Is the nuclear envelope a ‘generator’ of membrane?

Summary Early diplotene oocytes from Necturus maculosus ranging from 0.2 to 0.5 mm in diameter were examined by electron microscopy. In the smallest oocytes of this range, the cytoplasm is largely devoid of membranes, but contains primarily ribosomes and mitochondria. In slightly larger oocytes, smooth-surfaced cytomembranes first appear in the perinuclear cytoplasm. At this time, the outer layer of the germinal vesicle nuclear envelope (GVNE) shows frequent connections with long membranous lamellae that extend for considerable, but variable distances into the juxtanuclear ooplasm. The number of smooth membranous lamellae increases tremendously as the oocytes increase in diameter. In such oocytes as well, frequent continuities are observed between the outer membrane of the GVNE and many of the cytoplasmic membranes. Eventually, as the ooplasm becomes populated with extensive numbers of membranous lamellae, instances of continuity between the membranous lamellae and nuclear envelope now become sparse and eventually non-existent. The frequent connections observed between membranous lamellae and the outer membrane of the GVNE during a circumscribed interval of diplotene strongly implicate the GVNE in the generation of extensive amounts of cytoplasmic membrane. The ooplasm of larger oocytes in the size range indicated contain numerous Golgi complexes and large quantities of annulate lamellae most of which are positioned in the peripheral or subcortical ooplasm, as well as extensive quantities of smooth membranes of the endoplasmic reticulum and lipid droplets.     

adjuvant chemotherapy group, 56 patients received a

1%,26.6% and 27.7% respectively.there was no significant discrepancy(P>0.05).The 5-year survival in 3 or 4 cycles patients were 26.7% and the 5-year survival in 5 or 6 cycles patients were 28.9% .there was no significant discrepancy(P>0.05).Conclusion:Postoperative adjuvant chemotherapy with platinum-based regimen for 3 or 4 cycles can improve survival rate for stage Ⅲ NSCLC patients.Non-small-cell lung cancer; Surgery; Adjuvant chemotherapy; Survival rate0临床肿瘤学杂志Chinese Clinical Oncology19-21R734.2E0724E;E072_4潘泓;173-175长春瑞滨联合卡铂治疗老年晚期非小细胞肺癌胡兴胜;张湘茹;储大同; 中国医学科学院     

Remote care: bidding our ICD patients a fond farewell?

Remote follow-up has proven its safety and efficacy in the literature, and indeed in daily use. It saves the patient time and travel, allows earlier detection of events, and reduces inappropriate shocks. At the same time, it is not infallible and definitely not a universal substitute for in-office visits, as the 5 cases below demonstrate. It saves time, but also takes some time, with problems and challenges we were hitherto not familiar with. Hopes for the future include uniform definitions regarding policy and responsibilities, reimbursement, even better connectivity, better alert management and remote programmability. To end on a more utopic note, it would be a huge step forward if devices and leads were so reliable that we did not need remote care to detect malfunctions.     

Is gene therapy a good therapeutic approach for HIV-positive patients?

Background

Vaccination of neonates is generally difficult due to the immaturity of the immune system and consequent higher susceptibility to tolerance induction. Genetic immunization has been described as an alternative to trigger a stronger immune response in neonates, including significant Th1 polarization. In this investigation we analysed the potential use of a genetic vaccine containing the heat shock protein (hsp65) from Mycobacterium leprae (pVAXhsp65) against tuberculosis (TB) in neonate mice. Aspects as antigen production, genomic integration and immunogenicity were evaluated.

Methods

Hsp65 message and genomic integration were evaluated by RT-PCR and Southern blot, respectively. Immunogenicity of pVAXhsp65 alone or combined with BCG was analysed by specific induction of antibodies and cytokines, both quantified by ELISA.

Results

This DNA vaccine was transcribed by muscular cells of neonate mice without integration into the cellular genome. Even though this vaccine was not strongly immunogenic when entirely administered (three doses) during early animal's life, it was not tolerogenic. In addition, pVAXhsp65 and BCG were equally able to prime newborn mice for a strong and mixed immune response (Th1 + Th2) to pVAXhsp65 boosters administered later, at the adult life.

Conclusion

These results suggest that pVAXhsp65 can be safely used as a priming stimulus in neonate animals in prime-boost similar strategies to control TB. However, priming with BCG or pVAXhsp65, directed the ensuing immune response triggered by an heterologous or homologous booster, to a mixed Th1/Th2 pattern of response. Measures as introduction of IL-12 or GM-CSF genes in the vaccine construct or even IL-4 neutralization, are probably required to increase the priming towards Th1 polarization to ensure control of tuberculosis infection.     

Red blood cell transfusion in patients with ST-elevation myocardial infarction—a meta-analysis of more than 21,000 patients

Background

Red blood cell transfusion remains controversial in patients with acute coronary syndromes and particularly in patients with ST-elevation myocardial infarction (STEMI).

Methods

We systematically searched PubMed, Cochrane, EMBASE, and Web of Science for studies published until January 2017 describing the outcomes in patients with STEMI who received red blood cell transfusion, compared with patients who did not.

Results

A total of 21,770 patients with STEMI from 5 cohort studies were included in the meta-analysis, 984 (4.5%) received red blood cell transfusion and 20,786 (95.4%) did not. Red blood cell transfusion was associated with a higher risk of in-hospital and long-term mortality, emergency repeated percutaneous coronary intervention (PCI), reinfarction rate, stroke rate, and heart failure. The group with red blood cell transfusion had a slightly higher incidence of diabetes mellitus and hypertension, but a lower incidence of smoking. The two groups had the same incidence of prior myocardial infarction, prior coronary artery bypass graft surgery and malignancy. Prior heart failure, prior stroke and prior PCI were more frequent in the group that had received red blood cell transfusion. The mean nadir haemoglobin was 8.5?±?0.1?g/dl in the group with red blood cell transfusion and 12.5?±?0.4?g/dl in the control group, p?<?0.001.

Conclusions

Red blood cell transfusion increases the morbidity and mortality in patients with STEMI. This difference could not be explained by the higher morbidity in the red blood cell transfusion group alone. Further randomised controlled trials are required to provide a reliable haemoglobin threshold for these patients.

     

Oxidative DNA damage in cancer patients: a cause or a consequence of the disease development?

A wide variety of oxidative DNA lesions are present in living cells. One of the best known lesions of this type is 8-oxoguanine (8-oxoGua) which has been shown to have mutagenic properties. An influence of antioxidative vitamins and labile iron pool on the background level of 8-oxoGua in cellular DNA is discussed and oxidative damage to free nucleotide pool as a possible source of 8-oxo-2'-deoxyguanosine in DNA and urine is described. An involvement of 8-oxoGua in the origin and/or progression of cancer is reviewed. It is concluded that a severe oxidative stress manifested as a high level of 8-oxoGua in cellular DNA as well as in urine of cancer patients is a consequence of development of many types of cancer. Although at present it is impossible to answer directly the question concerning involvement of oxidative DNA damage in cancer etiology it is likely that oxidative DNA base modifications may serve as a source of mutations that initiate carcinogenesis (i.e. they may be causal factors responsible for the process).     

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis?

Background

Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM.

Methods

Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed.

Results

The mean loss of FEV₁ was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV₁ of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV₁ and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV₁ and FVC was demonstrated (3 months ΔFEV₁: 220 ± 82 ml, p = 0.024; 6 months ΔFEV₁: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy.

Conclusions

Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation.     

Is cardiac CT a reproducible alternative for cardiac MR in adult patients with a systemic right ventricle?

Objective

20 % of patients with a systemic RV are pacemaker dependent, and unsuitable to undergo cardiac magnetic resonance (CMR). Multidetector row computed tomography (MDCT) could provide a reproducible alternative to CMR in these patients. The aim of this study was to compare variability of MDCT with CMR.

Methods

Thirty-five patients with systemic RV underwent either MDCT (n = 15) or CMR (n = 20). Systemic RV volumes and ejection fraction were obtained, and intra- and interobserver variability for both modalities were assessed and compared.

Results

We found the intra- and interobserver variability of volumes and function measurements of the systemic RV obtained with MDCT to be higher compared with those obtained with CMR. However, these differences in variability were not significant, the only exception being the interobserver variability of systemic RV stroke volume.

Conclusions

MDCT provides a reproducible alternative to CMR for volumes and function assessment in patients with a systemic RV.     

Trace element imbalances in patients undergoing chronic hemodialysis therapy – Report of an observational study in a cohort of Portuguese patients

IntroductionPatients with end-stage renal disease undergoing hemodialysis therapy are at risk of developing deficiencies of essential trace elements and/or overload of toxic trace elements, both of which may significantly affect their clinical status of. Those imbalances may result from the disease itself but also from the quality of the therapeutic process, namely the hemodialysis process, which has greatly evolved in the last decades. Thus, old observations that have been assumed as very well-proven have been recently questioned. In this case-control study we evaluate the current trace elements status in a group of Portuguese patients under hemodialysis therapy.Material and methodsSerum samples from patients (n = 93), collected for the routine periodic control of Al levels, were analyzed for a wide panel of trace elements (Li, Al, Mn, Co, Ni, Cu, Zn, Se, Rb, Sr, Mo, Cd, Ba, Pb) using inductively coupled plasma mass spectrometry technique (hemodialysis patients’ group). For comparison purposes, samples of individuals with no evidence of renal disease according to standard laboratory analytical criteria (n = 50) were also analyzed (control group).ResultsThe results showed significant differences between the two groups, with higher values in hemodialysis patients group for Al (14.6 vs. 9.5 μg/L), Co, Ni, Sr, Mo (4.5 vs. 1.4 μg/L), Cd (0.058 vs. 0.025 μg/L) and Pb (0.55 vs. 0.30 μg/L); and lower values in hemodialysis patients group for Li (4.0 vs. 75.8 μg/L), Mn, Cu (943.5 vs. 1038.5 μg/L), Zn (943.5 vs. 1038.5 μg/L), Se (71.5 vs. 103.8 μg/L), Rb (202.4 vs. 300.3 μg/L) and Ba (0.65 vs. 8.7 μg/L).ConclusionThis study confirms that hemodialysis patients tend to present significant trace elements imbalances, which may be related to the higher morbidity and mortality observed in this specific patients’ group.     

Comorbidity among HHT patients and their controls in a 20 years follow-up period

Background

Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder with a wide variety of clinical manifestations due to the presence of multiple arteriovenous malformations in various tissues and organs.

Objective

To study the need for hospital admittance in a group of HHT patients and matched controls during a 20?years follow-up period commencing in 1995.

Methods

All HHT patients in the County of Funen, Denmark, were included. For each patient, three age and sex matched controls were identified at the time of enrolment. Data on all hospitalisations were extracted from the national health registers and compared with clinical records. The hospitalisations were grouped as HHT relevant or not HHT relevant based on the discharge diagnosis (International Classification of Diseases, ICD10) and with particular focus on infections, bleedings and thromboembolic events.Patients with HHT were compared with controls concerning the first time incidence of each discharge diagnosis.

Results

We included 73 HHT patients and 219 controls of which one control was lost to follow-up. HHT-patients had significantly more hospitalisations per person caused by infections in joints and bones, but not caused by infections in general. Bleeding episodes were, as expected, more frequent among the HHT-patients. The study revealed a similar incidence of abscesses and thromboembolisms, including in the central nervous system, among the HHT patients and controls.

Conclusions

Based on this study Danish HHT patients had an increased comorbidity of infections in joints and bones and of bleeding episodes. However, the incidence of thromboembolisms, cerebral abscesses and other conditions commonly considered related to HHT was comparable between the patients and the controls. The patients included in this study were closely monitored at a highly specialised HHT Centre where they received relevant diagnostic evaluation, treatment and counselling. Since this is assumed to benefit the overall health of the patients, it may explain why these patients were less prone to comorbidity than other studies have suggested.

     

Biosimilars 2.0: Guiding principles for a global “patients first” standard

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership, to outline the appropriate standards for these products and to facilitate increased access while meeting patients'' needs.Key words: biotechnology, biosimilars, generic drugs, monoclonal antibodies, pharmacodynamics, pharmacokinetics