The response to dupilumab was assessed by laboratory monitoring and gastroscopy, which showed a reduction of markers of type II inflammation and eosinophilic infiltrates in the esophagus. SUMMARY: Our report emphasizes the effective and safe use of dupilumab as a treatment option for EoE with concomitant beneficial effects on AA.

Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1.

Introduction: Ultraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown. Methods: Here, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress Ifnk in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure. Results: We identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. In vivo, overexpression of epidermal Ifnk resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1). Discussion: These data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB.

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.

Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. Here, we show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV)B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is significantly upregulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. Strikingly, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cGAS-STING activation compared to B-DNA. ZBP1 knockdown abrogates UV-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.

Pars Interarticularis Fractures Treated with Minimally Invasive Surgery: A Literature Review.

Recurrent stress on the isthmic pars interarticularis often leads to profound injury and symptom burden. When conservative and medical management fail, there are various operative interventions that can be used. The current review details the common clinical presentation and treatment of pars injury, with a special focus on the emerging minimally invasive procedures used in isthmic pars interarticularis repair. PubMed and Google Scholar database literature reviews were conducted. The keywords and phrases that were searched include but were not limited to; "history of spondylolysis", "pars interarticularis", "pars defect", "conventional surgical repair of pars", and "minimally invasive repair of pars". The natural history, conventional presentation, etiology, risk factors, and management of pars interarticularis injury are discussed by the authors. The surgical interventions described include the Buck's repair, Morscher Screw-Hook repair, Scott's Wiring technique, and additional pedicle screw-based repairs. Minimally invasive techniques are also reviewed, including the Levi technique. Surgical intervention has been proven to be safe and effective in managing pars interarticularis fractures. However, minimally invasive techniques often provide additional benefit to patients such as reducing damage of surrounding structures, decreasing postoperative pain, and limiting the time away from sports and other activities.

Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

Optical and Structural Properties of Aluminum Nitride Epi-Films at Room and High Temperature.

The high-quality aluminum nitride (AlN) epilayer is the key factor that directly affects the performance of semiconductor deep-ultraviolet (DUV) photoelectronic devices. In this work, to investigate the influence of thickness on the quality of the AlN epilayer, two AlN-thick epi-film samples were grown on c-plane sapphire substrates. The optical and structural characteristics of AlN films are meticulously examined by using high-resolution X-ray diffraction (HR-XRD), scanning electron microscopy (SEM), a dual-beam ultraviolet-visible spectrophotometer, and spectroscopic ellipsometry (SE). It has been found that the quality of AlN can be controlled by adjusting the AlN film thickness. The phenomenon, in which the thicker AlNn film exhibits lower dislocations than the thinner one, demonstrates that thick AlN epitaxial samples can work as a strain relief layer and, in the meantime, help significantly bend the dislocations and decrease total dislocation density with the thicker epi-film. The Urbach's binding energy and optical bandgap (Eg) derived by optical transmission (OT) and SE depend on crystallite size, crystalline alignment, and film thickness, which are in good agreement with XRD and SEM results. It is concluded that under the treatment of thickening film, the essence of crystal quality is improved. The bandgap energies of AlN samples obtained from SE possess larger values and higher accuracy than those extracted from OT. The Bose-Einstein relation is used to demonstrate the bandgap variation with temperature, and it is indicated that the thermal stability of bandgap energy can be improved with an increase in film thickness. It is revealed that when the thickness increases to micrometer order, the thickness has little effect on the change of Eg with temperature.

The role of limited access to students from more diverse nonfeeder medical schools in creating diversity inequities in neurosurgical residency.

OBJECTIVE: Improving racial/ethnic diversity in neurosurgery is a long-standing issue that needs to be addressed. The positive correlation between medical students with home neurosurgery programs and successful matriculation into neurosurgical residency is well documented. In this article, the authors explored the relationship between decreased racial/ethnic diversity in neurosurgery residency programs and racial/ethnic diversity in feeder medical schools. METHODS: The authors conducted a standardized review of the literature to evaluate potential causes for decreased racial/ethnic diversity within neurosurgery. Additionally, they calculated the average enrollment of Black/African American medical students at the top 5 neurosurgery feeder medical schools (determined by Antar et al. following the 2014-2020 match cycles) during the 2021-2022 school year and compared that with the enrollment at US allopathic medical schools with the highest enrollment of Black/African American students. They also compared these two groups in terms of how many students they sent into neurosurgery residency programs from 2014 to 2020. For each of these comparisons, the authors conducted a two-sample t-test to evaluate correlation between these two variables. RESULTS: There was significantly lower average enrollment of Black/African American students at the top 5 feeder medical programs into neurosurgery residency (80.6 ± 8.32) compared with the top 5 medical schools with Black/African American enrollment in the 2021-2022 school year (279 ± 122.00, p < 0.05). The authors also found a significant increase in the number of students entering neurosurgery residency programs between the top 5 feeder medical programs into neurosurgery residency (30.8 ± 6.06) and the top 5 medical programs for Black/African American enrollment (6 ± 6.16, p < 0.0001). CONCLUSIONS: In this paper, the authors examined, through a Black/African American lens, the role of racial/ethnic diversity in medical schools that historically send many students to neurosurgery residency. This study sought to provide insight into this problem and examine how Black/African American students from nonfeeder medical schools are disproportionately affected. The authors' findings suggest that the lack of Black/African American representation in neurosurgery is strongly correlated with the diversity efforts of medical schools. Lastly, the authors highlight the University of Miami's Summer Research Scholarship in Neurosurgery for Medical Students and other programs as potential solutions to combat the lack of racial/ethnic diversity in neurosurgery.

Catheter ablation of atrial fibrillation in elderly and very elderly patients: safety, outcomes, and quality of life.

BACKGROUND: Atrial fibrillation (AF) risk increases with age. We aim to assess the efficacy and safety of catheter ablation in the older population. METHODS: All patients undergoing AF ablation (2013-2021) at our institution were enrolled in a prospectively maintained registry. The primary endpoint was AF recurrence. Patients were divided into 3 groups: non-elderly (< 65 years), elderly (65-75 years), and very elderly (> 75 years). Patient surveys at baseline and during follow-up were used to calculate quality of life (QoL) metrics: the AF severity score as well as the AF burden. RESULTS: A total of 7020 patients were included (42% non-elderly, 42% elderly, and 16% very elderly). Periprocedural major complications were low (< 1.5%) and similar in all groups besides pericardial effusion which was more frequent with older age and similar between the elderly and very elderly. At 3 years, AF recurrence for persistent AF (PersAF) was highest in the very elderly group (48%), followed by the elderly group (42%), and was the lowest in the non-elderly group (36%). In paroxysmal AF (PAF), there was no difference in AF recurrence between the elderly and non-elderly, while the very elderly remained associated with a significantly increased risk. Multivariable Cox analysis confirmed these findings (PersAF; elderly: HR = 1.23, P = 0.003; very elderly: HR = 1.44, P < 0.001) (PAF; elderly: HR = 1.04, P = 0.62; very elderly: HR = 1.30, P = 0.01). Catheter ablation resulted in a significant improvement in quality of life, irrespective of age group. CONCLUSION: Catheter ablation in elderly and very elderly patients is safe, efficacious, and associated with QoL benefits. Overall, major complications were minimal and did not differ significantly between age groups, with the exception of pericardial effusions which were higher in the elderly and very elderly compared to non-elderly adults. Very elderly patients had a higher rate of AF recurrence when compared with elderly or non-elderly patients. Nevertheless, ablation resulted in a remarkable improvement in QoL and a reduction of AF burden and AF symptoms with a similar magnitude, irrespective of age.

Single-cell transcriptomics reveals prominent expression of IL-14, IL-18, and IL-32 in psoriasis.

RATIONALE: Psoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines. OBJECTIVES: Here we use single-cell transcriptomic analyses to identify relevant immune cell and nonimmune cell populations for an in-depth characterization of cell types and inflammatory mediators in this disease. METHODS: Psoriasis skin lesions of eight patients are analyzed using single-cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments. RESULTS: Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T-helper cells, dendritic cells, macrophages, and fibroblasts. Apart from well-known factors, IL-14 (TXLNA), IL-18, and IL-32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL-14, IL-18, and IL-32 was significantly higher in psoriatic skin compared with healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples, and in in vitro experiments. CONCLUSIONS: Taken together, we provide a differentiated view of psoriasis immune-cell phenotypes that support the role of IL-14, IL-18, and IL-32 in psoriasis pathogenesis.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ9-tetrahydrocannabinol (Δ9-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60%  of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ9-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ9-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ9-THC-induced reduction in oICSS and Δ9-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ9-THC-induced hypoactivity and catalepsy but failed to alter Δ9-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.

Anxiety in children and youth: Part 1-Diagnosis.

Anxiety disorders are the most common mental health concerns affecting Canadian children and adolescents. The Canadian Paediatric Society has developed two position statements that summarize current evidence regarding the diagnosis and management of anxiety disorders. Both statements offer evidence-informed guidance to support paediatric health care providers (HCPs) making decisions around the care of children and adolescents with these conditions. The objectives of Part 1, which focuses on assessment and diagnosis, are to: (1) review the epidemiology and clinical characteristics of anxiety disorders and (2) describe a process for assessment of anxiety disorders. Specific topics are reviewed, including prevalence, differential diagnosis, co-occurring conditions, and the process of assessment. Approaches are offered for standardized screening, history-taking, and observation. Associated features and indicators that distinguish anxiety disorders from developmentally appropriate fears, worries, and anxious feelings are considered. Note that when the word 'parent' (singular or plural) is used, it includes any primary caregiver and every configuration of family.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is a PPARg agonist and some endocannabinoids are natural activators of PPAR a and PPARg. Therefore, both the receptors are putative cannabinoid receptors. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are highly expressed in ~70% midbrain dopamine (DA) neurons and in ~50% GABAergic and ~50% glutamatergic neurons in the amygdala. However, no PPARα/γ signal was detected in GABAergic neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ 9 -THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ 9 -THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS, suggesting that dopaminergic PPARγ modulates DA-dependent behavior. Surprisingly, pretreatment with PPARα or PPARγ antagonists dose-dependently attenuated the Δ 9 -THC-induced reduction in oICSS and anxiogenic effects. In addition, a PPARγ agonist increased, while PPARa or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARa or PPARγ antagonists potentiated Δ 9 -THC-induced hypoactivity and catalepsy but failed to alter Δ 9 -THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARa/g in DA-dependent behavior and cannabinoid action.

Structural, Surface and Optical Studies of m- and c-Face AlN Crystals Grown by Physical Vapor Transport Method.

Bulk aluminum nitride (AlN) crystals with different polarities were grown by physical vapor transport (PVT). The structural, surface, and optical properties of m-plane and c-plane AlN crystals were comparatively studied by using high-resolution X-ray diffraction (HR-XRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Temperature-dependent Raman measurements showed that the Raman shift and the full width at half maximum (FWHM) of the E2 (high) phonon mode of the m-plane AlN crystal were larger than those of the c-plane AlN crystal, which would be correlated with the residual stress and defects in the AlN samples, respectively. Moreover, the phonon lifetime of the Raman-active modes largely decayed and its line width gradually broadened with the increase in temperature. The phonon lifetime of the Raman TO-phonon mode was changed less than that of the LO-phonon mode with temperature in the two crystals. It should be noted that the influence of inhomogeneous impurity phonon scattering on the phonon lifetime and the contribution to the Raman shift came from thermal expansion at a higher temperature. In addition, the trend of stress with increasing 1000/temperature was similar for the two AlN samples. As the temperature increased from 80 K to ~870 K, there was a temperature at which the biaxial stress of the samples transformed from compressive to tensile stress, while their certain temperature was different.

Treatment of severe cow's milk allergy with omalizumab in an adult.

BACKGROUND: The therapy of severe food allergy so far consists mainly of allergen abstinence and emergency treatment. The use of anti-IgE antibodies represents a promising therapy. CASE REPORT: We report on a 22-year-old male with severe cow's milk allergy with multiple anaphylactic reactions, known since infancy and persisting into adulthood with sometimes severe immediate-type reactions on accidental ingestion. The prick test for native whole milk was positive, the CAP-FEIA was also positive for milk protein, mare's milk, whey, sheep's milk whey as well as Bos d4, Bos d5, and Bos d8 and blue cheese; total IgE was 1,265 kU/L. The patient's history included well-controlled bronchial asthma. An off-label therapy with omalizumab (3 × 150 mg/month SC) and cetirizine 10 mg once daily was initiated. Under this therapy, we performed a double-blind oral exposure test to cow's milk in the patient after long term. Thereby 14 mL could be tolerated. After consumption of 30 mL of cow's milk, urticaria, dyspnea, and angioedema occurred. CONCLUSION: Under therapy with omalizumab, an increase of the tolerance to cow's milk was shown in our patient. As a consequence, reactions during accidental consumption could be prevented.

Dopamine D3/D2 Receptor Ligands Based on Cariprazine for the Treatment of Psychostimulant Use Disorders That May Be Dual Diagnosed with Affective Disorders.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

Angle-Dependent Raman Scattering Studies on Anisotropic Properties of Crystalline Hexagonal 4H-SiC.

Raman scattering spectroscopy (RSS) has the merits of non-destructiveness, fast analysis, and identification of SiC polytype materials. By way of angle-dependent Raman scattering (ADRS), the isotropic characteristics are confirmed for c-face 4H-SiC, while the anisotropic properties of a-face 4H-SiC are revealed and studied in detail via combined experiments and theoretical calculation. The variation functional relationship of the angle between the incident laser polarization direction and the parallel (perpendicular) polarization direction was well established. The selection rules of wurtzite 4H-SiC are deduced, and the intensity variations of the A1, E2, and E1 Raman phonon modes dependent on the incident angle are calculated, and well-matched with experimental data. Raman tensor elements of various modes are determined.

The systemic oral health connection: Biofilms.

Frequently, periodontal health and it's associated oral biofilm has not been addressed in those patients who have systemic health issues, especially those who are not responding to medical treatment via their physician. Oral biofilm may be present in the periodontal sulcus in the absence of clinical disease of periodontal disease (bleeding on probing, gingival inflammation) and periodontal reaction is dependent on the patient's immune response to the associated bacterial and their byproducts. Increasing evidence has been emerging the past decade connecting oral biofilm with systemic conditions, either initiating them or complicating those medical conditions. The patient's health needs to be thought of as a whole-body system with connections that may originate in the oral cavity and have distant affects throughout the body. To maximize total health, a coordination in healthcare needs to be a symbiosis between the physician and dentist to eliminate the oral biofilm and aid in prevention of systemic disease or minimize those effects to improve the patient's overall health and quality of life. Various areas of systemic health have been associated with the bacteria and their byproducts in the oral biofilm. Those include cardiovascular disease, chronic kidney disease, diabetes, pulmonary disease, prostate cancer, colon cancer, pancreatic cancer, pre-term pregnancy, erectile dysfunction Alzheimer's disease and Rheumatoid arthritis. This article will discuss oral biofilm, its affects systemically and review the medical conditions associated with the oral systemic connection with an extensive review of the literature.