Delayed Decline of Cognitive Function by Antihypertensive Agents: A Cohort Study Linked with Genotype Data.

BACKGROUND: Arterial hypertension is among factors with the potential for increasing the risk of cognitive impairment in elderly subjects. However, studies investigating the effects of antihypertensives on cognitive function have reported mixed results. METHODS: We have used the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to investigate the effect of each class of antihypertensives, both as single and combined, in reducing the rate of conversion from normal to mild cognitive impairment (MCI). RESULTS: The use of antihypertensive drugs was associated with 21% (Hazard ratio: 0.79, p<01001) delay in the rate of conversion to MCI. This effect was modulated by age, gender, and genotypic APOE4 allele. Among different antihypertensive subclasses, calcium channel blockers (CCBs) (24%, HR: 0.76, P=0.004), diuretics (21%, HR: 0.79, P=0.006), and α1-adrenergic blockers (α1-ABs) (23%, HR: 0.77, P=0.034) significantly delayed the rate of MCI conversion. A significant effect was observed with the selective L-type voltage-gated CCBs, dihydropyridines, amlodipine (47%, HR=0.53, P<0.001) and nifedipine (49%, HR=0.51, P=0.012), whereas non-DHPs showed insignificant effect. Loop diuretics, potassium sparing diuretics, and thiazides all significantly reduced the rate of MCI conversion. Combination of α1-AB and diuretics led to synergistic effects; combination of vasodilators plus ß-blockers (ßBs), and α1-AB plus ßBs led to additive effect in delaying the rate of MCI conversion, when compared to a single drug. CONCLUSION: Our results could have implications for the more effective treatment of hypertensive elderly adults who are likely to be at high risk of cognitive decline and dementia. The choice of combination of antihypertensive therapy should also consider the combination which would lead to an optimum benefit on cognitive function.

Osteoinductive potential of recombinant BMP-9 in bone defects of mice treated with antiresorptive agents.

The aim of the present study was to investigate the effects of recombinant human (rh)BMP-9 on bone regenerative potential in a mouse model of antibody-mediated antiresorptive therapy (AMART). A monoclonal anti-murine receptor activator of nuclear factor-kappa B ligand (RANKL) antibody (mAb) was used to create an AMART model in mice. rhBMP-9 combined with collagen membrane was implanted in calvarial defects in mAb-treated mice. After 4 weeks, the bone formative potential in the defects was evaluated by micro-computed tomography and histological approaches. The groups implanted with rhBMP-9-containing collagen membranes demonstrated substantial osteopromotive potential, with significantly greater new bone volume (Sham + BMP-9 group; 0.86 ± 0.29 mm3 and mAb + BMP-9 group; 0.64 ± 0.16 mm3) than control PBS-membranes (Sham + PBS group; 0.44 ± 0.29 mm3 and mAb + PBS group; 0.24 ± 0.12 mm3) in both sham and mAb-treated mice. In line with in vivo study, bone marrow cells isolated from both sham and mAb-treated mice confirmed greater osteogenic potential upon stimulation with rhBMP-9 in vitro. These findings suggest for the first time that local rhBMP-9 administration might be a strategy to accelerate bone regeneration in the context of AMART.

Pre-clinical testing of human size magnesium implants in miniature pigs: Implant degradation and bone fracture healing at multiple implantation sites.

Two miniature pig models to assess safety and performance of degradable osteosynthesis implants are presented. Both models provide multiple implantation sites with human size implants. In the first model, different types of magnesium plates and screws for fracture fixation were used to study local and systemic safety aspects in 14 Göttingen minipigs. Implant degradation, gas release and accumulation of alloying elements in organs were assessed for non-coated and plasmaelectrolytic coated magnesium implants and compared to the titanium reference. The observed implant degradation was mostly uniform and did not seem to depend on the implantation site and implant condition. The coating was effective in delaying initial gas release and degradation. No rare earth alloying elements could be detected in local lymph nodes, kidneys, livers or spleens. In the second model with Göttingen und Yucatan minipigs, full osteotomies were inflicted to four different anatomical sites and treated with magnesium plates and screws to assess fracture healing performance. Two Göttingen pilot minipigs showed promising results including a mandible osteosynthesis which healed within 6 weeks. The subsequent study was compromised by the more massive jaws of the used Yucatan minipigs. Three out of seven animals had to be sacrificed within two months as the stability of magnesium and titanium reference implants in the mandible was surpassed. In conclusion, the resorbable magnesium implants showed promising in vivo properties. For the analysis of human standard sized implants under full chewing load conditions, lighter Göttingen minipigs were more suitable than heavier Yucatan minipigs.

Central Noradrenergic Agonists in the Treatment of Ischemic Stroke-an Overview.

Ischemic stroke is the leading cause of morbidity and mortality with a significant health burden worldwide and few treatment options. Among the short- and long-term effects of ischemic stroke is the cardiovascular sympathetic autonomic dysfunction, presented in part as the by-product of the ischemic damage to the noradrenergic centers of the brain. Unlike high levels in the plasma, the brain may face suboptimal levels of norepinephrine (NE), with adverse effects on the clinical and functional outcomes of ischemic stroke. The intravenous administration of NE and other sympathomimetic agents, in an attempt to increase cerebral perfusion pressure, often aggravates the ischemia-induced rise in blood pressure (BP) with life-threatening consequences for stroke patients, the majority of whom present with hypertension at the time of admission. Unlike the systemic administration, the central administration of NE reduces BP while exerting anti-inflammatory and neuroprotective effects. These characteristics of centrally administered NE, combined with the short latency of response, make it an ideal candidate for use in the acute phase of stroke, followed by the use of centrally acting noradrenergic agonists, such as NE reuptake inhibitors and B2-adrenergic receptor agonists for stroke rehabilitation. In addition, a number of nonpharmacological strategies, such as transcutaneous vagus nerve stimulation (tVNS) and trigeminal nerve stimulation (TNS), have the potential to enhance the central noradrenergic functional activities and improve stroke clinical outcomes. Many factors could influence the efficacy of the noradrenergic treatment in stroke patients. These factors include the type of the noradrenergic agent; the dose, frequency, and duration of administration; the timing of administration in relation to the acute event; and the site and characteristics of the ischemic lesions. Having this knowledge, combined with the better understanding of the regulation of noradrenergic receptors in different parts of the brain, would pave the path for the successful use of the centrally acting noradrenergic agents in the management of ischemic stroke.

Thermal processing of bone: in vitro response of mesenchymal cells to bone-conditioned medium.

The autoclaving, pasteurization, and freezing of bone grafts to remove bacteria and viruses, and for preservation, respectively, is considered to alter biological properties during graft consolidation. Fresh bone grafts release paracrine-like signals that are considered to support tissue regeneration. However, the impact of the autoclaving, pasteurization, and freezing of bone grafts on paracrine signals remains unknown. Therefore, conditioned medium was prepared from porcine cortical bone chips that had undergone thermal processing. The biological properties of the bone-conditioned medium were assessed by examining the changes in expression of target genes in oral fibroblasts. The data showed that conditioned medium obtained from bone chips that had undergone pasteurization and freezing changed the expression of adrenomedullin, pentraxin 3, BTB/POZ domain-containing protein 11, interleukin 11, NADPH oxidase 4, and proteoglycan 4 by at least five-fold in oral fibroblasts. Bone-conditioned medium obtained from autoclaved bone chips, however, failed to change the expression of the respective genes. Also, when bone-conditioned medium was prepared from fresh bone chips, autoclaving blocked the capacity of bone-conditioned medium to modulate gene expression. These in vitro results suggest that pasteurization and freezing of bone grafts preserve the release of biologically active paracrine signals, but autoclaving does not.

Trigeminal cardiac reflex: new thinking model about the definition based on a literature review.

Trigeminocardiac reflex (TCR) is a brainstem reflex that manifests as sudden onset of hemodynamic perturbation in blood pressure (MABP) and heart rate (HR), as apnea and as gastric hypermotility during stimulation of any branches of the trigeminal nerve. The molecular and clinical knowledge about the TCR is in a constant growth since 1999, what implies a current need of a review about its definition in this changing context. Relevant literature was identified through searching in PubMed (MEDLINE) and Google scholar database for the terms TCR, oculocardiac reflex, diving reflex, vasovagale response. The definition of the TCR varies in clinical as well as in research studies. The main difference applies the required change of MABP and sometimes also HR, which most varies between 10% and 20%. Due to this definition problem, we defined, related to actual literature, 2 major (plausibility, reversibility) and 2 minor criteria (repetition, prevention) for a more proper identification of the TCR in a clinical or research setting. Latest research implies that there is a need for a more extended classification with 2 additional subgroups, considering also the diving reflex and the brainstem reflex. In this review, we highlighted criteria for proper definition and classification of the TCR in the light of increased knowledge and present a thinking model to overcome this complexity. Further we separately discussed the role of HR and MABP and their variation in this context. As another subtopic we gave attention to is the chronic TCR; a variant that is rarely seen in clinical medicine.

Biological monitoring of exposure and effects in workers employed in a selenium-processing plant.

PURPOSE: The aim of the study was to assess external and internal selenium exposure and potential biological effects in employees working in a selenium-processing plant. METHODS: Twenty male employees of a selenium-processing plant (exposed) and 20 age-matched male individuals without occupational selenium exposure (controls) participated in the study. Exposure to selenium at the workplace was determined by personal air sampling. Internal exposure was assessed by measuring total selenium concentration in plasma after a workshift and after holidays as well as by measuring the selenium concentration in urine before and after shift and after holidays. The activity of glutathione peroxidase (GPx) in blood and the prothrombin time were determined as biological effect parameters. RESULTS: The exposure to selenium in the workplace air ranged from 8 to 950 µg/m(3) and exceeded in a large part current occupational exposure limits. The selenium levels in plasma samples of the exposed ranged from 49 to 182 µg/L during exposure and were significantly higher than the plasma levels observed after holidays as well as in the control group. The selenium concentration in pre- and post-shift urine samples did not differ significantly, and the average urinary selenium levels of the employees (18-1,104 µg/g creatinine) were significantly higher than those measured after holidays or determined in controls. Both the concentration of selenium in plasma and in urine did not correlate with the current external exposure of the employees at the workplace. However, we found a strong and significant association between the two biomonitoring parameters. In spite of the considerable high external exposure to elemental selenium, we did not find any effect on the GPx activity in blood as well as on the prothrombin time. CONCLUSIONS: Both the selenium levels in plasma and urine may be used as biological monitoring parameters for the assessment of chronic occupational exposure to selenium. Nevertheless, the toxicokinetics of the urinary excretion of selenium remain still unclear and require further investigations. Moreover, our findings emphasise the necessity of a re-evaluation of occupational exposure limits for elemental selenium and inorganic selenium compounds.

Effect of a plasmaelectrolytic coating on the strength retention of in vivo and in vitro degraded magnesium implants.

The strength decrease in magnesium implants was studied in vitro and in vivo, with and without a protective plasmaelectrolytic coating. In vivo, degradation was examined by implanting rectangular plates on top of the nasal bone of miniature pigs. The presence of gas pockets in the soft tissue surrounding the implants was evaluated with intermediate X-rays and computed X-ray tomography scans before euthanasia. After 12 and 24 weeks of in vivo degradation, the large rectangular plates were removed and mechanically tested in three-point bending. In vitro, identical plates were immersed in simulated body fluid for 4, 8 and 12 weeks. In vitro and in vivo results showed that onset of gas release can be delayed by the plasmaelectrolytic coating. Mass loss and strength retention during in vivo degradation is about four times slower than during in vitro degradation for the chosen test conditions. Despite the slow degradation of the investigated WE43 alloy, the occurrence of gas pockets could not be completely avoided. Nevertheless, uniformity of degradation and reliable strength retention make this alloy a prime candidate for the use of magnesium in cranio-maxillofacial surgery.

Premature craniosynostosis--the role of skull base surgery in its correction. A surgical and radiological experience of 172 operated infants/children.

BACKGROUND: Most craniofacial abnormalities are non-syndromic craniosynostoses due to premature fusion of one or more craniofacial sutures. Functional impairment is caused either by a pathological growth pattern or increased intracranial pressure. The indications for surgery are to increase intracranial volume and to correct aesthetics. PATIENTS AND METHODS: We retrospectively reviewed 172 patients who had been operated on for premature craniosynostosis, including fronto-orbital advancement, from 1992 to 2002. Demographic data, clinical follow-up findings, and regular photo documentation were analyzed. RESULTS: After a mean follow-up of 6 years the overall outcome for those operated on within the first 6 months of life was satisfactory in 97%. The remaining 3% were reoperated at between 4 and 6 years of age. All cephalometric indices normalized postoperatively. Eight patients underwent SPECT studies which showed preoperative perfusion asymmetry corresponding to the fused sutures that were normalized following surgical decompression. No severe perioperative complications were seen. DISCUSSION: Cephalometric parameters represent an excellent method to compare the postoperative outcome. Standard skull base procedures need to be adapted carefully to the individual form of craniosynostosis to avoid an unfavourable result. Single Photon Emissin Computed Tomography (SPECT) studies give evidence that correction of single cranial suture synostosis allows for normalization of cerebral blood flow and should be performed within first 6-8 months of life.

[Comparison of early retinal microvascular changes and microalbuminuria as indicators for increased cardioascular risk]. / Vergleich von frühen Veränderungen der retinalen Mikrostrombahn und Mikroalbuminurie als Zeichen eines erhöhten kardiovaskulären Risikos.

INTRODUCTION: Prevention of cardiovascular disease is an important goal in clinical medicine and public health. In the process, the diagnosis of early end-organ damage is a priority beside the treatment of classic cardiovascular risk factors. To achieve this, the ophthalmoscopic examination of the retinal vessels plays a prominent role. Alternatively, the quantification of low quantities of albumin in the urine (microalbuminuria) allows the detection of early vascular damage in the kidney. The question is addressed as to whether these two methods are interchangeable or are rather complementary. PATIENTS AND METHODS: We examined 226 members of the staff of the University Hospital Erlangen who volunteered to participate in a preventive campaign. A comprehensive history was taken, and height, weight and blood pressure were measured. Analysis of serum lipids and determination of the urinary albumin/creatinine ratio were performed. Fotos of the central fundus were taken with a non-mydriatic camera and analysed by an experienced ophthalmologist in a standardised fashion. The risk for cardiovascular mortality within the next ten years was estimated from age, sex, blood pressure and serum cholesterol using the euroSCORE tables for Germany. RESULTS: There was no signficant correlation between the arteriovenous ratio of the retinal vessels and the urinary albumin/creatinine ratio. Neither parameter correlated with the euroSCORE Germany. Arteriovenous crossings and focal narrowing of the retinal vessels were associated signficantly with an elevated euroSCORE risk. CONCLUSIONS: In large population-based studies, the arteriovenous ratio and the urinary albumin/creatinine ratio have been confirmed as markers of cardiovascular risk. In our study, there was no correlation between these two parameters. Thus, they seem to present independent risk markers. The presence of arteriovenous crossings and focal narrowing seems to be linked more closely to the classic cardiovascular risk factors from which the euroSCORE is calculated. The ophathlmolscopic examination of retinal vessels and the analysis of urinary albumin/creatinine ratio seem to complement rather than replace each other.

Cerebral hemodynamic changes during the trigeminocardiac reflex: description of a new animal model protocol.

The trigeminocardiac reflex (TCR) is a well-known brainstem reflex, first described in skull base and neurosurgery by the senior author in 1999, leading to reflex apnea, bradycardia, and changes of mean arterial pressure. There seem to be differences between peripheral and central stimulation of the TCR, and there is a lack of clear data about the cerebral hemodynamic changes during the TCR. However, the research of this reflex principally focused on clinical cases for peripheral and central stimulation during the last years, and on rabbits for peripheral stimulation several decades ago, so there was a need for an animal model that allows us to use the current state-of-the-art imaging methods. The new animal model protocol as introduced by the authors gives, for the first time, deep insights into the cerebral hemodynamic changes during the TCR and gives substantial evidence whether the TCR represents an oxygen-conserving reflex or not.

New molecular knowledge towards the trigemino-cardiac reflex as a cerebral oxygen-conserving reflex.

The trigemino-cardiac reflex (TCR) represents the most powerful of the autonomous reflexes and is a subphenomenon in the group of the so-called "oxygen-conserving reflexes". Within seconds after the initiation of such a reflex, there is a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF), with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently. Features of the reflex have been discovered during skull base surgery, mediating reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus, which finally engage a small population of neurons in the cortex. This cortical center appears to be dedicated to transduce a neuronal signal reflexively into cerebral vasodilatation and synchronization of electrocortical activity; a fact that seems to be unique among autonomous reflexes. Sympathetic excitation is mediated by cortical-spinal projection to spinal preganglionic sympathetic neurons, whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to the brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Previous studies showed a great variability in the human TCR response, in special to external stimuli and individual factors. The TCR gives, therefore, not only new insights into novel therapeutic options for a range of disorders characterized by neuronal death, but also into the cortical and molecular organization of the brain.

Ankylosing spondylitis in sub-Saharan Africa.

Ankylosing spondylitis (AS) represents a chronic inflammatory bone disease of the axial skeleton that manifests as chronic back pain and progressive stiffness of the spine. It characteristically affects young adults with a peak age of onset between 20-30 years. In contrast to Western Europe and North America, the disease is rare in Sub-Saharan Africa where the majority of the population is HLA-B27 negative. Even in some African populations where HLA-B27 is prevalent (for example, in Gambia and Senegal, where 3-6% of the general population has HLA-B27), the disease is also said to be rare. However, some other genetic markers may be involved in the causation of AS in the HLA-B27 negative population, and when it occurs in this subgroup of patients it has a similar manifestation with HLA-B27 negative white patients and these patients rarely develop anterior uveitis. The clinical presentation of the disease in Africa is generally milder; most affected individuals do not have a family history of AS, the patients are older at onset of the disease, and the majority of them lack extra-articular manifestations such as anterior uveitis compared with the situation in Western Europe and North America. In conclusion, AS in sub-Saharan Africa seems to represent a subgroup of the disease, which may open the window to a greater understanding of the pathophysiology of the condition.

Oxygen-conserving reflexes of the brain: the current molecular knowledge.

The trigemino-cardiac reflex (TCR) may be classified as a sub-phenomenon in the group of the so-called 'oxygen-conserving reflexes'. Within seconds after the initiation of such a reflex, there is neither a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF) with no changes in the cerebral metabolic rate of oxygen (CMRO(2)) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO(2) or CMRglc provides the brain with oxygen rapidly and efficiently and gives substantial evidence that the TCR is an oxygen-conserving reflex. This system, which mediates reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus which finally engage a small population of neurons in the cortex. This cortical centre appears to be dedicated to reflexively transduce a neuronal signal into cerebral vasodilatation and synchronization of electrocortical activity. Sympathetic excitation is mediated by cortical-spinal projection to spinal pre-ganglionic sympathetic neurons whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Better and more detailed knowledge of the cascades, transmitters and molecules engaged in such endogenous (neuro) protection may provide new insights into novel therapeutic options for a range of disorders characterized by neuronal death and into cortical organization of the brain.

Gender-related differences in pituitary adenomas.

Pituitary adenomas account for about 10% of all intracranial neoplasms and for about 85% of all pituitary tumors. In addition, prospective studies of normal persons and postmortem examinations reveal pituitary adenomas in up to 10% of adults indicating that not all pituitary adenomas are clinically significant. With clinically significant pituitary adenomas, patients may present with hyper- or under-secretion of pituitary hormones or with symptoms and signs of space occupying intracranial tumor like headache and visual compromise. Like other differentiated neuroendocrine cells, the anterior pituitary displays remarkable plasticity in response to physiological demands, as exemplified by the lactotroph differentiation and proliferation of pregnancy or the thyrotroph hyperplasia of primary hypothyroidism. These reversible changes are mediated by a diverse array of signals that have been interpreted to support a role for hormonal stimulation in the pathogenesis of pituitary adenomas. Different investigators have shown a tendency to gender-related differences not only in surgical outcome, but also in the presenting symptoms and signs, duration of symptoms, tumor size, tumor histology, and restoration of normal pituitary function in patients who are surgically treated and histologically proven pituitary adenomas. In this review, we will try to give a systematic insight into gender related differences of pituitary adenomas. Special reference is given on potential different biology of these tumors as suggested by the gender related differences. The manuscript therefore gives new insights into the cellular understanding of the pituitary adenomas.