Encouraging regeneration in the central nervous system: is there a role for olfactory ensheathing cells?

The olfactory system holds a privileged position within the adult mammalian central nervous system; olfactory neurons undergo continual replacement and regeneration of synaptic contacts following injury, a feature shared by only a select few neuronal systems. The olfactory ensheathing cell, a glial cell found only in this system, is thought to play a central role in this regenerative process and has hence been the focus of numerous studies into promoting CNS regeneration following injury, in particular of the spinal cord. In trials, olfactory ensheathing cells have achieved some of the most promising results yet in promoting CNS regeneration, including a degree of functional recovery in humans following CNS injury. Comparatively, numerous other strategies, both those involving cellular transplantation and those examining neutralisation of inhibitory factors of the CNS, have achieved limited success. A combinational strategy, with olfactory ensheathing cells at its centre, is arguably the best way forward in encouraging effective recovery following CNS injury. This review examines the inhibitory environment of the CNS and the research to date on overcoming its effects on the regrowth of injured axons. The efficacy of therapies involving olfactory ensheathing cells, and the place of these therapies among the many other strategies being developed is examined.     

Haemorrhaging lesion in the breast: is there a role for embolisation?

Angiosarcoma of the breast is an extremely rare condition. This case illustrates the use of embolisation as a modality of treatment for primary breast angiosarcoma. No other case has been reported on the use of embolisation for this disorder.     

The neural crest is contiguous with the cardiac conduction system in the mouse embryo: a role in induction?

In this study we present data on the spatial relationship between neural crest-derived cells (NCC) and the specialized cardiac conduction system (CCS) in the developing murine heart. Using Wnt1-Cre/R26R conditional reporter mice that express -galactosidase from ROSA26 upon Cre-mediated recombination, two populations of NCC are seen: one migrates through the arterial pole and contributes to the bundle branches, whereas the second population enters by way of the venous pole and provides cells to the sinoatrial and atrioventricular node areas. The CCS/lacZ construct is found in the myocardium of the early embryonic heart and afterward only persists in the definitive CCS and is acknowledged as a reporter for the developing conduction system. The contiguous expression of both reporters is suggestive for a potential role of cardiac NCC in the induction of the final differentiation of the CCS.     

Is there a role for mesenchymal stem cells in autoimmune diseases?

Recent reports have highlighted that adult stem cells are granted with yet poorly understood properties other than multipotentiality. In particular, mesenchymal stem cells (MSCs) represent a subset of adult stromal cells that can down-regulate several functions of the immune cells. In addition, MSCs may promote survival of damaged cells and tissues through paracrine mechanisms, possibly under the guidance of environmental cues. Thus, MSCs clinical application in autoimmune diseases seems an appealing opportunity and preclinical results in different experimental models of autoimmunity further support this strategy. Despite the absolute need for caution related to several clinical and technical issues, MSCs are now on the edge of a new era of clinical applications.     

Hyperuricaemia and preeclampsia: is there a pathogenic link?

OBJECTIVE: A hypothesis, based on animal studies and human observational studies, was developed proposing a direct pathogenic link between hyperuricemia and preeclampsia. Epidemiological characteristics of preeclampsia such as its uniqueness to humans and an increased incidence of preeclampsia in multiple pregnancies, increased body mass index, renal and hypertensive disease all have uric acid as their common denominator. Animal studies have linked hyperuricaemia to hypertensive, cardiovascular and renal disease. The aim of the study was to determine whether lowering the serum uric acid levels in preeclampsia would affect biochemical parameters and hypertensive control. DESIGN: A randomized, double-blind, placebo controlled study. SETTING: A tertiary referral center. POPULATION: Forty women with preeclampsia between 26 and 32 weeks gestation. INTERVENTION: Probenecid 250 mg twice daily for seven days. MAIN OUTCOME MEASURES: Renal function and haematological parameters, hypertensive control. RESULTS: In the Probenecid group, there was a significant drop in the serum uric acid levels. Lower uric acid levels in the Probenecid group had no significant effect on blood pressure. Patients in the Probenecid group had a significantly lower serum creatinine value at the end of the study when compared to patients in the placebo group. Other renal function parameters (creatinine clearance, urea, 24 h urinary protein excretion) did not show any significant difference between the two groups. Platelet count differed between the two groups with the platelet count being significantly higher in the Probenecid group at the end of the study. CONCLUSION: The significant improvement in the platelet count in the Probenecid group warrants further study.     

Hypersociability in Williams syndrome: a role for the amygdala?

We read with great interest the paper of Riby et al. regarding atypical, unfamiliar face processing in Williams syndrome (WS; Riby, Doherty-Sneddon, & Bruce, 2008a). It offers considerable insight into the mechanism of facial perception in humans and a further elaboration of the hypersociability observed in patients with Williams syndrome. We would like to suggest that the neurologic mechanisms underlying the hypersociability in WS may be attributable to an impaired recognition of facial expressions of threat, a feature that localises to the amygdala.     

Tension headaches and muscle tension: is there a role for magnesium?

Although many theories and hypotheses have been offered for the etiology of tension-type headache (TH), no one previous hypothesis seems to adequately explain TH. This may, in large measure, account for why it is often difficult to effectively treat TH. Herein, we review current and old hypotheses of TH and offer a new hypothesis which is consistent with what is known about TH. We show that magnesium (Mg) metabolism may be pivotal in both the etiology and treatment of TH. Measurement of serum ionized Mg2+ (IMg2+) levels and brain intracellular free Mg2+ ([Mg2+]i) appear to offer excellent methods for establishing the validity of our hypothesis. Since approximately 70% of patients who have a TH exhibit muscular tightness and tenderness, it is distinctly possible that problems in Mg metabolism and dietary intake are the links to concomitant muscle tension and TH. The significance of release of pain mediators, muscle cramps, muscle strains (and damage) and muscle tension to TH, and its relationship to Mg metabolism, are reviewed. These are all associated with a Mg-deficient state. It seems clear from the available data that TH's are more associated with muscle tension or scalp tension than any other headache type. From the data available, Mg supplementation appears to be of great benefit in many of these situations. We believe there is a great need for clinicians to examine Mg2+ metabolism, bioavailable Mg2+ in muscle tissues and blood, and the effectiveness of Mg salts (in a double-blinded, placebo-controlled manner) in subjects with TH and muscle tension.     

Prolonged controlled hemorrhagic shock in a swine model: is there a role for mechanical circulatory assistance?

Outcomes of mechanical circulatory assistance during hemorrhagic shock were evaluated in a swine model. Pigs were bled to a mean arterial pressure of 35 mm Hg (group I, n = 3) or 40 mm Hg (group II, n = 5; group III, n = 5), maintained there for 30 minutes, and then resuscitated with fluids alone (groups I and II) or fluids plus mechanical circulatory assistance (group III). Mean blood loss was greater in group I than in groups II or III (1,037 +/- 212 vs. 862 +/- 387 ml vs. 681 +/- 117 ml, respectively; I vs. III, p < 0.05) and survival was shorter (230 +/- 25.5 min vs. 709 +/- 251 min vs. 662 +/- 428 min, respectively; I vs. II or III, p < 0.05). Cardiac arrhythmia caused death in most cases. Mean biochemical parameters increased progressively in all cases. Left anterior descending coronary artery flow stayed relatively constant in group II but increased in group III. Superior mesenteric artery flow returned to baseline in group II but increased in group III. Cardiac output was similar in groups II and III, but SGOT levels significantly differed (750 +/- 135 U/L vs. 359 +/- 157 U/L; p < 0.005). These results suggest that the swine model will be useful for studying ways to improve outcomes after prolonged hemorrhagic shock.     

Treatment of severe forms of paracoccidioidomycosis: is there a role for corticosteroids?

Despite their immunosuppressive effects, corticosteroids have long been used as adjunct therapy (aCST) in the treatment of infectious diseases. The rationale is that in certain infections it is necessary to decrease the exacerbated host's inflammatory response, which can otherwise result in tissue damage and organ dysfunction. In fact, a major concern in treating paracoccidioidomycosis (PCM) is the host's intense inflammatory response to Paracoccidioides brasiliensis, which can be further intensified by antifungal therapy. Depending on its localization, this immunological phenomenon may be life threatening or result in permanent sequels, as is the case for some patients with cerebral or laryngeal involvement. However, the literature on aCST in paracoccidioidomycosis treatment is scarce and as a result we present our recent experience in the management of four patients with severe PCM manifestations, i.e., cerebral paracoccidioidal granuloma, laryngeal stenosis, compressive abdominal mass, and exacerbated inflammatory response with tissue destruction. In addition to the antifungal therapy, these patients required aCST, which probably promoted their clinical improvement and/or prevented serious complications. We suggest that aCST: (a) can potentially help in the management of selected cases of severe forms of PCM, particularly when there is a risk of acute complications, and (b) that it can be used safely provided that the risk-benefit ratio is carefully weighed. Well-controlled, prospective studies of aCST in the treatment of severe cases of paracoccidioidomycosis are needed to better define its role in the management of PCM.     

Waking up properly: is there a role of thermoregulation in sleep inertia?

We assume that alertness should be highest at the end of a sleep episode: it is not. There is always sleep inertia upon awakening, which can last minutes to hours, and whose underlying physiological mechanisms are largely unknown. Previously, we had found a functional relationship between the degree of distal vasodilatation (as measured by the distal-proximal skin temperature gradient (DPG) and sleepiness (as measured by subjective ratings), promoting rapid sleep onset. This led us to hypothesize that the dissipation of sleep inertia (sleepiness) would be associated with reverse thermoregulatory mechanisms, i.e. distal vasoconstriction. In two sets of experiments with either a nocturnal sleep episode (study 1) or an afternoon nap (study 2) we could show that vasodilatation of hands and feet increased after lights off and that this was reversed after lights on. The time course of the DPG was significantly and positively correlated with subjective sleepiness (KSS), reflecting similar temporal relationships in both studies 1 and 2. The extremities cooled at a rate very closely parallel to the decay of sleepiness [time constants for the exponential decline calculated for study 2: DPG, 0.286 +/- 0.048 h versus KSS, 0.332 +/- 0.050 h; NS], indicating redistribution of heat from the shell to the core during dissipation of sleepiness. There was no statistical evidence that the time course of sleep inertia and its thermophysiological correlates depend on sleep structure prior to awakening. The symmetry between the thermoregulatory processes initiating sleepiness and those dissipating it is striking. In order to directly test our hypothesis, further studies with thermophysiological interventions (e.g. cooling the extremities) are needed.     

Why hepatocellular carcinoma cells are unlikely to metastasize: is there a role for tissue inhibitor of metalloproteinase-1?

The question ‘Why hepatocellular carcinoma cells are unlikely to metastasize although they have a high proliferative activity?’ is a major point of interest from a cancer physiopathological viewpoint. Recent articles about the roles and relationships of some cytokines with matrix degrading enzymes and their inhibitors in various types of normal tissues and malignancies give rise to another question: ‘Does tissue inhibitor of metalloproteinase-1 prevent the extrahepatic metastasis of hepatocellular carcinoma cells?’ On the basis of many evidences, it is highly probable that under the effect of a possible inducing mechanism of the cytokines interleukin-6, -1beta and transforming growth factor beta, the increase in concentration of tissue inhibitor of metalloproteinase-1 in hepatocellular carcinoma cause increased type I collagen accumulation and consequent prevention of cellular detachment, which explains why highly proliferative malignant hepatocytes have less metastatic ability.     

Is there a role for viruses in triggering autoimmune hepatitis?

A role for viruses in autoimmune hepatitis (AH) has been repeatedly proposed but convincing evidence links only two viruses, hepatitis A and Epstein-Barr virus, to the type 1 form of the disease, and only in those rare cases where a genetic predisposition exists and the viral infection occurs at the right time, i.e. when other unknown factors are cooperating. In spite of an impressive amount of information conclusively showing molecular mimicry between cytochrome P450IID6 (the target autoantigen of autoantibodies characteristic of AH type 2) sequences and viral (hepatitis C virus, herpes simplex virus 1, cytomegalovirus, human T lymphotropic viruses 1 and 2) or bacterial (Salmonella typhimurium) antigens, no infectious agent is clearly able to induce this second form of the disease. In conclusion, the molecular mimicry theory has so far found little clinical evidence in its support and many more clinical observations are needed in order to unreveal possible links between viruses and AH.     

Time trial performance in normal and high ambient temperature: is there a role for 5-HT?

The original central fatigue hypothesis suggested that fatigue during prolonged exercise might be due to higher 5-HT activity. Therefore, we examined the effects of acute administration of a selective 5-HT reuptake inhibitor (SSRI) on performance and thermoregulation. Eleven healthy trained male cyclists completed four experimental trials (two in 18°C, two in 30°C) in a double-blind randomised crossover design. Subjects ingested either a placebo (PLA: lactose 2 × 10 mg) or citalopram (CITAL 2 × 10 mg) on the evening before and the morning of the trial. Subjects cycled for 60 min at 55% W _max, immediately followed by a time trial (TT) to measure performance. The significance level was set at P < 0.05. Acute SSRI did not significantly change performance on the TT (18°C P = 0.518; 30°C P = 0.112). During recovery at 30°C, core temperature was significantly lower in the CITAL trial (P < 0.012). At 30°C heart rate was significantly lower after exercise in CITAL (P = 0.013). CITAL significantly increased cortisol concentrations at rest (P = 0.016), after the TT (P = 0.006) and after 15-min recovery (P = 0.041) at 30°C. 5-HT reuptake inhibition did not cause significant reductions in performance. Core temperature was significantly lower only after the time trial in heat after CITAL administration. The present work failed to prove whether or not 5-HT has an exclusive role in the onset of centrally mediated fatigue during prolonged exercise in both normal and high ambient temperature.     

Is there a role for immunotherapy in controlling HIV infection?

Although HAART restores immune function in patients with HIV infection, restoration is incomplete. Functional restoration is seen primarily in responses to antigens that are prevalent in HIV-infected persons. Immunization is required to restore responses to antigens that are not predictably present. As an exception, HIV-specific responses are also generally not restored despite the prevalence of these antigens. This may be because HIV replication specifically targets and either destroys or renders nonfunctional HIV-reactive CD4+ T cells. Perhaps because HIV selectively targets HIV-reactive immune cells, therapeutic immunization strategies are particularly important areas of investigation in the treatment of HIV disease. Strategies designed to restore HIV-specific CD4+ T-cell function must also enhance the activity of HIV-specific cytolytic T cells, since these are the likely key mediators of defense against HIV replication. Both active immunization strategies and treatment interruption strategies may enhance HIV-specific immune responses. Treatment interruption, by increasing exposure to HIV antigens through heightened HIV replication, also runs the risk of permitting sufficient HIV replication to damage HIV-responsive CD4+ cells as well as enhancing the losses of other CD4+ cell populations that may protect against opportunistic complications of HIV disease. Thus, treatment interruption strategies require careful and sophisticated monitoring and should not be tried at home.     

The treatment of psychotic major depression: is there a role for adjunctive psychotherapy?

BACKGROUND: Psychotic depression is a relatively prevalent mood disorder associated with greater symptom severity, a poorer course of illness and higher levels of functional impairment compared with nonpsychotic depression. Separate lines of investigation suggest that various forms of cognitive-behavioral therapy are efficacious for treating severe forms of nonpsychotic depression as well as primary psychotic disorders. However, there currently are no empirically supported psychotherapies specifically designed for treating psychotic depression. METHOD: We review the efficacy of current somatic treatments for the disorder and discuss the limited data to date on potentially useful psychotherapeutic approaches. In particular, we describe the clinical improvement observed in a subgroup of hospitalized patients with psychotic depression treated with Acceptance and Commitment Therapy as part of a larger clinical trial. RESULTS: Pilot results demonstrated that Acceptance and Commitment Therapy was associated with clinically significant reductions in acute symptom severity and impairment compared with treatment as usual. CONCLUSION: The findings suggest that patients with psychotic depression can benefit from psychotherapy. Clinical and research recommendations in this area are presented.