Kinetics of HTT lowering in brain of YAC 128 mice following single and repetitive intranasal dosing of siRNA packaged in chitosan-based nanoparticle.

This report describes the kinetics of Huntington's Disease (HD) gene (HTT) lowering in brains of YAC 128 mice. Lowering (or "knock-down") of HTT mRNA expression was achieved by intranasal administration of specially designed siRNA loaded into chitosan nanoparticles. Kinetic patterns of HTT lowering observed in different brain regions allowed calculation of cumulative lowering effects that result from multiple consecutive administrations. Mathematical modeling generated dosing schedules for approaching a steady knock-down effect and for prediction of magnitude and duration of HTT lowering. Kinetic modeling of HTT lowering with our algorithm will be useful in determining intranasal dosing schedules to produce chronic, therapeutically significant lowering effect of gene expression.

Chronic Treatment with Opiate Agonists in Bulgaria - Assessing the Quality of Life Using SF 36 v. 2.

INTRODUCTION: Drug addictions to psychoactive substances are disorders with a complex bio-psycho-social genesis, which are characterized with chronic relapses. Substance addiction causes multifactorial damage to the normal functioning of individuals and requires a multicenter approach for the treatment process. AIM: The aim of the study was to assess the quality of life of patients undergoing chronic treatment with the opiate agonist methadone using a standardized questionnaire method in Bulgarian. MATERIAL AND METHODS: The study included patients aged 18 to 40 years undergoing chronic treatment with methadone for at least six months. The study included 100 subjects. Seventy-six patients were from 5 clinical programs in Bulgaria; twenty- four clinically healthy age-matched subjects with no history of drug abuse, psychiatric and somatic diseases were the control group. RESULTS: We found significant differences between patients and controls in all components of the survey (P<0.05). The patients had lower scores than the control group in the SF-36 in terms of all eight components and both the physical and mental component summaries of the SF-36-survey. Patients compared between the groups by dose, duration of treatment with methadone and period of heroin abuse before initiating treatment did not show significant differences. There were no significant differences between patients with and without hepatitis C virus. CONCLUSIONS: Opiate addiction is a state associated with poor quality of life. The duration of treatment, the methadone dose, period of heroin abuse before initiating treatment and illness of hepatitis C virus does not correlate with lower results.

Penile enhancement using autologous tissue engineering with biodegradable scaffold: a clinical and histomorphometric study.

INTRODUCTION: Autologous tissue engineering with biodegradable scaffolds is a new treatment option for real penile girth enhancement. AIM: The aim of this article is to evaluate tissue remodeling after penile girth enhancement using this technique. METHODS: Between June 2005 and May 2007, a group of 12 patients underwent repeated penile widening using biodegradable scaffolds enriched with expanded autologous scrotal dartos cells. Clinical monitoring was parallel to histological investigation of tissue remodeling. During second surgical procedure, biopsies were obtained 10-14 months after first surgery (mean 12 months, N=6) and compared with those obtained after 22-24 months (mean 23 months, N=6), and control biopsies from patients who underwent circumcision (N=5). Blind evaluation of histomorphometrical and immunohistochemical finding was performed in paraffin sections. MAIN OUTCOME MEASUREMENTS: Penile girth gain in a flaccid state ranged between 1.5 and 3.8 cm (mean 2.1 ± 0.28 cm) and in full erection between 1.2 and 4 cm (mean 1.9 ± 0.28 cm). Patients' satisfaction, defined by a questionnaire, was good (25%) and very good (75%). RESULTS: In biopsies obtained 10-14 months after first surgery, highly vascularized loose tissue with collagen deposition associated with small foci of mild chronic and granulomatous inflammation surrounding residual amorphous material was observed. Fibroblast-like hyperplasia and small vessel neoangiogenesis occurred intimately associated with the progressive growth of vascular-like structures from accumulation of CD34 and alpha-smooth muscle actin-positive cells surrounding residual scaffold-like amorphous material. Capillary neoangiogenesis occurred inside residual amorphous material. In biopsies obtained after 22-24 months, inflammation almost disappeared and tissue closely resembled that of the dartos fascia of control group. CONCLUSIONS: Autologous tissue engineering using expanded scrotal dartos cells with biodegradable scaffolds is a new and promising method for penile widening that generates progressive accumulation of stable collagen-rich, highly vascularized tissue matrix that closely resemble deep dartos fascia.

Current surgical management of severe peyronie's disease.

OBJECTIVES: To report the principles of penile resculpturing of different deformities caused by M. Peyronie: restoration of penile length, girth and shape with or without penile prosthesis implantation. METHODS: In the period between February 2007 and March 2009, we performed grafting surgery for M. Peyronie in 98 patients aged between 24 and 72 years (mean 52 years). Penile deformities were diferent: dorsal curvature in 54 (55%), lateral in 7 (7%), ventral in 11 (11%), and combined curvature in 21 (21%) associated corporal narrowing was present in 24 patients (24%). Four (4%) patients presented isolated penile shortening without other deformity. Isolated diffuse corporal narrowing without shortening was found in two (2%) patients. Severity of curvature ranges from 60 to 90 degrees, mean 72. Thirty one (31%) patients had associated ED. Surgical options for severe Peyronie's disease were: single grafting in 26 pts (26%), complex grafting including circular tunical incision in 36 pts (36%), and in patients with ED the same procedures combined with penile prosthesis implantation (37 pts, 38%). Surgical correction was based on measurement of the tunical defect and precise calculation of graft size and shape. Penile straightening and lengthening was achieved by equalizing of shortened penile side/s with the longest one (convex) and grafting. Penile width is reestablished with additional longitudinal incision/s and grafting; graft width is determined by measurement of difference in circumference between normal and narrowed part of the corpora. We used Intexen LP (AMS) as a grafting material in all cases. RESULTS: The mean follow-up was 15 months (6-25). Mean penile length gain without prosthesis was 2.8cm (1.5-4.2) and with prosthesis 3.2cm (2-4.5cm). Insuficient straightening was in 5 patients (>15 degree) where Neuro Vascular Bundle (NVB) was limiting factor. Twenty four patients reported hypoesthesia and reduced orgasmic sensitivity that recovered spontaneously after 3-6 months. De-novo ED occurred in 6 pts and progression of disease in 6 patients. Infection occurred only in one patient with penile prosthesis implantation. Overall patients' satisfaction was 95%. CONCLUSIONS: Complete tunical reconstruction in IPP can be performed as a safe procedure by transversal, longitudinal and circular grafting with or without simultaneous penile prosthesis implantation. Maximum penile length, girth and shape restoration can be achieved using geometrical calculation, regardless of type of deformity.

Severe penile injuries: a problem of severity and reconstruction.

OBJECTIVES: To report our experience of treating severe penile injuries with different causes and treatments, as penile trauma presents a difficult physical and psychological problem, and the type and extent of injury varies from mild to severe, sometimes even with total amputation. PATIENTS AND METHODS: We analysed retrospectively 43 patients (mean age 28 years, range 5-52 years) with severe penile injuries referred to us from March 1999 to August 2007. The causes of penile injuries differed, including iatrogenic trauma (20), traffic accidents (11), burns (three), self-amputation (two), ritual circumcision (two), penile fracture (two), gunshot trauma (two) and electrocution (one). The management required a wide variety of surgical techniques tailored to each patient depending on the type and extent of injury. RESULTS: The mean (range) follow-up was 47 (10-108) months. The aesthetic and functional results, including satisfactory sexual intercourse were good in 35 patients. There were complications in seven patients; infection after implanting an inflatable penile prosthesis in one, protrusion of a semirigid prosthesis in one, urethral complications (one stenosis and two fistulae) in three and partial skin flap necrosis in two. CONCLUSIONS: Severe penile injuries should be treated on an individual basis, applying different techniques. However, treatment can be effective and safe only in specialized centres.

Metoidioplasty as a single stage sex reassignment surgery in female transsexuals: Belgrade experience.

INTRODUCTION: Metoidioplasty represents one of the variants of phalloplasty in female transsexuals. Its main characteristic is that it is a one-stage procedure. It involves lengthening and straightening of hypertrophied clitoris to create a neophallus, urethral lengthening to enable voiding while standing, and scrotal reconstruction with insertion of testicle prostheses. AIM: Our aim is to describe our technique and highlight its advantages. METHODS: Between September 2002 and April 2007, 82 female transsexuals, aged 18-54 years (mean age 31) underwent one-stage metoidioplasty. Clitoris is lengthened and straightened by division of clitoral ligaments and short urethral plate. Urethroplasty is done with combined buccal mucosa graft and genital skin flaps. Scrotum is created from labia majora in which two testicle prostheses are inserted. Simultaneously, female genitalia are removed. MAIN OUTCOME MEASURES: Patients' personal satisfaction about sensitivity and length of neophallus, possibility to void in standing position, real length of reconstructed urethra as well as complication rate comparing to other published data. RESULTS: The median follow-up was 32 months (range 14-69). The mean neophallic length was 5.7 cm (range 4-10). Voiding in standing position was reported in all patients, while dribbling and spraying were noticed in 23 cases and solved spontaneously. There were two urethral strictures and seven fistulas that required secondary minor revision. All patients reported preserved sensation and normal postoperative erection. Testicle prostheses rejection was not observed in any of the patients. CONCLUSIONS: Metoidioplasty is a single-stage and time-saving procedure. It could be an alternative to total phalloplasty in female transsexuals who do not wish to have sexual intercourse. Also, it represents a first step in cases where additional augmentation phalloplasty is required.

Serum Levels of Incretin Hormones - GLP-1 and GIP in Patients with Type 1 Diabetes Mellitus.

BACKGROUND: The glucagon-like peptide-1 (GLP-1) and the glucose- dependent Insulinotropic peptide (GIP) are natural incretin hormones, which are secreted respectively by the L- and K-cells of the intestinal mucosa in response to the physiological gastrointestinal glucose absorption. In patients with type 2 diabetes mellitus, the incretin effect is reduced, whereas the results in type 1 diabetes mellitus (T1DM) are heterogeneous, in some patients normal incretin response is observed. AIM: Comparative analysis of the basal serum levels of the incretin hormones GLP-1 and GIP in patients with type 1 DM and in individuals without carbohydrate disorders. MATERIALS AND METHODS: The study included 27 patients with diagnosed T1DM and a control group of 39 individuals without carbohydrate disorders. All participants in the study were subjected to the following clinical measurements and laboratory tests - height, weight, bioimpedance analysis of body composition, fasting blood sugar (BS 0'), postprandial blood sugar (PPBS), glycated haemoglobin (HbA1c) in T1DM patients, total cholesterol (TC), HDL cholesterol (HDL chol), triglycerides (TG), transaminase (AST and ALT), basal serum levels of GLP-1 and GIP. RESULTS: The serum levels of GIP in the patients with type T1DM were significantly higher, compared to the individuals without carbohydrate disorders (P<0.05), while there was no statistically significant difference in the GLP-1 levels. CONCLUSION: The significantly higher GIP levels and the similar GLP-1 levels in our patients with type 1 DM, compared to the individuals without carbohydrate disorders, support the hypothesis of intact incretin effect in this type of diabetes mellitus Key Words: Glucagon-like peptide-1, Glucose-dependent insulinotropic peptide, Type 1 diabetes mellitus.

New insight into surgical anatomy of epispadiac penis and its impact on repair.

PURPOSE: Surgical anatomy of the epispadiac penis is still not fully described. Using our complete disassembly technique, we discovered some anatomical features of epispadiac penis that may have significant impact on surgical outcome. MATERIALS AND METHODS: A total of 52 patients 2 days to 19 years old (mean age 43 months) underwent primary repair of epispadias between October 1996 and December 2006. After complete penile disassembly, ie full mobilization of the corporeal bodies, neurovascular bundles and urethral plate, reassembly of the penile entities was done. The urethral plate is tubularized and ventralized. The corporeal bodies are straightened and lengthened by 2 transverse incisions and grafting, joined medially and fixed to the glans cap. The glans is reconstructed, and the neurovascular bundles are moved dorsally and joined. The skin is reconstructed using different local flaps. RESULTS: Investigating the anatomical features of the epispadiac penis, we discovered several distinguishing features. The corporeal bodies are separated and triangular in shape. They represent the main substrate of dorsal curvature due to the significant disproportion in length between the long ventral and short wedge-shaped dorsal sides. The length of the neurovascular bundles is determined by their course-they are longer if they overlie the ventral side of the corpora and shorter if positioned over the dorsal side. The skin between the scrotum and penis has characteristics similar to penile skin. A good functional and esthetic outcome was achieved in 46 patients. Erection and glanular sensitivity were preserved in all patients. There was no necrosis of the glans or corporeal bodies. Complications included urethral fistula in 4 patients, stenosis in 2 and mild residual curvature in 2. CONCLUSIONS: New insights into the anatomical features of the epispadiac penis can have a significant impact on surgical outcomes.

Buccal mucosa grafts for repair of stenotic catheterizable continent stoma.

PURPOSE: Different tubular structures have been used to create cutaneous catheterizable continent urinary stomas. The most common complication is stomal stenosis on the cutaneous end of the tubes. We present a variant of stomal stenosis repair that uses a buccal mucosa graft. MATERIALS AND METHODS: Between January 2000 and March 2006 stenotic stomal repair was performed in 10 patients between 3 and 17 years old (mean age 6). A Mitrofanoff channel was created from a bladder tube in 4 patients, from appendix in 3, from ileum in 2 and from the ureter in 1. The procedure involved the removal of scar tissue and the creation of well vascularized dermal beds by skin de-epithelialization (epidermis removal). After that we formed 2 elliptical dermal flaps. Two elliptical buccal mucosa grafts were quilted to the recipient bed (the dermal flap) and anastomosed with the mucosa of the normal part of the channel. The flaps were joined, tubularized and sutured to the skin. An indwelling catheter was left in the channel for 2 weeks. Postoperatively the buccal mucosa was wetted with saline solution for 4 consecutive days. RESULTS: Followup was between 12 and 39 months (mean 22). There was no partial or total graft necrosis. None of the patients experienced repeat stenosis. The stoma was visible (uncovered) and the esthetic appearance was satisfactory in all patients. CONCLUSIONS: Repair of Mitrofanoff stomal stenosis using a buccal mucosa graft is a minor procedure. It is a good salvage procedure that excludes the need to create a new channel.

Can low level exposure to ochratoxin-A cause parkinsonism?

Mycotoxins are fungal metabolites with pharmacological activities that have been utilized in the production of antibiotics, growth promoters, and other classes of drugs. Some mycotoxins have been developed as biological and chemical warfare agents. Bombs and ballistic missiles loaded with aflatoxin were stockpiled and may have been deployed by Iraq during the first Gulf War. In light of the excess incidence of amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert Storm, the potential for delayed neurotoxic effects of low doses of mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common mycotoxin with complex mechanisms of action, similar to that of the aflatoxins. Acute administration of OTA at non-lethal doses (10% of the LD(50)) have been shown to increase oxidative DNA damage in brain up to 72 h, with peak effects noted at 24 h in midbrain (MB), caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and its metabolites in the striatum (e.g., CP) were shown to be decreased in a dose-dependent manner. The present study focused on the effects of chronic low dose OTA exposure on regional brain oxidative stress and striatal DA metabolism. Continuous administration of low doses of OTA with implanted subcutaneous Alzet minipumps caused a small but significant decrease in striatal DA levels and an upregulation of anti-oxidative systems and DNA repair. It is possible that low dose exposure to OTA will result in an earlier onset of parkinsonism when normal age-dependent decline in striatal DA levels are superimposed on the mycotoxin-induced lesion.

Neuroanatomical mapping of DNA repair and antioxidative responses in mouse brain: Effects of a single dose of MPTP.

The primary objective of this study was to map the normal distribution of the base excision enzyme oxyguanosine glycosylase (OGG1) across mouse-brain regions as a prelude to assessing the effects of various neurotoxicants, ranging from highly selective molecules like MPTP to more global toxic agents. This research is based on the hypothesis that regional brain vulnerability to a toxicant is determined, in part, by variation in the intrinsic capacity of cellular populations to successfully repair oxidative DNA damage. After mapping the normal distributions of OGG1 and superoxide dismutase (SOD) across 44 loci dissected from mouse brain, MPTP, a mitochondrial toxicant with selective dopamine (DA) neuron cytotoxicity was used to elicit focal oxidative stress and DNA repair responses. A single dose of MPTP (20mg/kg, i.p.) elicited time- and region-dependent changes in both SOD and OGG1, with early increases in DNA repair and anti-oxidant activities throughout all regions of brain. In some sampled loci, notably the substantia nigra (SN) and hippocampus, the heightened DNA repair and antioxidant responses were not maintained beyond 48h. Other loci from cerebellum, cerebral cortex and pons maintained high levels of activity up to 72h. Levels of dopamine (DA) were decreased significantly at all time points and remained below control levels in nigro-striatal and mesolimbic systems (ventral tegmental area and nucleus accumbens). Assessment of apoptosis by TUNEL staining revealed a significant increase in number of apoptotic nuclei in the substantia nigra at 72h and not in other loci. The marked degree of apoptosis that became evident in SN at 72h was associated with large decreases in SOD and DNA repair activity at that locus. In conclusion, MPTP elicited global effects on DNA repair and antioxidant activity in all regions of brain, but the most vulnerable loci were unable to maintain elevated DNA repair and antioxidant responses.

Acute neurotoxic effects of the fungal metabolite ochratoxin-A.

Ochratoxin-A (OTA) is a fungal metabolite with potential toxic effects on the central nervous system that have not yet been fully characterized. OTA has complex mechanisms of action that include evocation of oxidative stress, bioenergetic compromise, inhibition of protein synthesis, production of DNA single-strand breaks and formation of OTA-DNA adducts. The time course of acute effects of OTA were investigated in the context of DNA damage, DNA repair and global oxidative stress across six brain regions. Oxidative DNA damage, as measured with the "comet assay", was significantly increased in the six brain regions at all time points up to 72 h, with peak effects noted at 24 h in midbrain (MB), CP (caudate/putamen) and HP (hippocampus). Oxidative DNA repair activity (oxyguanosine glycosylase or OGG1) was inhibited in all regions at 6 h, but recovered to control levels in cerebellum (CB) by 72 h, and showed a trend to recovery in other regions of brain. Other indices of oxidative stress were also elevated. Lipid peroxidation and superoxide dismutase (SOD) increased over time throughout the brain. In light of the known vulnerability of the nigro-striatal dopaminergic neurons to oxidative stress, levels of striatal dopamine (DA) and its metabolites were also measured. Administration of OTA (0-6 mg/kg i.p.) to mice resulted in a dose-dependent decrease in striatal DA content and turnover with an ED50 of 3.2 mg/kg. A single dose of 3.5 mg/kg decreased the intensity of tyrosine hydroxylase immunoreactivity (TH(+)) in fibers of striatum, TH(+) cells in substantia nigra (SN) and TH(+) cells of the locus ceruleus. TUNEL staining did not reveal apoptotic profiles in MB, CP or in other brain regions and did not alter DARPP32 immunoreactivity in striatum. In conclusion, OTA caused acute depletion of striatal DA on a background of globally increased oxidative stress and transient inhibition of oxidative DNA repair.

Rubratoxin B elicits antioxidative and DNA repair responses in mouse brain.

Rubratoxin B (RB) is a mycotoxin with potential neurotoxic effects that have not yet been characterized. Based on existing evidence that RB interferes with mitochondrial electron transport to produce oxidative stress in peripheral tissues, we hypothesized that RB would produce oxidative damage to macromolecules in specific brain regions. Parameters of oxidative DNA damage and repair, lipid peroxidation, and superoxide dismutase (SOD) activity were measured across six mouse brain regions 24 h after administration of a single dose of RB. Lipid peroxidation and oxidative DNA damage were either unchanged or decreased in all brain regions in RB-treated mice compared with vehicle-treated mice. Concomitant with these decreased indices of oxidative macromolecular damage, SOD activity was significantly increased in all brain regions. Oxyguanosine glycosylase activity (OGG1), a key enzyme in the repair of oxidized DNA, was significantly increased in three brain regions--cerebellum (CB), caudate/putamen (CP), and cortex (CX)--but not in the hippocampus (HP), midbrain (MB), and pons/medulla (PM). The RB-enhanced OGG1 catalytic activity in these brain regions was not due to increased OGG1 protein expression, but was a result of enhanced catalytic activity of the enzyme. In conclusion, specific brain regions responded to an acute dose of RB by significantly altering SOD and OGG1 activities to maintain the degree of oxidative DNA damage equal to, or less than, that of normal steady-state levels.

Protection of tea melanin on hydrazine-induced liver injury.

The protective activity of melanin derived from tea (MDFT) was studied using hydrazine as a DNA-reactive chemical agent. Intra-peritoneal administration of MDFT at the doses of 5 or 20 mg/kg dose-dependently prevented liver toxicity induced by hydrazine in rats. It normalized rises in serum alanine transferase activity and a decrease in the glutathione level in the liver. It also reduced the hepatic malondialdehyde concentration. Monitoring the intensity of chemiluminescence showed that MDFT could prevent the production of free radicals that are generated owing to metabolic transformation of hydrazine. It also prevented the formation 8-hydroxy-deoxyguanosine (8-OH-dG) DNA adducts. The results obtained in vivo and in vitro suggest that MDFT confers marked protection of the liver against hydrazine-induced oxidative toxicity.

Synthesis of 3-aryl-1-[(4-phenyl-1-piperazinyl)butyl]indazole derivatives and their affinity to 5-HT1A serotonin and dopamine D1 receptors.

Eight 3-arylindazole derivatives have been synthesized and their affinity to 5-HT1A serotonin and D1 dopamine receptors was investigated by radioligand analysis. Quantitative structure-activity relationships were studied using the Free-Wilson model. An increase in affinity to dopamine D1 receptors within substituents Br > Cl > CH3 at the 5-position of the 3-arylindazole molecule has been observed. Addition of a chlorine atom to the ortho-position the of phenyl ring let to even highest activity. Replacement of the hydrogen atom at the first position of the 3-arylindazole on the (phenylpiperazine)butyl substituent caused an increase of affinity and did not change the trends of affinity dependence on structure. An inverse dependence on the structure of the studied compounds was observed for the serotonin 5-HT1A receptors. Compounds containing a methyl group at the 5-position of molecule were more active than compounds containing halogens. A chlorine atom at the ortho-position of the phenyl ring decreased affinity. Replacement of the hydrogen atom at the first position of the molecule on the phenylpiperazine)butyl substituent led to an increase in affinity. Selectivity of the studied compounds varied within a wide range. Generally, the presence of the 3-aryl-indazole fragment in the new buspirone analogues increased their affinity to dopamine receptors and reduced their affinity to serotonin receptors. Compounds containing a bromine atom in the 3-arylindazole moiety may be promising ligands for D1 receptors.

Complex case of urethral duplication with megalourethra.

Urethral duplication and megalourethra are very rare anomalies and their concomitant presence is extremely rare, with only a few published cases. We present a complex case of complete urethral duplication with dorsal megalourethra that was severely stenotic in its bulbar part and meatus, with the ventral urethra atretic distally and dilated proximally. Both the corpus spongiosum and the cavernosum were missing. He had associated upper urinary tract abnormalities. Urethral patency was restored successfully by meatoplasty, staged buccal mucosa graft urethroplasty, and tailoring of the megalourethra. This report is unique regarding the use of a buccal mucosa graft for urethral reconstruction in patients with associated urethral duplication and megalourethra.

Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice.

Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased CNS. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow-derived cells and by its direct actions on CNS cells. The overall objective of the study was to determine if G-CSF administration in a mouse model of Alzheimer's disease (AD) (Tg APP/PS1) would impact hippocampal-dependent learning by modifying the underlying disease pathology. A course of s.c. administration of G-CSF for a period of less than three weeks significantly improved cognitive performance, decreased beta-amyloid deposition in hippocampus and entorhinal cortex and augmented total microglial activity. Additionally, G-CSF reduced systemic inflammation indicated by suppression of the production or activity of major pro-inflammatory cytokines in plasma. Improved cognition in AD mice was associated with increased synaptophysin immunostaining in hippocampal CA1 and CA3 regions and augmented neurogenesis, evidenced by increased numbers of calretinin-expressing cells in dentate gyrus. Given that G-CSF is already utilized clinically to safely stimulate hematopoietic stem cell production, these basic research findings will be readily translated into clinical trials to reverse or forestall the progression of dementia in AD. The primary objective of the present study was to determine whether a short course of G-CSF administration would have an impact on the pathological hallmark of AD, the age-dependent accumulation of A beta deposits, in a transgenic mouse model of AD (APP+ PS1; Tg). A second objective was to determine whether such treatment would impact cognitive performance in a hippocampal-dependent memory paradigm. To explain the G-CSF triggered amyloid reduction and associated reversal of cognitive impairment, several mechanisms of action were explored. (1) G-CSF was hypothesized to increase activation of resident microglia and to increase mobilization of marrow-derived microglia. The effect of G-CSF on microglial activation was examined by quantitative measurements of total microglial burden. To determine if G-CSF increased trafficking of marrow-derived microglia into brain, bone marrow-derived green fluorescent protein-expressing (GFP+) microglia were visualized in the brains of chimeric AD mice. (2) To assess the role of immune-modulation in mediating G-CSF effects, a panel of cytokines was measured in both plasma and brain. (3) To test the hypothesis that reduction of A beta deposits can affect synaptic area, quantitative measurement of synaptophysin immunoreactivity in hippocampal CA1 and CA3 sectors was undertaken. (4) To learn whether enhanced hippocampal neurogenesis was induced by G-CSF treatment, numbers of calretinin-expressing cells were determined in dentate gyrus.

Re: a new technique of vaginal reconstruction with the deep inferior epigastric perforator flap: a preliminary report.

Wang and colleagues described the use of fasciocutaneous flap based on deep inferior epigastric perforator (DIEP) vessels for vaginal reconstruction. They presented four patients with congenital vaginal agenesis and one with vaginal tumor. The rhombus-shaped abdominal flap was designed according to the location of deep inferior epigastric vessels perforators. The size of the flap ranged from 9 x 12 to 11 x 12 cm. The flap was elevated without underlying muscle, dissecting perforators together with the pedicle-deep inferior epigastric vessels up to their origin. The fully mobilized flap was tabularized, transposed paravesically to the previously prepared vaginal bed, and anastomosed to vaginal introitus. Primary donor-site closure was accomplished in all patients with conspicuous scars. All flaps survived and the authors reported a normal appearance of external genitalia with sufficient neovaginal depth and width. During the short follow-up (6-14 mo), two patients reported satisfactory sexual intercourse.