Brain aging: The zinc connection

At variance with other organs, where the functional and structural units are repeated, the brain is a composite assembly of groups of cells with different metabolic features and functional units. Deterioration of brain function occurs when the number of neurons or their connections decrease below a critical reserve level and coping with environmental stimulation is seriously hampered. Physiopathological alterations of the synaptic junctional areas are reported to play a central role in the process of brain aging. Current research is documenting an age-related numeric loss of synapses which is paired by a significant enlargement of the persisting contact zones: the final outcome of these balanced changes is a significant reduction of the overall synaptic junctional area per unit volume of neuropil. The progressive decline of the mitochondrial metabolic competence, i.e. the capacity of select pools of organelles to provide adequate amounts of adenosine triphosphate is supposed to represent a key determinant in synaptic aging. Cytochemical estimations of the activity of cytochrome oxidase confirm that mitochondrial dysfunctions play an early role in synaptic deterioration. Zinc ions act as physiological neuromodulators at glutamatergic synapses, however, in order to avoid neurotoxic damage, the intracellular free Zn⁺⁺ concentration ([Zn⁺⁺]_i) must be tightly controlled by: (i) extrusion (Zn⁺⁺ transporters); (ii) buffering (metallothioneins) and (iii) sequestration (mitochondria) systems. In physiological aging, if any of these systems is impaired and/or not adequately coordinated with the other two, the resulting significant rise of ([Zn⁺⁺]_i) may inhibit the cellular energy providing systems and affect mitochondria as primary target.     

The copper-iron connection: hereditary aceruloplasminemia

Hereditary aceruloplasminemia is an autosomal recessive disorder of iron homeostasis due to loss-of-function mutations in the ceruloplasmin gene. Affected individuals may present in adulthood with evidence of hepatic iron overload, diabetes, peripheral retinal degeneration, dystonia, dementia, or dysarthria. Laboratory studies demonstrate microcytic anemia, elevated serum ferritin, and a complete absence of serum ceruloplasmin ferroxidase activity. Consistent with the observed neurologic findings, magnetic resonance imaging reveals iron accumulation within the basal ganglia. Histologic studies detect abundant iron in hepatocytes, reticuloendothelial cells of the liver and spleen, beta cells of the pancreas, and astrocytes and neurons throughout the central nervous system. Characterization of this disorder reveals an essential role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and provides new insights into the mechanisms of human iron metabolism.     

The clinical connection: drugs and crime

The relationship between drugs and crime is examined, with emphasis on the clinical importance of combining treatment with criminal justice authority. Selected studies are reviewed, and the historical importance of the criminal justice system for drug abuse treatment is stressed. Examples are used to depict dilemmas surrounding drugs and crime.     

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.     

The poppers-HIV connection

Nitrite inhalants called "poppers" are receiving renewed attention by researchers regarding the drug's role in the gay community, its contribution to risky sexual behavior, and its ability to fuel the AIDS epidemic. Research shows the effects of poppers cause a euphoria that can reduce inhibitions, increase sexual drive, and intensify the sensations of orgasm. Poppers have been associated with a decrease in condom use. In addition, research has found that popper use suppresses natural killer (NK) cell function, which increases vulnerability to infectious agents, produces sustained alterations in the immune system, and may be a Kaposi's sarcoma (KS) cofactor. The combined data implicate that the use of poppers may well pose as a significant risk factor for seroconversion.     

Atherosclerosis and diabetes: The rage connection

Diabetes mellitus begins as a disorder of glucose metabolism that progressively compromises the function of virtually every organ system as the secondary complications inexorably develop. The quality of life for patients with diabetes is diminished by the consequences of these complications. Accelerated and aggressive atherosclerosis is the greatest cause of morbidity and mortality with diabetes, emphasizing the importance of determining underlying mechanisms. This review highlights the role of the multiligand receptor for advanced glycation endproducts (RAGE) and two of its ligands, advanced glycation endproducts (AGEs) and S100/calgranulins, in the pathogenesis of atherosclerosis associated with diabetes. The results of the studies reviewed herein suggest that RAGE is a potential therapeutic target for macrovascular disease in diabetes.     

The allergy-asthma connection.

Asthma and allergic rhinitis are both common conditions and, therefore, often present in the same patients. Also, among the various triggers for asthma, allergy is an extremely common provoking factor for both adult and pediatric patients. The nose and lungs are connected by neural reflexes, and nasal allergen provocation can cause bronchoconstriction, and bronchial challenge can result in nasal inflammation. Treatment of allergic rhinitis with nasal steroids improves asthma control of symptoms, decreases bronchial hyperreactivity, and improves forced expiratory volume in 1 second. Treatment of subjects who have both allergic rhinitis and asthma with antihistamines (both alone and in combination with decongestants) and/or leukotriene receptor antagonists results in improvements in both conditions.     

Adiponectin and insulin cross talk: The microvascular connection

Adiponectin exerts both vasodilatory and insulin-sensitizing actions and its levels are decreased in insulin-resistant humans and animals. The mechanisms underlying adiponectin?s insulin-sensitizing effect have been extensively investigated but remain largely unclear. Muscle microvasculature critically regulates muscle insulin action by modulating insulin delivery to the microvessels nurturing the muscle cells and the trans-endothelial insulin transport. We have recently reported that adiponectin exerts its insulin-sensitizing effect via recruiting muscle microvasculature, expanding the endothelial surface area, and increasing insulin delivery to and thus action in muscle. The current review focuses on the microvascular connection between the adiponectin and insulin cross talk.     

The bladder-brain connection: putative role of corticotropin-releasing factor

The coordination of pelvic visceral activity with appropriate elimination behaviors is a complex task that requires reciprocal communication between the brain and pelvic organs. Barrington's nucleus, located in the pons, is central to a circuit involved in this function. Barrington's nucleus neurons project to both pelvic visceral motorneurons and cerebral norepinephrine neurons that modulate behavior. This circuit coordinates the descending limb of the micturition reflex with a central limb that initiates arousal and shifts the focus of attention to facilitate elimination behavior. The same circuitry that links the bladder and brain enables pathological processes in one target of the circuit to be expressed in the other. Urological disorders can, therefore, have cognitive and behavioral consequences by affecting components of this circuit; and in the opposing direction, psychosocial stressors can produce voiding dysfunctions and bladder pathology. The stress-related neuropeptide, corticotropin-releasing factor, which is prominent in Barrington's nucleus neurons, is a potential mediator of these effects.     

The HNF-1alpha-SNARE connection

Maturity-onset diabetes of the young (MODY) is a monogenic form of type 2 diabetes mellitus that is characterized by impairment of glucose-stimulated insulin secretion from pancreatic beta-cells. We previously reported that heterozygous mutations of the hepatocyte nuclear factor (HNF)-1alpha gene cause a form of MODY (MODY3). We have subsequently found that collectrin, a recently cloned kidney-specific gene of unknown function, is a novel target of HNF-1alpha in pancreatic beta-cells. In addition, we have demonstrated that collectrin forms a complex with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex by direct interaction with snapin, a protein that is thought to be involved in neurotransmission by binding to synaptosomal-associated protein, 25 KD (SNAP25). Collectrin favours the formation of SNARE complexes and controls insulin exocytosis.     

The nitric oxide-endothelin-1 connection

Nitric oxide (NO) and endothelin-1 (ET-1) are endothelium-derived mediators that play important roles in vascular homeostasis. This review is focused on the role and reciprocal interactions between NO and ET-1 in health and diseases associated with endothelium dysfunction. We will also discuss the clinical significance of NO donors and drugs that antagonize ET receptors.