基于“同气相求”理论的激痛点疗法治疗顽固性偏头痛15例

笔者基于"同气相求"理论,遵循经络辨证,以"求同气、通经络"为治则,针刺患侧或双侧手足少阳经远端激痛点及井穴,同时按揉近端激痛点,治疗顽固性偏头痛15例,现报道如下。1临床资料15例患者均为2018年1月至2018年6月包头医学院第二附属医院针灸科门诊就诊的顽固性偏头痛患者,其中男6例,女9例;单侧头痛9例,双侧6例;年龄15~65岁,平均46岁;病程0.5~15年,平均2年。均表现为单侧或双侧颞部反复发作的搏动性疼痛,伴失眠、健忘,痛甚者恶心,行头颅CT或MRI检查未见异常。     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Oncogene-mediated propagation of tracheal epithelial cells from two cystic fibrosis fetuses with different mutations. Characterization of CFT-1 and CFT-2 cells in culture

Abstract. Primary tracheal epithelial cells obtained from two fetuses with cystic fibrosis (CF) were successfully transfected with a plasmid vector recombined with the large T oncogene of SV40. The resulting tracheal cells were propagated in culture for up to 25 passages and retained the mutations of the CF genes carried by the two fetuses, one heterozygous for the S549N and N1303K substitutions (CFT-I cells), and the other homozygous for the most common deletion ΔF508 (CFT-2 cells). The transfected cells: (a) expressed the SV40 large T oncogene, as determined by immunofluorescence and Northern blot analysis; (b) retained typical epithelial morphology, as assessed by the presence of microvilli, desmosomes, gap junctions, and cytokeratin expression; (c) were fully responsive to the cAMP-stimulating agents isproterenol, forskolin and vasoactive intestinal peptide for cAMP production and PKA activation; (d) do not produce any tumour in the athymic nude mice; (e) were diploid and tetraploid with a normal chromosomal complement at early passages, and (f) exhibited the abnormal regulation of chloride conductance characteristic of CF.
These results indicate that CFT-1 and CFT-2 cells constitute a suitable model for: (a) comparison of the maturation and function of the CFTR protein mutated in the two nucleotide-binding domains; (2) analysis of the biochemical defect in CF epithelial airway cells, (c) development of new therapeutic agents, and correction of the CF defect by gene replacement therapy in vitro .     

Effect of Short Atrioventricular Delay on Cardiac Output

RONASZEKI, A., ET AL.: Effect of Short Atrioventricular Delay on Cardiac Output. Short atrioventricular (AV) delay modifies late diastolic filling dynamics. The effect of this change on cardiac output [CO) was studied in closed chest, AV blocked canine preparations (N: 10), during AV sequential pacing (80 bpm). CO (thermodilution technique) and transmitral flow velocity (TMFV, pulsed-wave Doppler) were measured and compared (paired t-test) on the basis of TMFV pattern, when atrial contraction (A wave) started just after early diastolic transmitral flow deceleration [PR:219 ± 25 ms, mean ± SD) and when A wave occurred at the end of late diastole and shortened due to the next ventricular contraction (PR: 56 ± 11 ms). The short AV delay resulted in 12.0 ± 5.9% decrease of CO, reflecting the interrupted late diastolic atrial transport. Properly timed atrial contraction is necessary for optimal AV sequential pacing.     

Clinical Interest of a Sensor Driven Algorithm Limiting Ventricular Pacing Rate During Supraventricular Tachycardia in Dual Chamber Pacing

A sensor driven algorithm limiting ventricular pacing rate during supraventricular tachycardia (SVT) is included in a dual chamber rate modulated pacemaker sensitive to acceleration forces (Relay, 294-03, Intermedics Inc.). According to the intensity of concomitant exercise, the ventricular pacing rate is limited either to the programmed maximum pacing rate (MPR) or to an interim lower limit, called "conditional ventricular tracking limit" (CVTL). The MPR prevails over the CVTL when the sensor calculated pacing rate exceeds the minimal rate by more than 20 beats/mm. The purpose of the study is to determine the clinical safety and efficacy of this algorithm in patients with intermittent SVT. Method: a Relay was implanted in four patients with a bradycardia/tachycardia syndrome and in four patients with complete atrioventricular block (CAVB). All had episodes of paroxysmal atrial tachycardia. The units were programmed in DDDR: rate responsive parameters were adjusted by simulating the rate response during three levels of exercise to let the MPR override the CVTL only during strenuous exercise. Holter monitors and exercise testings were performed at 3-month follow-up. Results: in seven patients, Holter recordings showed Supraventricular arrhythmias at rest with a ventricular pacing rate limited to the CVTL. Appropriate rate increases during exercise testings were also demonstrated. Three devices had to be reprogrammed in DDIR tone patient suffering from nearly permanent atrial flutter and two patients not tolerating the CVTL pacing rate at rest). Conclusion: the CVTL algorithm is effective in protecting against high ventricular pacing rates during Supraventricular arrhythmias. It allows the selection of the DDDR mode even with a high MPR in patients with intermittent SVT.     

The effect of antibody against TNF alpha on cytokine response in Jarisch-Herxheimer reactions of louse-borne relapsing fever

Severe Jarisch Herxheimer reaction (J-HR) precipitated by antibiotic treatment of louse-borne relapsing fever (LBRF) is associated with a transient, marked rise in circulating tumour necrosis factor alpha (TNF alpha), interleukin 6 (IL-6) and interleukin 8 (IL-8). Ovine polyclonal anti-TNF alpha antibody fragments (Fab) were used in a randomized double blind placebo controlled trial in an attempt to prevent this reaction. Within 4 h after penicillin, in controls (n = 29), a several- fold rise in cytokines occurred, concomitant with a fall in spirochaetes and maximal clinical manifestations of the J-HR. An intravenous infusion of anti-TNF alpha Fab, 30 min before penicillin in 20 patients reduced peak plasma levels of IL-6 and IL-8 (but not IL-1 beta) compared with controls (p = 0.01 and < 0.001, respectively) and the incidence of the J-HR, indicating some neutralization of TNF alpha. An apparent fall in TNF alpha reflected interference of anti-TNF alpha in the immunoassay.      

Identification of a 94-kilodalton antigen on Leishmania promastigote forms and its specific recognition in human and canine visceral leishmaniasis

We have analysed by immunoblotting sera from humans and dogs with visceral leishmaniasis, from the Old World as well as the New. When lysates of promastigotes are used as antigens, antibodies against a 94 kDa Leishmania component are detected, regardless of the age and geographical origin of the patient, the serum antibody titre as measured by indirect immunofluorescence, and the number of arcs in counterimmunoelectrophoresis. Low dilutions of sera from patients with Old and New World cutaneous leishmaniasis did not react with the 94-kDa antigen, whatever the species of Leishmania used as antigens. Sera from patients with other infections than leishmaniases, or without infection, are negative, even at low dilution. Anti-94 kDa antibodies were detected in the sera of Leishmania-infected dogs from both the Old and the New World. When lysates of Leishmania mexicana axenic amastigotes are used as antigens, the 94-kDa antigen was little or none identified by sera from humans and dogs with visceral leishmaniasis, and never recognized by control sera. Thus, the specific recognition of the 94-kDa promastigote antigen in human and canine visceral leishmaniasis suggests that this antigen could be a potential candidate in the differential immunodiagnosis of the disease.     

Induction of apoptotic cell death in chronic lymphocytic leukemia by 2- chloro-2'-deoxyadenosine and 9-beta-D-arabinosyl-2-fluoroadenine

2-Chloro-2'-deoxyadenosine (CldAdo) and 9-beta-D-arabinosyl-2- fluoroadenine (F-ara-A) have shown marked activity in the treatment of indolent lymphoid malignancies. Based on the susceptibility of various lymphocyte populations to apoptosis, we investigated whether CldAdo or F-ara-A would induce this process in lymphocytes from patients with chronic lymphocytic leukemia (CLL). In vitro exposure of leukemic lymphocytes to CldAdo or F-ara-A for 24 to 72 hours elicited features of apoptosis visible by light and electron microscopy. Analysis of DNA integrity showed DNA cleavage into nucleosomal-sized multimers. Using a quantitative assay, drug-induced DNA fragmentation was both time and dose dependent. Inhibition of active macromolecular synthesis did not prevent drug-induced fragmentation; however, both drug-induced and spontaneous DNA fragmentation were prevented by intracellular calcium chelation. In vitro culture with phorbol ester generally decreased drug- induced DNA cleavage. After prolonged incubation, CLL cells exhibited spontaneous cleavage; albeit, at significantly lower rates than drug- treated cells. Heterogeneity was observed for spontaneous and drug- induced DNA fragmentation and was significantly lower in B-leukemic cells obtained from patients with high-risk and refractory disease. We conclude that CldAdo and F-ara-A are potent inducers of apoptotic death in CLL and that this feature correlates with the disease status.