Influence of H-2 antigen expression on killer T cell specificity, differentiation, and induction.

Murine cytotoxic T lymphocytes (CTL) and helper cells are H-2 antigen restricted in their specificity: recognition of foreign antigen by these cells requires the concomitant recognition of self-H-2 molecules. Which H-2 antigens T cells treat as "self" is determined by the particular H-2 antigens expressed on radioresistant cells of the thymus in which these T cells mature. Using tetraparental [(P1 + P2) leads to F1] radiation chimeras with in situ F1 thymuses, we have found that the H-2 genotype of the stem cells does not influence their H-2 restriction specificity. This has allowed us to use tetraparental chimeras that have been thymectomized and grafted with parental (P1, P2, or both) thymus lobes to study the requirements for H-2-restricted T--T interactions during CTL ontogeny and induction. In animals that have received thymus grafts of both parental origins, CTL display no preference for maturation within a syngeneic thymus graft, a finding that is not compatible with a suggested requirement for intrathymic H-2-restricted T--T interactions in the maturation of precursor CTL. We have also grafted thymectomized tetraparental radiation chimeras with thymus grafts from only one parent to compare the induction of P1 and P2 CTL in environments in which peripheral (extrathymic) T cell interactions are restricted to one H-2 haplotype. Again, we find no evidence for preferential induction of CTL precursors syngeneic to the thymus graft, contrary to expectation if CTL induction requires that T helper cells restricted to thymic H-2 antigens interact directly with precursor CTL. In those animals with one parental thymus graft, there is variability in the ratios of P1 and P2 cells induced with several antigens, a finding that may be indicative of an H-2-restricted suppression mechanism operating in the periphery.     

Rapid prenatal diagnosis of beta thalassemia using DNA amplification and nonradioactive probes

We used in vitro DNA amplification by the polymerase chain reaction and nonradioactive probes for prenatal diagnosis of beta thalassemia in Chinese from the Guangdong province. Exact molecular diagnoses were made in all 20 fetuses studied over a 6-month period. We conclude that this method of prenatal diagnosis for beta thalassemia is a viable approach in many parts of the world where this disease is common.     

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

From data to decisions? Exploring how healthcare payers respond to the NHS Atlas of Variation in Healthcare in England

Purpose

Although information on variations in health service performance is now more widely available, relatively little is known about how healthcare payers use this information to improve resource allocation. We explore to what extent and how Primary Care Trusts (PCTs) in England have used the NHS Atlas of Variation in Healthcare, which has highlighted small area variation in rates of expenditure, activity and outcome.

Methods

Data collection involved an email survey among PCT Chief Executives and a telephone follow-up to reach non-respondents (total response: 53 of 151 of PCTs, 35%). 45 senior to mid-level staff were interviewed to probe themes emerging from the survey. The data were analysed using a matrix-based Framework approach.

Findings

Just under half of the respondents (25 of 53 PCTs) reported not using the Atlas, either because they had not been aware of it, lacked staff capacity to analyse it, or did not perceive it as applicable to local decision-making. Among the 28 users, the Atlas served as a prompt to understand variations and as a visual tool to facilitate communication with clinicians. Achieving clarity on which variations are unwarranted and agreeing on responsibilities for action appeared to be important factors in moving beyond initial information gathering towards decisions about resource allocation and behaviour change.

Conclusions

Many payers were unable to use information on small area variations in expenditure, activity and outcome. To change this what is additionally required are appropriate tools to understand causes of unexplained variation, in particular unwarranted variation, and enable remedial actions to be prioritised in terms of their contribution to population health.     

Challenges and opportunities of hydrothermal carbonisation in the UK; case study in Chirnside

The latest research and development in hydrothermal carbonisation (HTC) processes are reviewed and the feasibility of application to small towns in the UK is assessed. The HTC process designed in this report is theoretically evaluated for the biodegradable municipal waste and sewage waste produced by the small town of Chirnside, in the Scottish Borders. Calculation of mass and energy balances of the process are carried out alongside the evaluation of challenges and environmental, social and economic opportunities presented. The hypothetical HTC plant is capable of processing 267.14 t per year of food waste and 105.12 t per year of faecal sludge produced by Chirnsides estimated 2250 residents in 2041. The plant would be capable of producing 99.08 t per year of hydrochar with an estimated total energy content of 540.26 MWh per year. When used in a Biomass Combined Heat and Power Plant, the hydrochar would be capable of supplying Chirnsides residents with 0.71% and 3.43% of its domestic thermal energy demand and domestic electrical energy demand in 2041, respectively. Both the expected opportunities and challenges for the application of HTC are discussed, shedding light on the associated research in regards to this sustainable technology.

The latest research and development in hydrothermal carbonisation (HTC) processes are reviewed and the feasibility of application to small towns in the UK is assessed.     

Expression of protocadherin-γC4 protein in the rat brain

It has been proposed that the combinatorial expression of γ-protocadherins (Pcdh-γs) and other clustered protocadherins (Pcdhs) provides a code of molecular identity and individuality to neurons, which plays a major role in the establishment of specific synaptic connectivity and formation of neuronal circuits. Particular attention has been directed to the Pcdh-γ family, for which experimental evidence derived from Pcdh-γ-deficient mice shows that they are involved in dendrite self-avoidance, synapse development, dendritic arborization, spine maturation, and prevention of apoptosis of some neurons. Moreover, a triple-mutant mouse deficient in the three C-type members of the Pcdh-γ family (Pcdh-γC3, Pcdh-γC4, and Pcdh-γC5) shows a phenotype similar to the mouse deficient in whole Pcdh-γ family, indicating that the latter is largely due to the absence of C-type Pcdh-γs. The role of each individual C-type Pcdh-γ is not known. We have developed a specific antibody to Pcdh-γC4 to reveal the expression of this protein in the rat brain. The results show that although Pcdh-γC4 is expressed at higher levels in the embryo and earlier postnatal weeks, it is also expressed in the adult rat brain. Pcdh-γC4 is expressed in both neurons and astrocytes. In the adult brain, the regional distribution of Pcdh-γC4 immunoreactivity is similar to that of Pcdh-γC4 mRNA, being highest in the olfactory bulb, dentate gyrus, and cerebellum. Pcdh-γC4 forms puncta that are frequently apposed to glutamatergic and GABAergic synapses. They are also frequently associated with neuron-astrocyte contacts. The results provide new insights into the cell recognition function of Pcdh-γC4 in neurons and astrocytes.     

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography–tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11–13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m² with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m² (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.     

牙列缺损的计算机三维建模

目的 建立牙列缺损的计算机三维模型。方法 采用表面绘制法,依据CT扫描头颅骨标本获得的二维断层图像数据在3D Studio Max中沿牙体长轴放样、微调并赋以材质,得到牙列缺损的计算机三维模型。结果 能在计算机中方便快速地模拟任意类型的牙列缺损,并可全方位地旋转、放大和缩小。结论 提供了一种牙列缺损三维建模的新方法,有利于三维义齿专家系统的开发和计算机辅助教学。     

Requirements for bone marrow-derived antigen-presenting cells in priming cytotoxic T cell responses to intracellular pathogens

Bone marrow (BM)-derived antigen-presenting cells (APCs) are potent stimulators of T cell immune responses. We investigated the requirements for antigen presentation by these cells in priming cytotoxic T lymphocyte (CTL) responses to intracellular bacterial and viral pathogens. [Parent-->F(1)] radiation BM chimeras were constructed using C57BL/6 donors and (C57BL/6 x BALB/c)F(1) recipients. Infection of chimeric mice with either Listeria monocytogenes or vaccinia virus expressing the nucleoprotein (NP) antigen from lymphocytic choriomeningitis virus (LCMV) primed H2-D(b)-restricted, but not H2-K(d)-restricted CTL responses, demonstrating the requirement for BM-derived APCs for successful priming of CTL responses to these pathogens. Surprisingly, this did not hold true for chimeric mice infected with LCMV itself. LCMV-infected animals developed strong CTL responses specific for both H2-D(b)- and H2-L(d)-restricted NP epitopes. These findings indicate that in vivo priming of CTL responses to LCMV is remarkably insensitive to deficiencies in antigen presentation by professional BM-derived APCs.