Stochastic model for estimating the risk of transfusion-transmitted hepatitis B in Vietnam.

BACKGROUND AND OBJECTIVE: Transfusion-transmitted hepatitis B virus (HBV) infection may originate from hepatitis B surface antigen (HBsAg) false-negative blood donors, HBsAg negative and anti-HBc positive blood donors and blood donors with both tests negative. HBV DNA may be present in all these cases and blood may be infectious. The aim of the study was to estimate the risk of transfusion-transmitted HBV in Vietnam using a stochastic Monte Carlo model. METHODS: A cross-sectional study of HBV prevalence in 1200 potential blood donors in rural Vietnam is used as basis for the Monte Carlo model together with expert panel estimates of occult hepatitis B infection (OBI) prevalence in blood donors. RESULTS: With 1 000 000 blood donors running in the model, the potential OBI ranged from 658 to 747 blood units per million at 5 percentile and from 1342 to 2507 blood units per million at 95 percentile resulting in the risk of post-transfusion hepatitis ranging from 66 to 250 blood units per million assuming that risk of post-transfusion from potential OBI is 10%. Using the manufacturer's HBsAg sensitivity, the mean rate of blood units per million donations having false-negative HBsAg results was 298 (5-95 percentile: 14-893). When the test sensitivity was set lower, false-negative tests was observed at a mean of 1087 per million (5-95 percentile: 762-3220). The fraction of potential OBI donors increased with the increasing age in both genders. CONCLUSION: Current HBsAg screening in Vietnam is insufficient in eliminating the risk of transfusion-transmitted HBV infection. The major risk factors are HBsAg false-negative results and OBI. Increased test sensitivity and locally validated HBsAg assays are recommended.

Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour.

The atypical antipsychotic bifeprunox is a partial dopamine D(2) and 5-HT(1A) receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons. Interestingly, bursting activity was markedly reduced (by 70-100%), bursting being associated with a larger synaptic dopamine release than single spike firing. Both ligands reduced inhibition of firing rate induced by the full dopamine receptor agonist apomorphine, whereas the D(2) receptor antagonist haloperidol prevented these inhibitory effects, confirming partial D(2)-like agonistic properties. On 5-HT neurons, bifeprunox was more potent than aripiprazole to suppress firing activity. The 5-HT(1A) receptor antagonist WAY-100,635 prevented their effects. In the USV test of anxiolytic-like activity, bifeprunox had higher potency than aripiprazole to reduce vocalisations. Both WAY-100,635 and haloperidol reversed the effects of both agonists. The present in-vivo study shows that bifeprunox is a potent partial D(2)-like and 5-HT(1A) receptor agonist reducing preferentially the phasic activity of dopamine neurons. Thus, bifeprunox would be expected to be an effective compound against positive and negative symptoms of schizophrenia.

Changed concentrations of tachykinins and neuropeptide Y in brain of a rat model of depression: lithium treatment normalizes tachykinins.

Lithium's therapeutic mechanism of action is unknown. In lithium-treated normal rats, increased striatal concentrations of neurokinin A (NKA)-like immunoreactivity (LI), substance P (SP-LI) and neuropeptide Y (NPY-LI) have been reported. To investigate whether these effects might be of therapeutic relevance, Flinders Sensitive Line rats (FSL), an animal model of depression, and control Flinders Resistant Line (FRL) rats were during a 6-week period fed chow to which either lithium or vehicle was admixed. Following sacrifice, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. NKA-LI and SP-LI were markedly decreased in striatum and increased in frontal cortex in FSL compared to control FRL animals. Lithium treatment abolished these differences. Basal concentrations of NPY-LI were decreased in hippocampus of FSL rats, but unaffected by lithium. The present study suggests that changed tachykinins and NPY may underlie the characterized depressive-like phenotype of the FSL rats. It is hypothesized that altering tachykinin peptidergic neurotransmission in striatum and frontal cortex constitutes a mechanism of action of lithium and that such a mechanism might be of therapeutic relevance.

Early maternal deprivation alters hippocampal levels of neuropeptide Y and calcitonin-gene related peptide in adult rats.

Stressful events early in life are reported to be more prevalent among patients with an adult life psychiatric disorder. Early maternal deprivation is considered an animal model of early life stress. Maternally deprived adult rats display long-term alterations in the neuroendocrine system, brain and behavior that are in many ways analogous to depressive and schizophrenic symptomatology. Neuropeptide Y (NPY) and calcitonin-gene related peptide (CGRP) have been implicated in both disorders and also been suggested to play a role in the neuroadaptational response to stress. Consequently, male Wistar rat-pups were subjected to early maternal deprivation or control handling, on postnatal day (pnd) 9. On pnd 21, pups were weaned and split into two groups that were reared either on a saw-dust floor or on a grid-floor, considered to be a mild stressor. On pnd 67, all animals were subjected to the prepulse inhibition test. One week later, the animals were sacrificed, the brains removed and dissected on ice. Levels of NPY-like immunoreactivity (LI) and CGRP-LI were quantified by radioimmunoassay in brain regional extracts. Maternal deprivation led to a significant reduction in basal startle amplitude and disruption of prepulse inhibition. These findings were paralleled by significantly reduced levels of NPY and CGRP in the hippocampus and occipital cortex. It is hypothesised that these changes may be of relevance to aspects of schizophrenic and affective symptomatology. The present study further shows that brain NPY and, in particular, CGRP are sensitive to long-term mild stress and further implicate the involvement of these peptides in the neuroendocrine stress response.

Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram.

Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvulsive stimuli (ECS) has been shown to increase mRNA and peptide levels of NPY in rat brain tissue. Consequently, parameters reflective of NPYergic neurotransmission were studied in the hippocampus of rats following chronic treatment with lithium, ECS or the selective serotonin re-uptake inhibitor (SSRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) treatments caused a marked increase in levels of preproNPY mRNA in the CA1 area and dentate gyrus (DG). This increase was accompanied by an increase in extracellular levels of NPY in the dorsal hippocampus of freely moving rats as determined by microdialysis, suggesting that lithium and ECS treatments lead to an increased biosynthesis and release of NPY in this area. (125)I-peptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG following the same treatments, showing that the increased release is accompanied by a down-regulation of corresponding binding sites. In contrast, citalopram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in (125)I-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extracellular NPY in the hippocampus were unaffected. The results indicate that various agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram all increase NPYergic neurotransmission in the hippocampus by distinct modes of action. Moreover, NPY (6 microg) given intracerebroventricularly (i.c.v.) induced an antidepressant-like effect in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of various antidepressant treatments in the alleviation of depression.

Extracellular levels of neuropeptide Y are markedly increased in the dorsal hippocampus of freely moving rats during kainic acid-induced seizures.

In this microdialysis study we measured the extracellular neuropeptide Y (NPY) levels in the dorsal hippocampus of conscious rats. During potassium-induced depolarisations, a 93% increase in extracellular levels of NPY was observed. NPY has been demonstrated to reduce kainic acid-induced convulsions in rats, but it is unknown whether NPY neurotransmission is affected by seizures. During seizures induced by kainic acid we observed a 104% increase in levels of NPY, suggesting that convulsions are associated with a dramatically increased NPYergic neurotransmission.

Neuropeptide Y inhibits in vitro epileptiform activity in the entorhinal cortex of mice.

Previous studies show that neuropeptide Y (NPY) inhibits in vitro seizures in rodent hippocampus. Here, we explored the effect of NPY application on epileptiform discharges induced by perfusion with magnesium-free solution in slices of entorhinal cortex from two different mouse strains. NPY significantly reduced the duration of epileptiform discharges with a peak effect of 36-50%. This is the first study showing anti-epileptiform effect of NPY in the entorhinal cortex and also the first evidence that NPY inhibits seizures in a cortical region in mice. The entorhinal cortex has a central role in transferring information between the hippocampus and the rest of the brain. Therefore our data further strengthen the concept of NPY and its receptors as widespread regulators of epileptiform activity and as a potential future target for antiepileptic therapy.

Low doses of domoic acid during postnatal development produce permanent changes in rat behaviour and hippocampal morphology.

It is well established that the developing brain is a highly dynamic environment that is susceptible to toxicity produced by a number of pharmacological, chemical and environmental insults. We report herein on permanent behavioural and morphological changes produced by exposing newborn rats to very low (subconvulsive) doses of kainate receptor agonists during a critical window of brain development. Daily treatment of SD rat pups with either 5 or 20 microg/kg of domoic acid (DOM) from postnatal day 8-14 resulted in a permanent and reproducible seizure-like syndrome when animals were exposed to different tests of spatial cognition as adults. Similar results were obtained when animals were treated with equi-efficacious doses of kainic acid (KA; 25 or 100 microg/kg). Treated rats had significant increases in hippocampal mossy fiber staining and reductions in hippocampal cell counts consistent with effects seen in adult rats following acute injections of high doses of kainic acid. In situ hybridization also revealed an elevation in hippocampal brain derived neurotrophic factor (BDNF) mRNA in region CA1 without a corresponding increase in neuropeptide Y (NPY) mRNA. These results provide evidence of long-lasting behavioural and histochemical consequences arising from relatively subtle changes in glutamatergic activity during development, that may be relevant to understanding the aetiology of seizure disorders and other forms of neurological disease.

Effects of early prehospital life support to war injured: the battle of Jalalabad, Afghanistan.

OBJECTIVE: To study the effects of early, advanced prehospital life support on the survival rate of war casualties during the battle of Jalalabad, Afghanistan from 1989-1992. METHOD: The outcomes of simple trauma care administered from 1989-1990 were compared to the outcomes of advanced trauma care administered from 1991-1992 in the combat zone. The outcomes were measured by the number of deaths at admission to the referral surgical hospitals in Pakistan. RESULTS: A total of 3,890 war casualties were treated in the combat zone by paramedics, and were evacuated through light, forward, field clinics to surgical hospitals in Pakistan. Advanced trauma care that was administered in the combat zone reduced the prehospital mortality rate from 26.1% to 13.6% (95% CI for difference = 9.7-15.4%). CONCLUSION: In scenarios with protracted evacuation, early and advanced trauma care should be included in the chain of survival. Local paramedics can provide such trauma care with a minimum of resources.

Distally based perforator flaps for reconstruction of post-traumatic defects of the lower leg and foot. A review of the anatomy and clinical outcomes.

STUDY AIMS: To report the surgical anatomy of the perforator arteries at the lower leg, analyse clinical outcomes in previous studies, and forward methodological recommendations for future studies of post-traumatic perforator flap reconstructions. METHODS: A study sample of 640 human patients drawn from 24 clinical reports was included for review. The sample comprised of four subsets: sural flap reconstructions (n=257), saphenous flaps (n=122), supramalleolar flaps (n=92), and propeller flaps (n=169). RESULTS: Statistical analysis of samples from anatomical studies documents significant differences in the perforator distribution from the tibial and peroneal artery; peroneal perforator arteries are randomly organised whereas tibial artery perforators are clustered at three definite levels. The failure rates in clinical studies ranged from 0% to 6%, being lowest for supramalleolar flap reconstructions and highest for saphenous flaps; however, differences between the four subsets were not statistically significant at the 95% confidence level. Due to methodological flaws, outcome comparisons in the actual study sample should be interpreted cautiously; in most clinical studies both risk variables and outcome indicators are poorly defined. The outcome of Dynamic Infrared Thermography imaging of post-transposition changes of flap perfusion is reported. SUMMARY: Fasciocutaneous perforator flaps seem to have high survival rates and represent a feasible approach to post-traumatic reconstructions, especially in low-resource settings. A template for data gathering is recommended for higher accuracy in future comparative studies, and for scientific analysis of success and risk factors. New imaging techniques indicate a promising potential of micro-circular angiogenesis during the first two weeks after flap transpose.

[Saphenous perforator flap]. / Der Saphenusperforatorlappen.

OBJECTIVE: Replacement of full thickness soft tissue defects in the lower leg and ankle, appropriate to the defect and following the course of blood vessels feeding the skin of a distally hinged fasciocutaneous flap most reliably based on the individual anatomy of distal perforators of the posterior tibial artery. INDICATIONS: Full thickness soft tissue defects, up to 12 cm in length and up to 8 cm in width. Sufficient vascularization of the foot required, in osteomyelitis, and when joints, fractures, implants and tendons are exposed and when a split skin graft, a local flap, a suralis perforator flap or a free flap is not indicated. CONTRAINDICATIONS: For patients, in whom a 1-2 h operation is not possible; necessity of angioplasty; decollement or scars around the distal perforators of the posterior tibial artery; local infection or necrosis of soft tissues and/or bone, which cannot be totally excised. SURGICAL TECHNIQUE: Radical debridement; flap dissection without tourniquet; microdissection; design of the flap on the skin: pivot point ~ 10 cm (6-14 cm) proximal of the tip of the medial malleolus; base ~ 5 cm in width, between the course of the saphenous nerve and of the great saphenous vein and the Achilles tendon; adipofascial pedicle up to 15 cm in length sited over the septum between soleus and flexor digitorum muscles, following the course of the saphenous nerve, with a central skin stripe, which expands into a proximal skin island; skin island is outlined similar to the defect, but larger by 1 to 2 cm, surrounded by an adipofascial border: adjustment of the planning as well as of the elevation of these flaps according to the individual position and the caliber of perforators requires in each case the search for a perforator at the estimated pivot point. Delay of transposition, if the division of more than one perforator proximal to the pivot point obviously diminishes circulation. No "tunnelling "of the pedicle; defects of skin due to the elevation of the flap are replaced by split and meshed skin grafts or temporary by "artificial skin". A gap in the bandage over the skin island allows for observation. POSTOPERATIVE MANAGEMENT: Protocol of controls of vascularization: color and time for revascularization; antibiotic treatment according to bacteriological testing. In case of edema or discoloration of the flap: immediate removal of sutures, administration of leeches, operative revision. Split skin graft 1 week after flap transposition, if the skin had been temporary substituted. RESULTS: Retrospective uncontrolled study with over 70 saphenous perforator flaps from 1995-2011. Full soft tissue defects 62 times with osteomyelitis, 3 times with endoprothesis, 3 times with fractures, 2 times with exposed tendons. From 1995-2006, 44/50 (88 %) flaps healed completely or at least to 3/4 without the necessity of further flaps; from 2007-2011, 13/20 (65 %) flaps healed completely and 6/20 (30 %) flaps healed at least to 3/4 without the necessity of further flaps, loss of one flap (5 %).

Sural perforator flap for reconstructive surgery in the lower leg and the foot: a clinical study of 86 patients with post-traumatic osteomyelitis.

BACKGROUND: The treatment of post-traumatic osteomyelitis of the lower leg and the foot remains a challenge in reconstructive surgery. MATERIAL AND METHODS: Eighty-six patients with lower leg post-injury chronic osteomyelitis were included in a retrospective, non-controlled clinical study conducted from 1995 to 2006. All study patients were managed by distally based sural neuro-fascio-cutaneous perforator flap. An endpoint survey was conducted after flap surgery and had a mean follow-up period of 5.5 years, wherein the response rate was 48%. RESULTS: Seven patients had a short-term flap failure (8%; 95% CI 3-16%). An additional eight patients (7%) had flap necrosis of less than one-fourth of the flap that healed without surgical revision. Based on the endpoint data, the long-term success rate was 87% (95%, CI 72-96%). Local and/or systemic physiological compromise was a risk factor for flap failure. Other assumed risk factors had no statistically significant impact on short- or long-term results. CONCLUSION: Sural perforator flap is a robust flap with low failure rate, even in high-risk patients. The success rate compares favourably with results of free flap transfers in the management of post-traumatic osteomyelitis. The flap has a wide range, and the surgical technique is rather simple. The sural flap is a feasible option for post-traumatic reconstructions of osteomyelitis, especially in low-resource settings.

Exacerbated loss of cell survival, neuropeptide Y-immunoreactive (IR) cells, and serotonin-IR fiber lengths in the dorsal hippocampus of the aged flinders sensitive line "depressed" rat: Implications for the pathophysiology of depression?

Impairment of hippocampal neurogenesis has been proposed to provide a cellular basis for the development of major depression. Studies have shown that serotonin (5-HT) and neuropeptide Y (NPY) may be involved in stimulating cell proliferation in the dentate gyrus. The Flinders-sensitive line (FSL) rat represents a genetic model of depression with characterized 5-HT and NPY abnormalities in the hippocampus. Consequently, it could be hypothesized that hippocampal neurogenesis in the FSL rat would be impaired. The present study examined the relationship among 1) number of BrdU-immunoreactive (IR) cells, 2) NPY-IR cells in the dentate gyrus, and 3) length of 5-HT-IR fibers in the dorsal hippocampus, as well as volume and number of 5-HT-IR cells in the dorsal raphé nucleus, in adult and aged FSL rats and control Flinders-resistant line (FRL) rats. Surprisingly, adult FSL rats had significantly more BrdU-IR and NPY-IR cells compared with adult FRL rats. However, aging caused an exacerbated loss of these cell types in the FSL strain compared with FRL. The aged FSL rats also had shortened 5-HT-IR fibers in the dorsal hippocampus, indicative of an impaired 5-HT innervation of this area, compared with FRL. These results suggest that, for "depressed" FSL rats, compared with FRL rats, aging is associated with an excacerbated loss of newly formed cells in addition to NPY-IR cells and 5-HT-IR dendrites in the hippocampus. These observations may be of relevance to the depression-like behavior of the FSL rat and, by inference, to the pathophysiology of depression.

Surgery in Afghanistan: a light model for field surgery during war.

Owing to a poor capability for evacuation, mobile medical teams were sent to the area of Gazni in Afghanistan to work with local paramedics as part of a medical programme for the area. The teams were equipped to perform major surgery. During 1 month a surgical team inside Afghanistan performed 53 operations. The operations were performed in the patients' homes at night. The team had to move frequently so as not to be spotted by the Soviet and government surveillance. Equipment equivalent to a light field hospital was stored in a safe place and the team carried supplies for 1 or 2 days on their bicycles. One postoperative death and one wound infection were recorded. It is concluded that adequate surgery can be performed inside territories where enemy forces have air control and under primitive conditions with an acceptable rate of complications. However, due to the nature of the guerrilla warfare with scattered military confrontations over vast areas, the average time between injury and treatment for war casualties was 36 h.

The siege of Tripoli 1983: war surgery in Lebanon.

When Syrian-backed troops attacked the city of Tripoli and the surrounding Palestinian refugee camps in November and December 1983, the authors worked in the Palestine Red Crescent Society (PRCS) Hospital in the area. The hospital was situated close to the front line of the battle at all times and the transportation of casualties was therefore short. During the first month of the battle this hospital received approximately 1,500 casualties, and 390 primary and 24 secondary operations were performed. Multiple shrapnel wounds dominated, and high-velocity missile wounds were also frequently seen. The common treatment principles for missile wounds with radical debridement and delayed primary suture, in some cases secondary suture, were followed. Exploratory surgery was carried out in cases of suspected intra-abdominal and vascular injuries. Limited resources made an efficient selection necessary. Surgery under conditions of war is extremely demanding upon resources: equipment and personnel. By leaving minor debridements and a large amount of the emergency treatment to experienced nurses, a high capacity could be maintained.

Levetiracetam prevents changes in levels of brain-derived neurotrophic factor and neuropeptide Y mRNA and of Y1- and Y5-like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood-stabilizing properties.

The amygdala-kindling model has been proposed as a model of sensitization processes with relevance to epilepsy as well as affective disorders. Levetiracetam is a novel anticonvulsant drug that delays the process of kindling, i.e., possesses antiepileptogenic properties. Preliminary reports also suggest a mood-stabilizing potential for levetiracetam. Brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) are central modulators of seizure activity, which undergo plastic changes during kindling epileptogenesis. Consequently, we investigated the regulation of BDNF and NPY mRNA and Y1-, Y2-, and Y5-like receptor binding in the hippocampus of vehicle-pretreated, partially and fully amygdala-kindled rats and corresponding levetiracetam-pretreated rats (40 mg/kg i.p.). The present data indicate that the process of kindling is associated with an upregulation of hippocampal BDNF and NPY mRNA levels and downregulation of Y1- and particularly Y5-like receptors. Pretreatment with levetiracetam markedly delays the progression of kindling and, in addition, exhibits a clear anticonvulsant effect. These effects are associated with abolition of the kindling-induced rise in BDNF and NPY mRNA and increasing levels of Y1- and particularly Y5-like receptors in all hippocampal subfields. Lastly, the present study reveals that an identical dose of levetiracetam reduced immobility in the rat forced swim test, the first experimental evidence indicative of an antidepressant and/or mood stabilizer-like profile of this drug. Considering that animal depression models display impairments in hippocampal NPY systems that become normalized following mood-stabilizing treatment, and that exogenous NPY exerts anticonvulsant as well as antidepressive-like activity in rodents, it is a heuristic possibility that increased hippocampal excitability and affective symptomatology may converge on an impaired hippocampal NPY function. Speculatively, the ability of levetiracetam to increase hippocampal Y1- and Y5-like receptor levels may have implications for the antiepileptic properties of levetiracetam, as well as its purported mood-stabilizing properties.