Molecular characterization of human factor XSan Antonio

Enzymatic amplification technique was used to isolate all eight exons and sequences around the splice junctions, putative promoter, and polyadenylation sites of human factor X DNA from a patient with factor X deficiency. Two genetic changes in factor X have been observed in this patient. The patient is most likely a compound heterozygote since there is only 14% activity associated with factor X. A point mutation that resulted in the substitution of cysteine (TGC) for arginine (CGC) at amino acid 366 was found in exon VIII of one allele of the factor X gene. This mutation, which occurs in the catalytic domain, can affect the formation of a disulfide bridge and thus could result in a reduction in factor X activity. Sequencing all the regions revealed a second mutation: a deletion of one nucleotide (TCCT to TCT) in exon VII that would cause a frame shift at amino acid 272 followed by termination. We have also shown that the point mutation in exon VIII creates an ApaL1 restriction site and destroys the HinP1 site. Enzymatic DNA amplification followed by restriction digestion provides a quick, reliable, and sensitive method for carrier detection and antenatal diagnosis in affected kindreds. This is the first characterization of factor X deficiency at the molecular level. We propose to name this mutation Factor XSan Antonio.     

Sexual and developmental differences in peptides regulating growth hormone secretion in the rat

Sex differences in the hypothalamic control of growth hormone (GH) secretion were investigated by measuring rat GH-releasing factor (rGRF) and somatostatin in male and female rats. Rat GRF-like immunoreactivity (rGRF-IR) was higher in the median eminence and hypothalamic tissue outside of the median eminence of adult (90-day-old) male compared to female rats. A similar pattern of rGRF-IR content was found in the median eminence of 35-day-old rats. This sex difference developed between days 25 and 35 of age, during which time serum concentrations of insulin-like growth factor (IGF-1) and body weight increased in both sexes. To a lesser extent, the content of somatostatin-like immunoreactivity (SLI) was higher in the median eminence of adult female rats compared to male rats. Whole hypothalamic rGRF-IR and SLI contents were influenced only moderately by adult gonadectomy or gonadal steroid treatments. For example, estrogen increased rGRF-IR content in castrated rats, but orchidectomy alone or orchidectomy followed by testosterone did not influence rGRF-IR content. Additionally, whole hypothalamic SLI content was unaffected by orchidectomy or orchidectomy followed by testosterone or estrogen. One month after ovariectomy, rGRF-IR and SLI in whole hypothalamic fragments were similar to their respective contents in gonad-intact males. However, ovariectomy followed by estrogen or testosterone did not restore rGRF-IR content and partially restored SLI content to levels seen in gonad-intact females.     

Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients

Virally inactivated, high-purity factor XI concentrates are available for treatment of patients with factor XI deficiency. However, preliminary experience indicates that some preparations may be thrombogenic. We evaluated whether a highly purified concentrate produced signs of activation of the coagulation cascade in two patients with severe factor XI deficiency infused before and after surgery. Signs of heightened enzymatic activity of the common pathway of coagulation (elevated plasma levels of prothrombin fragment 1 + 2 and fibrinopeptide A) developed in the early post-infusion period, accompanied by more delayed signs of fibrin formation with secondary hyperfibrinolysis (elevated D-dimer and plasmin-antiplasmin complex). These changes occurred in both patients, but were more severe in the older patient with breast cancer when she underwent surgery, being accompanied by fibrinogen and platelet consumption. There were no concomitant signs of heightened activity of the factor VII-tissue factor mechanism on the factor Xase complex (plasma levels of activated factor VII and of factor IX and X activation peptides did not increase). The observed changes in biochemical markers of coagulation activation indicate that concentrate infusions increased thrombin generation and activity and that such changes were magnified by malignancy and surgery. Because some factor XI concentrates may be thrombogenic, they should be used with caution, especially in patients with other risk factors for thrombosis.     

Intra-amygdala infusion of the NPY Y1 receptor antagonist BIBP 3226 attenuates operant ethanol self-administration

BACKGROUND: Neuropeptide Y (NPY) is the most abundant and widely distributed peptide in the mammalian central nervous system. Evidence suggests that NPY transmission at Y1 receptors may regulate alcohol self-administration in rodent models. The purpose of the present study was to test the involvement of NPY Y1 receptors in the amygdala in the reinforcing effects of alcohol. METHODS: Long-Evans rats were trained to self-administer ethanol (10% v/v) vs. water on a concurrent FR-1 schedule of reinforcement using a sucrose fading procedure. After a 1 month baseline period, bilateral injector cannulae were surgically implanted to terminate 1 mm dorsal to the central nucleus of the amygdala. Daily (Monday through Friday) operant self-administration sessions were conducted for 6 months after surgery. Then, the effects of intra-amygdala infusion of the high-affinity nonpeptide NPY Y1 receptor antagonist BIBP 3226 (1, 10, or 20 microMg) were determined on parameters of operant alcohol self-administration. RESULTS: Intra-amygdala administration of 10 microM or 20 microM BIBP 3226 decreased total alcohol-reinforced responding and dose of self-administered ethanol (g/kg) without significantly altering total water responses or intake compared with vehicle control. Response onset was unaffected. Analysis of the temporal pattern of ethanol- and water-reinforced responding showed that BIBP 3226 decreased cumulative ethanol-reinforced responding during the 30 to 60 min period of the sessions. Water-reinforced responses were increased by the low dose of BIBP 3226 (1 microM) during the 50 to 60 min period. CONCLUSIONS: Results from this study indicate that alcohol-reinforced responding is reduced by acute blockade of NPY Y1 receptors in the amygdala of rats with a long-term history of alcohol self-administration. These data are consistent with the hypothesis that alcohol self-administration is maintained by NPY neurotransmission at Y1 receptors in the central nucleus of the amygdala.     

The impact of diabetes mellitus on survival after myocardial infarction: can it be modified by drug treatment?

Aims/hypothesis. Mortality of diabetic patients after myocardial infarction remains high despite recent improvement in their management. This study population-based evaluates the impact of cardiovascular drug therapy on mortality within 28 days and during 5-year follow-up in diabetic compared with non-diabetic patients.¶Methods. Using the MONICA Augsburg register from 1985 to 1992, 2210 inpatients with incident Q-wave myocardial infarction aged 25–74 years were included, of whom 468 had diabetes. Primary end point was mortality within 28 days and over 5 years. General linear model procedures were used for age-adjustment, controlling for sex, and testing significance; hazard risk ratios were calculated using multivariable Cox proportional hazards model procedures.¶Results. During the 5-year follow-up, 598 subjects died (396 diabetic, 202 non-diabetic). The mortality rate within 28 days was 12.6 % in diabetic patients (women 18.0 %, men 9.9 %) and 7.3 % in non-diabetic patients (p = 0.001). Mortality in diabetic patients over 5 years was increased by 64 % (95 % confidence interval 1.39–1.95) compared with non-diabetic patients. This was considerably reduced (p < 0.001) in patients treated with thrombolytic drugs (risk ratio: diabetes 0.57, no diabetes 0.65) and with beta blockers (0.62 and 0.64) and antiplatelets (0.76 and 0.74) at hospital discharge. Mortality of diabetic patients treated with these drugs was reduced to that of non-diabetic patients without such treatment (risk ratio 1.01 to 1.27; p > 0.1).¶Conclusion/interpretation. Diabetic patients after myocardial infarction are at particularly high risk of dying, but benefit clearly from treatment with thrombolytics, beta blockers and antiplatelets. This study does not, however, allow any inferences to be drawn for treatment with angiotensin converting enzyme inhibitors or the impact of left ventricular function. [Diabetologia (2000) 43: 218–226]     

Facilitating culture-centered communication between health care providers and veterans transitioning from military deployment to civilian life

Objective

To describe returning veterans’ transition experience from military to civilian life and to educate health care providers about culture-centered communication that promotes readjustment to civilian life.

Methods

Qualitative, in-depth, semi-structured interviews with 17 male and 14 female Iraq and Afghanistan veterans were audio recorded, transcribed verbatim, and analyzed using Grounded Practical Theory.

Results

Veterans described disorientation when returning to civilian life after deployment. Veterans’ experiences resulted from an underlying tension between military and civilian identities consistent with reverse culture shock. Participants described challenges and strategies for managing readjustment stress across three domains: intrapersonal, professional/educational, and interpersonal.

Conclusions

To provide patient-centered care to returning Iraq and Afghanistan veterans, health care providers must be attuned to medical, psychological, and social challenges of the readjustment experience, including reverse culture shock. Culture-centered communication may help veterans integrate positive aspects of military and civilian identities, which may promote full reintegration into civilian life.

Practice implications

Health care providers may promote culture-centered interactions by asking veterans to reflect about their readjustment experiences. By actively eliciting challenges and helping veterans’ to identify possible solutions, health care providers may help veterans integrate military and civilian identities through an increased therapeutic alliance and social support throughout the readjustment process.     

Time since last vaccine dose in PCR-positive and PCR-negative children with suspected pertussis to monitor pertussis vaccine effectiveness

We evaluated whether the results of diagnostic polymerase chain reaction (PCR) testing combined with time since last vaccine dose could be used to monitor the effectiveness of acellular pertussis vaccines. In 258 consecutive nasopharyngeal swabs from children and adolescents with typical pertussis symptoms, 80 were positive and 178 were negative in PCR for Bordetella pertussis DNA (IS 481). Time since last vaccine dose was available for 152 patients, of which 120 were fully immunised. Among the fully vaccinated patients, the median age of 41 PCR-positive patients was 8.4 years (range 0.9–12.3) and that of 79 PCR-negative cases was 3.3 years (range 0.4–14.1) (p?<?0.01). The median time since last pertussis vaccine dose was 6.05 years [95 % confidence interval (CI): 0.5–10.9] in PCR-positive cases and 2.22 years (95 % CI: 0.04–9.23) in PCR-negative cases (p?<?0.001). The use of diagnostic PCR results from pertussis cases together with time since last vaccine dose permits estimates of the duration of protection after vaccination with acellular pertussis vaccines that are in keeping with more complex studies.     

The Role of Sex Differences in Autophagy in the Heart During Coxsackievirus B3-Induced Myocarditis

Under normal conditions, autophagy maintains cardiomyocyte health and integrity through turnover of organelles. During stress, oxygen and nutrient deprivation, or microbial infection, autophagy prolongs cardiomyocyte survival. Sex differences in induction of cell death may to some extent explain the disparity between the sexes in many human diseases. However, sex differences in gene expression, which regulate cell death and autophagy, were so far not taken in consideration to explain the sex bias of viral myocarditis. Coxsackievirus B3 (CVB3)-induced myocarditis is a sex-biased disease, with females being substantially less susceptible than males and sex hormones largely determine this bias. CVB3 was shown to induce and subvert the autophagosome for its optimal viral RNA replication. Gene expression analysis on mouse and human, healthy and CVB3-infected, cardiac samples of both sexes, suggests sex differences in autophagy-related gene expression. This review discusses the aspects of sex bias in autophagy induction in cardiomyocytes.     

燕滨扶正胶囊治疗代偿期及失代偿期肝硬化临床疗效观察研究

目的 研究中药燕滨扶正胶囊治疗肝硬化（代偿期或失代偿期）临床疗效。方法 选择代偿期及失代偿期肝硬化患者41例,随机分为治疗组（21例）及对照组（20例）。治疗组给予燕滨扶正胶囊1500 mg/次,口服,2次/日。对照组给予扶正化瘀胶囊2500 mg/次,3次/日。两组疗程均为48周。两组依据病情给予抗病毒,护肝降酶、对症支持等一般治疗（替比夫定、甘利欣、消炎利胆片、茵栀黄胶囊等）,观察两组患者症状、血常规、肝功能、门静脉宽度、腹水、肝脏及脾脏形态。结果 中药燕滨扶正胶囊联合抗病毒药物可使代偿期及失代偿期肝硬化患者门静脉宽度、脾肿大回缩或复常,可使纤维化指标复常或大幅下降且肝脏功能好转或复常。结论 燕滨扶正胶囊可改善肝硬化。