Evolocumab and lipoprotein apheresis combination therapy may have synergic effects to reduce low‐density lipoprotein cholesterol levels in heterozygous familial hypercholesterolemia: A case report

A 49 years old woman (weight 68 kg, BMI 27.3 kg/m²) with heterozygous familial hypercholesterolemia (HeFH) and multiple statin intolerance with muscle aches and creatine kinase elevation, presented at the Outpatient Lipid Clinic of Verona University Hospital in May 2015. Hypercholesterolemia was firstly diagnosed during adolescence, followed in adulthood by a diagnosis of Cogan's syndrome, a rheumatologic disorder characterized by corneal and inner ear inflammation. No xanthomas, corneal arcus, or vascular bruits were detectable at physical examination. Screening for macrovascular complications did not reveal relevant damages. Ongoing medical therapy included salicylic acid, methylprednisolone, methotrexate, and protonic‐pump inhibitor. In the absence of specific lipid‐lowering therapy, plasma lipid levels at first visit were: total‐cholesterol = 522 mg/dL, LDL‐cholesterol = 434 mg/dL, HDL‐cholesterol = 84 mg/dL, triglycerides = 120 mg/dL, Lp(a) = 13 mg/dL. On December 2015, evolocumab 140 mg sc every 2 weeks was initiated. After a 24‐week treatment, the LDL‐cholesterol levels decreased by an average of 21.2% to 342 ± 22 mg/dL (mean ± SD). On May 2016, LDL‐apheresis (H.E.L.P.system) was started as add‐on therapy. Compared to the average levels obtained during the evolocumab monotherapy period, the LDL‐cholesterol was reduced by 49.4%, thus reaching an inter‐apheresis level (mean ± SD) of 173 ± 37 mg/dL. This report suggests that a combination therapy with evolocumab and lipoprotein‐apheresis may have synergic effects on circulating lipid levels. Its relevance as a highly effective treatment option for hyperlipidemia in HeFH patients warrants further investigation in larger datasets.     

Studies on Theileriidae (Sporozoa) in Tanzania. X. A large-scale field trial on immunization against cattle Theileriosis.

50 cattle immunized by an infection and treatment method with 3 strains of Theileria parva (Mugaga, Kiambu 5 and Serengeti transformed), together with 19 controls, were exposed to natural tick infestation in Tanzania, in a site where a continuous influx of infected ticks from different regions of the country may be expected to occur. Exposure lasted for 2 months, monitoring continued for 3 more weeks after exposure ended. All 19 controls contracted East Coast Fever and died. 40 of the 50 immunized animals survived the whole period of monitoring; the other 10 died of accidents (2), heartwater (3) and unidentified causes (5); none died of ECF. It is recommended that this method of immunization be routinely applied to protect valuable animals at risk. An attempt to immunize against pathogenic Theileria mutans, by injecting blood containing piroplasms of a strain of low pathogenicity, showed that this method may protect against high parasitaemias caused by natural tick-borne infections and may be useful in eliminating the confusing factor of T. mutans in future trials on East Coast Fever.     

What Does a Mathematical Model Tell About the Impact of Reinfection in Korean Tuberculosis Infection?

Objectives

According to the Korea Centers for Disease Control and Prevention, new active tuberculosis (TB) cases have increased since 2001. Some key factors explain and characterize the transmission dynamics of Korean TB infection, such as a higher ratio of latent individuals and a new reporting system implemented in 2001, among others.

Methods

We propose a mathematical TB model that includes exogenous reinfection to gain a better understanding of the recent trend for TB incidence. We divide the simulation time window into two periods, 1970–2000 and 2001–2012, according to the implementation date of a new TB detection system.

Results

Two sets of parameters, including the transmission rate, the latent period, the recovery rate, and the proportion of exogenous reinfection, are estimated using the least-squares method and calibrated to data on the incidence of active TB.

Conclusion

Among some key parameters in the model, the case finding effort turned out to be the most significant impacting component on the reduction in the active TB cases.     

Effects of demeclocycline on psychiatric polydipsia in schizophrenic patients]

Excess intake of water by schizophrenic patients is referred to as psychiatric polydipsia. This symptom causes incontinence, vomiting and hyponatremia, and may sometimes lead to death. We have no effective therapeutic methods other than administrating sodium chloride solution and diuretics, or restricting the intake itself. A case was reported stating that demeclocycline, used in case where there is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), was effective for the treatment of psychiatric polydipsia. We administered demeclocycline to 8 schizophrenic patients with psychiatric polydipsia, and noticed improvement in incontinence, vomiting and hyponatremia. There was also a decrease of polydipsic behavior. Demeclocycline inhibits the antidiuretic effect of vasopressin on the distal renal tubule. Considering the function of demeclocycline and the relevance of vasopressin to the central nervous system, it has been suggested that demeclocycline has effects on the central nerve through vasopressin or cyclic AMP.     

Operational feasibility of using loop-mediated isothermal amplification for diagnosis of pulmonary tuberculosis in microscopy centers of developing countries

The characteristics of loop-mediated isothermal amplification (LAMP) make it a promising platform for the molecular detection of tuberculosis (TB) in developing countries. Here, we report on the first clinical evaluation of LAMP for the detection of pulmonary TB in microscopy centers in Peru, Bangladesh, and Tanzania to determine its operational applicability in such settings. A prototype LAMP assay with simplified manual DNA extraction was evaluated for accuracy and ease of use. The sensitivity of LAMP in smear- and culture-positive sputum specimens was 97.7% (173/177 specimens; 95% confidence interval [CI], 95.5 to 99.9%), and the sensitivity in smear-negative, culture-positive specimens was 48.8% (21/43 specimens; CI, 33.9 to 63.7%). The specificity in culture-negative samples was 99% (500/505 specimens; CI, 98.1 to 99.9%). The average hands-on time for testing six samples and two controls was 54 min, similar to that of sputum smear microscopy. The optimal amplification time was 40 min. No indeterminate results were reported, and the interreader variability was 0.4%. Despite the use of a single room without biosafety cabinets for all procedures, no DNA contamination was observed. The assay was robust, with high end-point stability and low rates of test failure. Technicians with no prior molecular experience easily performed the assay after 1 week of training, and opportunities for further simplification of the assay were identified.     

Studies on Theileriidae (Sporozoa) in Tanzania. VI. Second field trial on immunization against cattle theileriosis.

Nine cattle, immunized by an infection and treatment method with 3 strains of Theileria parva (Muguga, Kiambu 5 and Serengeti transformed) and nine controls, were exposed to natural tick infestation in Tanzania. All controls contracted fatal East Coast Fever within 2 months of exposure. All immunized animals survived the period of exposure (over 2 months), but later one died of ECF, one of heart-water, one of an undetermined cause (not a theileriosis), and one disappeared from the herd. The 5 remaining animals survived for over 3 months after exposure ended. It is thought that this method of immunization is of value in protecting valuable animals at risk. An attempt to immunize against pathogenic Theilereia mutans, by injecting blood containing an apathogenic strain of this parasite, gave inconclusive results as no pathogenic strains were encountered during the trial.     

Dipyridamole enhancement of etoposide sensitivity

Dipyridamole (DPM) enhanced the sensitivity of human ovarian carcinoma 2008 cells to etoposide (VP-16) producing a 5.5-fold reduction in 50% inhibitory concentration at a DPM concentration of 20 microM. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM increased the steady-state VP-16 content of 2008 cells; a DPM concentration of 4 microM increased VP-16 content by 2-fold. DPM was 25 times less potent when cells were incubated in human plasma. In tissue culture medium 96% of the DPM was free, whereas in plasma only 15% was non-protein bound. DPM did not displace VP-16 from proteins under either condition. DPM did not increase the initial influx of VP-16 but did inhibit the initial efflux, reducing the efflux rate constant by 27%. DPM had no effect on the later stages of drug efflux, nor did it irreversibly bind VP-16 in the cell. The effect of DPM was evident within 1 min; once removed, the effect disappeared within 2 min. DPM is a potent nucleoside membrane transport inhibitor and can also inhibit cyclic AMP (cAMP) phosphodiesterase in platelets. Nitrobenzylthioinosine, another nucleoside transport inhibitor which competes for binding with DPM, did not enhance sensitivity to VP-16 or increase VP-16 cellular accumulation and did not block the effect of DPM. In 2008 cells, DPM did not increase cAMP; when cAMP was increased by incubation with dibutyryl cyclic 3':5'-AMP, there was no synergy with VP-16. The results indicate that enhanced sensitivity to VP-16 was not due to an effect of DPM on the protein binding of VP-16 or on cellular cAMP and suggest that it is not directly related to inhibition of nucleoside transport. This effect appears to be a newly identified mechanism of action for this agent.