Differential role of N‐methyl‐D‐aspartate receptor‐mediated glutamate transmission in the nucleus accumbens shell and core in nicotine seeking in rats

Nicotine, a major psychoactive component of tobacco smoke, increases glutamate transmission in the nucleus accumbens (NAcc). However, the role of the N‐methyl‐D‐aspartate (NMDA)‐mediated glutamatergic neurotransmission in the NAcc shell and core subdivisions in nicotine‐dependent behaviors has not been studied. The present study evaluated, in rats, the effects of bilateral administration of the competitive NMDA receptor antagonist LY235959 (0, 0.1, 1, and 10 ng/0.5 μL/side) into the NAcc shell or core on intravenous nicotine (fixed‐ and progressive‐ratio schedules) and food (fixed‐ratio schedule) self‐administration, and cue‐induced reinstatement of nicotine‐seeking behavior. In addition, the effects of LY235959 injections in the NAcc shell were evaluated on nicotine‐induced conditioned taste aversion, a procedure that assesses the aversive effects of nicotine. LY235959 injections into the NAcc shell significantly increased nicotine self‐administration under both fixed‐ and progressive‐ratio schedules, and decreased food self‐administration, but had no effect on nicotine‐induced conditioned taste aversion or cue‐induced nicotine seeking. Furthermore, injections of LY235959 in the lateral septal nucleus, originally intended as an anatomical control site for the NAcc shell, increased nicotine self‐administration and decreased food self‐administration under the fixed‐ratio schedule. In contrast, LY235959 injections into the NAcc core increased the cue‐induced reinstatement of nicotine seeking and decreased food self‐administration, but had no effect on nicotine self‐administration. The present data suggest that NMDA receptor‐mediated glutamatergic neurotransmission in the NAcc shell and core differentially regulates food‐ and nicotine‐maintained responding. Importantly, the data suggest an inhibitory role for NMDA‐mediated glutamatergic neurotransmission in the NAcc shell and core in nicotine self‐administration and the cue‐induced reinstatement of nicotine seeking, respectively.     

Electro-Mechanical Finger Prosthesis: A Novel Approach for Rehabilitation of Finger Amputees

Prosthesis refers to artificial replacement of an absent part of the human body. These prostheses help in psychological support of the patients and enhance their social acceptance. Complete or partial finger amputations are some of most frequently encountered forms of partial hand loss. Micro vascular reconstruction is the first choice of rehabilitation but when it is contraindicated, unavailable, unsuccessful or unaffordable, the prosthetic rehabilitation is an alternative for improving the psychological status of an individual. Most of these artificial prostheses make use of silicone. The present paper tries to combine aesthetics with function. The authors have created functionally active finger prosthesis with the help of electromechanical controls. The prosthesis is battery-powered, light-weight, and allows the user to regain complete control of flexion and extension movements of an artificial finger.

     

Panel 2.10: reproductive, mental, and child health

This is a summary of the presentations and discussion of Panel 2.10, Reproductive, Mental, and Child Health of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related to reproductive, mental, and child health as pertain to the responses to the damage created by the Tsunami. It is presented in the following major sections: (1) background; (2) key issues; (3) discussion; and (4) recommendations. Key issues discussed included: (1) coordination/collaboration; (2) provision of services; and (3) raising awareness and advocacy.     

Argininosuccinate Synthetase-1 (ASS1) Loss in High-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20

High-grade neuroendocrine carcinomas (HGNECs) of the urinary bladder encompass small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). Currently, recommended initial management is with systemic chemotherapy, followed by consolidative therapy with either radical cystectomy or radiotherapy in patients with localized disease. Nevertheless, survival in this setting remains poor. We therefore evaluated the potential to modify arginine metabolism as an alternative, targeted therapy approach in these carcinomas. In humans, arginine is a semi-essential amino acid and its synthesis enzyme argininosuccinate synthetase (ASS1) represents the rate-limiting step in arginine biosynthesis. Neoplasms that show low to absent ASS1 expression require extracellular arginine for cancer cell survival, and thus can be targeted using arginine-degrading enzymes such as pegylated arginine deiminase (ADI-PEG 20). An initial study by our group of 19 patients demonstrated that a high percentage of SCNEC lack ASS1 expression. Herein, we evaluated an expanded cohort of 74 radical cystectomy patients with HGNEC, including 63 SCNEC, 5 LCNEC, and 6 mixed morphology HGNEC patients. ASS1 expression was assessed through immunohistochemistry. Fifty-eight (of 74, 78%) patients with HGNEC showed absent ASS1 expression, including all patients with LCNEC and mixed morphology (11 of 11, 100%). Ten-year survival from disease-specific death was not statistically significant between ASS1-expressing and ASS1-deficient cases (p?=?0.75). Our results show that HGNEC of the bladder may be candidates for arginine deprivation therapy using drugs such as ADI-PEG 20. Further studies are needed to validate these findings and to determine the therapeutic efficacy of such agents.     

Role of granulosa cell mitogen-activated protein kinase 3/1 in gonadotropin-mediated meiotic resumption from diplotene arrest of mammalian oocytes

In mammals, preovulatory oocytes are encircled by several layers of granulosa cells (GCs) in follicular microenvironment. These follicular oocytes are arrested at diplotene arrest due to high level of cyclic nucleotides from encircling GCs. Pituitary gonadotropin acts at the level of encircling GCs and increases adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) and activates mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathway. The MAPK3/1 disrupts the gap junctions between encircling GCs and oocyte. The disruption of gap junctions interrupts the transfer of cyclic nucleotides to the oocyte that results a drop in intraoocyte cAMP level. A transient decrease in oocyte cAMP level triggers maturation promoting factor (MPF) destabilization. The destabilized MPF finally triggers meiotic resumption from diplotene arrest in follicular oocyte. Thus, MAPK3/1 from GCs origin plays important role in gonadotropin-mediated meiotic resumption from diplotene arrest in follicular oocyte of mammals.     

CD47 regulates the phagocytic clearance and replication of the Plasmodium yoelii malaria parasite

Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFP-expressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47^hi)-expressing young RBC. Importantly, C57BL/6 CD47^−/− mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47^−/− mice was associated with a higher percentage of splenic F4/80⁺ cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing antibody caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47^hi young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC.Malaria, caused by Plasmodium parasites, remains a major cause of mortality and morbidity in the developing world. Among the four principal human Plasmodium species, Plasmodium falciparum is the most virulent, being responsible for more than 90% of malaria-associated deaths. Likewise, Plasmodium species that infect rodents and nonhuman primates also differ widely in their fulminant nature and in the mortality they cause (1–3). How different Plasmodium species have evolved to exhibit this wide array of virulence and disease severity remains one of the major unsolved questions in malaria biology and pathogenesis.One important factor that is associated with Plasmodium parasite burden and disease severity is the age constraint of the host red blood cells (RBC) they infect. The age-based preference for restricted invasion of RBC by the Plasmodium parasite is characterized as young RBC (reticulocyte), aged RBC (mature), or both young and aged RBC. Plasmodium species that preferentially infect and grow inside young RBC generally cause a low-grade, self-resolving infection that is rarely fatal (e.g., Plasmodium vivax and Plasmodium ovale), whereas those that infect both young and aged RBC cause more fulminant infection that can be fatal in the absence of immunity (e.g., P. falciparum) (1, 4–6). Thus, along with host genetic background and immune response, restriction for age-specific RBC invasion is a major determinant of the severity and outcome of malaria infection.Malaria parasites have evolved to use redundant receptors and pathways to invade the RBC. For example, sialic acid (7) and Duffy antigen (8) are the major RBC receptors for invasion of P. falciparum and P. vivax, respectively, although other receptors and invasion pathways are known to exist (9, 10). Although a redundancy in RBC receptor use would ensure successful invasion by mitigating the effects of polymorphism and immune targeting, the reasons behind the RBC age-based preference for invasion are not fully clear and remain a subject of debate.Survival of normal cells through the course of their life cycle is essential to maintain homeostasis, and aberrant cells (e.g., senescent or foreign antigen-expressing cells) are eliminated through a sophisticated programmed cell removal system that relies on the recognition of self and nonself determinants (11). CD47, a cell surface molecule in the Ig superfamily, is ubiquitously expressed on many cell types, including RBC, and is a marker of self to avoid early clearance by phagocytic cells through ligation of signal regulatory protein alpha (12). In contrast, altered expression or conformational changes in CD47 may lead to a molecular switch that triggers a phagocytic signal to remove aged or damaged cells (11). Recent studies have shown that the level of CD47 expression is higher in progenitor cells and declines as they undergo maturation and are subsequently aged (13). This age-dependent difference in CD47 expression shields young cells but allows clearance of aging and damaged cells from the system.CD47 is overexpressed in cancer cells (11, 14, 15), and the CD47–signal regulatory protein alpha interaction is considered a major pathway of immune evasion by tumor cells (15). Administration of anti-CD47 antibodies enabled the phagocytosis of tumor cells in vitro, reduced their growth, and prevented the metastasis of human patient tumor cells (14). In this article, using the murine Plasmodium yoelii nonlethal model, we provide quantitative evidence for age of RBC as the basis for the survival and growth of malaria parasites and provide supporting data that suggest that P. yoelii nonlethal parasites prefer to grow inside younger RBC, which allows them to evade immune clearance by phagocytic cells through a CD47-mediated process, and that CD47 modulates the clearance of malaria infection. To our knowledge, this is the first report that provides a molecular basis for the age-dependent preference for infection of RBC by a Plasmodium parasite and sheds light on its implications for the severity of malaria infection in a host.     

Improving postoperative pain management in subpectoral tissue expander implant reconstruction of the breast using an elastomeric pump

IntroductionPostoperative pain after breast surgery is one of the major factors contributing to delay in mobilisation and prolonged hospital stay. A retrospective analysis was performed of patients undergoing skin sparing mastectomy and insertion of a subpectoral implant. The aim was to determine whether the use of an elastomeric local anaesthetic pump improved pain control and length of stay.MethodsTwenty-five consecutive patients undergoing the above procedure were sited with an elastomeric local anaesthetic infusion pump intraoperatively, in addition to standard regular and pro re nata analgesia. The control group comprised 25 patients undergoing the same procedure in the same year who received standard analgesia alone. Visual analogue scale scores were recorded for the duration of inpatient stay, as was any further analgesic requirement.ResultsThe median age was 51 years (range: 26–75 years) in the intervention group and 50 years (range: 28–70 years) in the control group. The mean visual analogue scale score was 0.28 (standard deviation [SD]: 0.61) at 24 hours for the intervention group and 1.84 (SD: 0.37) for the control group (p<0.0001). The mean length of stay was 1.8 days (SD: 0.71 days) for the intervention group and 2.28 days (SD: 0.94 days) for the control group (p=0.15). There were no complications involving catheter placement, leakage or toxicity relating to use of the local anaesthetic.ConclusionsThere was significantly reduced pain with the use of the local anaesthetic infusion pump. The elastomeric pump is a step towards enhanced patient recovery after breast surgery in the case of skin sparing mastectomy and subpectoral tissue expander reconstruction.