Some aspects of the genetics and etiology of spontaneous diabetes mellitus

Summary Human DM consists of a heterogeneous group of metabolic disorders which have as a common denominator diminished carbohydrate tolerance. Genetic factors are probably important in the etiology of almost all cases of DM, excluding perhaps only those produced by pancreatectomy. However, the precise mechanisms of expression of the genetic defects related to DM have been elucidated only in a few cases whereas the majority, especially those of MOD, should probably be considered multifactorial in origin (complex interplay between polygenic and environmental factors). Several less frequent forms of DM can be inherited in a typical Mendelian way, either alone (e.g. probably MODY) or associated with certain well defined genetic diseases (where carbohydrate intolerance is a frequent component of the clinical picture). JOD should most probably be attributed to the action of some as yet unidentified environmental factors, perhaps viruses, in subjects with a particular genetic predisposition. This predisposition seems to be closely associated with certain HLA antigens, particularly those of the D series. The mechanisms responsible for this association remain a matter of controversy. Autoimmune phenomena appear to be important in the pathogenesis of JOD. The ability of certain viruses to induce DM has been clearly demonstrated in a few experimental systems by infecting genetically susceptible animals. Under such conditions, DM is produced by a destruction of the pancreatic islets. On the other hand, there is as yet no conclusive evidence concerning the possibility that exogenous and/or endogenous viruses may play a role in the etiology of human DM. Patients with certain chromosome abnormalities are prone to develop DM. On the other hand, there are no available data concerning a possible effect of DM on the incidence of chromosome abnormalities in patients with the disease or in the embryos and fetuses of diabetic mothers. The possibility of congenital transmission of a predisposition to DM (which might possibly be inherited thereafter) through the action of some unknown epigenetic mechanisms has been suggested on the basis of limited clinical and experimental observations. However, further information is necessary in order to clarify the validity of such a curious possibility.     

In vitro antibody-mediated macrophage activity on Breinlia macropi microfilariae. II. Ultrastructural and video recording investigations of adherence and cytotoxicity

Video recordings and ultrastructural studies have revealed an intricate sequence of antibody-mediated cytotoxic activity by quokka peritoneal macrophages on Breinlia macropi microfilariae. The microfilaricidal activity was effected by at least two types of macrophages measuring 17 micrometers and 8 micrometers in diameter respectively. The relatively large macrophages were responsible for trapping, encircling and eventually degrading the highly motile microfilariae in a sequence of events in which the participating macrophages may interdigitate. The smaller macrophages adhered transiently to a number of adjacent sites on the surface of a trapped microfilaria, resulting in a series of damaged spots. This activity of the small macrophages was interpreted as responsible for killing the microfilaria. Thus the microfilaricidal activity was interpreted to be accomplished by the co-operative functions of the relatively large and small macrophages.     

Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release

The time at which the N-ethylmaleimide-sensitive factor (NSF) acts during synaptic vesicle (SV) trafficking was identified by time-controlled perturbation of NSF function with a photoactivatable inhibitory peptide. Photolysis of this caged peptide in the squid giant presynaptic terminal caused an abrupt (0.2 s) slowing of the kinetics of the postsynaptic current (PSC) and a more gradual (2-3 s) reduction in PSC amplitude. Based on the rapid rate of these inhibitory effects relative to the speed of SV recycling, we conclude that NSF functions in reactions that immediately precede neurotransmitter release. Our results indicate the locus of SNARE protein recycling in presynaptic terminals and reveal NSF as a potential target for rapid regulation of transmitter release.     

Brush cells in the human fetal trachea

We performed a morphologic examination of human fetal lung tissue, using scanning and transmission electron microscopy, in order to establish the presence of brush cells in extrapulmonary and intrapulmonary airways, and developing acinar epithelium. Brush cells, characterized by a border of regular straight microvilli containing a filamentous core, were observed within the tracheal epithelium of a 19-20 week gestational age fetus. These cells constituted 0.5% of the total epithelial cell population. Brush cells were not seen within the bronchial, bronchiolar or developing acinar epithelium. Our study shows that brush cells occur infrequently but normally in the developing tracheal epithelium of the second trimester fetus.     

Anti-gamete antibodies block transmission of human vivax malaria to mosquitoes

Antibodies were raised in rabbits by immunizing against fresh unfixed or cryopreserved female gametes of the human malaria pathogen Plasmodium vivax. The antibodies were shown to react with the surface of gametes by the indirect immunofluorescent test. When parasite isolates from P. vivax infected individuals were fed through a membrane to Anopheles tessellatus mosquitoes in the presence of immune rabbit sera, they completely blocked the infectivity of the parasite isolates to the vector. Immunoglobulins separated from these sera also blocked infectivity to the same extent as did the immune sera indicating that antibodies were responsible for the transmission blocking effect of the sera. This study indicated that P. vivax like other malaria parasites is highly susceptible to anti gamete transmission blocking immunity.     

Stage-specific effects of host plasma factors on the early sporogony of autologous Plasmodium falciparum isolates within Anopheles gambiae

Summary Quantitatively assessing the impact of naturally occurring transmission-blocking (TB) immunity on malaria parasite sporogonic development may provide a useful interpretation of the underlying mechanisms. Here, we compare the effects of plasma derived from 23 naturally infected gametocyte carriers (OWN) with plasma from donors without previous malaria exposure (AB) on the early sporogonic development of Plasmodium falciparum in Anopheles gambiae. Reduced parasite development efficiency was associated with mosquitoes taking a blood meal mixed with the gametocyte carriers' own plasma, whereas replacing autologous plasma with non-immune resulted in the highest level of parasite survival. Seven days after an infective blood meal, 39.1% of the gametocyte carriers' plasma tested showed TB activity as only a few macrogametocytes ingested along with immune plasma ended up as ookinetes but subsequent development was blocked in the presence of immune plasma. In other experiments (60.9%), the effective number of parasites declined dramatically from one developmental stage to the next, and resulted in an infection rate that was two-fold lower in OWN than in AB infection group. These findings are in agreement with those in other reports and go further by quantitatively examining at which transition stages TB immunity exerts its action. The transitions from macrogametocytes to gamete/zygote and from gamete/zygote to ookinete were identified as main targets. However, the net contribution of host plasma factors to these interstage parasite reductions was low (5-20%), suggesting that irrespective of the host plasma factors, mosquito factors might also lower the survival level of parasites during the early sporogonic development.     

The impact of six rounds of single-dose mass administration of diethylcarbamazine or ivermectin on the transmission of Wuchereria bancrofti by Culex quinquefasciatus and its implications for lymphatic filariasis elimination programmes

Lymphatic filariasis (LF) is targeted for global elimination. Transmission interruption through repeated annual single-dose mass administration of anti-filarial drugs is the mainstay of the LF elimination strategy. This study examined the ability of six rounds of mass administration of diethylcarbamazine (DEC) or ivermectin (IVM) to interrupt transmission of Wuchereria bancrofti by Culex quinquefasciatus, the predominant parasite and vector species, respectively. After six rounds of mass drug administration (MDA), received by 54-75% of the eligible population (> or =15 kg body weight), the resting vector infection and infectivity rates fell by 83% and 79% in the DEC arm, 85% and 84% in the IVM arm and 31% and 45% in the placebo arm, respectively. The landing vector infection and infectivity rates fell by 83% and 94% in the DEC arm, 63% and 75% in the IVM arm and 1% each in the placebo arm, respectively. The filarial larval load per resting mosquito declined by 92% and 93% and per landing mosquito by 83% and 69% in the DEC and IVM arms, respectively. The annual infective biting rate (AIBR) fell from 735 to 93 (87%) in the DEC arm, 422 to 102 (76%) in the IVM arm and 472 to 398 (16%) in the placebo arm. The annual transmission potential (ATP) declined from 2514 to 125 (95%), 1212 to 241 (80%) and 1547 to 1402 (9%) in the DEC, IVM and placebo arms, respectively. However, mosquitoes with infection [microfilaria/larva 1/larva 2 (Mf/L1/L2)] were found in all study villages. Three of five villages in the IVM arm and two of five in the DEC arm recorded no resting mosquitoes with infective-stage (L3) larva. Although the ATP, after six rounds of MDA, fell substantially and remained at 125 and 241 in the DEC and IVM arms, respectively, the cumulative exposure to infective stage larvae (ATP) during the treatment period of 6 years was as high as 2995 in the DEC arm and 1522 in the IVM arm, because of considerable level of transmission during the initial (1-3) rounds of MDA. We conclude that (i) six rounds of MDA, even with 54-75% treatment coverage, can reduce LF transmission very appreciably; (ii) better treatment coverage and a few more rounds of MDA may achieve total interruption of transmission; (iii) high vector densities may partly nullify the reductions achieved in vector infection and infectivity rates by MDA and (iv) achievement of 'true zero' Mf prevalence in communities and 0% infection rate (mosquitoes with Mf/L1/L2) in mosquitoes may be necessary to totally interrupt Culex-transmitted LF.     

输入性恶性疟在中华按蚊媒介地区传播接受性探讨

永康市１９８５～１９９４年１０年间共发生输入性恶性疟１３４例，据感染和发病特征分析，病例均属外地感染的输入性恶性疟，１０年来未出现当地感染病例。由于病例治疗条件较差，复燃率高，带虫时间长，客观上对当地起到传染源作用。但由于当地是单纯中华按蚊媒介地区，因此未出现传播。结果表明，在北纬２５°以北大部分地区，出现恶性疟流行主要与嗜人按蚊有关，单纯中华按蚊地区即使有一定数量的恶性疟传染源输入，但传播和流行可能性不大。但在监测措施上仍应值得重视。     

Phylogenetic evidence, by multiple clone analysis of hypervariable region 1, for the transmission of hepatitis C virus to chronic haemodialysis patients

We analysed hepatitis C virus (HCV) sequences to determine whether nosocomial transmission of HCV occurred in a haemodialysis unit. Twenty patients positive for serum HCV RNA were investigated. All were undergoing haemodialysis therapy in the same room. The hypervariable region 1 (HVR1) sequence of HCV was amplified and multiple clones sequenced. Phylogenetic analysis of these sequences revealed five genetic clusters consisting of HCV isolates from 11 of the 20 patients. In addition to two genetic clusters of HCV isolates from the four currently seroconverting patients and another patient who had been persistently infected, we identified three other phylogenetic relationships in HCV isolates from six patients. The patients grouped into the same cluster received haemodialysis individually on the same shift and/or side-by-side. Phylogenetic analysis of HCV HVR1 sequences corroborated the patient-to-patient HCV transmission suggested by an epidemiological study and that unrecognized transmission of HCV occurs in the dialysis room. Our multiple clone analysis of HCV isolates provides detailed information on nosocomial transmission of HCV. Transmission occurs more frequently when treatment is performed at the same time than in consoles located close to each other.     

用量子波的频率改变人的内分泌和外分泌及神经系统

此报告是量子波的频率作用于人体的实验结果分析。以心跳的可控为例分析求证是量子波的作用。量子波的频率透射人体势垒,其能量能够引起量子跃迁事件的发生,使得组成人的原子、分子的电子结构发生变化,人体内的酶、糖、蛋白质、脂肪等生物大分子相应发生变化,从内分泌到外分泌再到神经系统等可以向事先计划的方面变化。通过改变势垒而改变波的频率并且利用这个频率提供的能引导改变人是很现实的事。