Leadless pacemaker implantation via the internal jugular vein.

BACKGROUND: Leadless pacemaker therapy was introduced to overcome lead- and pocket-related complications in conventional transvenous pacemaker therapy. Implantation via the femoral vein, however, may not always be feasible. The aim of this study was to evaluate leadless pacemaker implantation using a jugular vein approach and compare it to the standard implantation approach through the femoral vein. METHODS: The records of the first consecutive 100 patients undergoing MicraTM leadless pacemaker implantation via the right internal jugular vein from two centers were included in this study. Periprocedural safety and efficacy of the jugular approach were compared to the first 100 patients having undergone a femoral implantation approach at the University Hospital Zurich. RESULTS: 100 patients underwent successful implantation of a leadless pacemaker via the internal jugular vein (mean age, 81.18 ± 8.29, 60% males). Mean procedure time was 35.63 ± 10.29 min with a mean fluoroscopy time of 4.66 ± 5.16 min. The device was positioned at the inferior septum in 25 patients, at the high septum in 24 and mid-septum in 51 patients. The mean pacing threshold was 0.56 ± 0.35 V at 0.24 ms pulse width with a sensed amplitude of 10.0 ± 4.4 mV. At follow-up, electrical parameters remained stable in all patients. Compared with femoral implantation, patients undergoing jugular transvenous pacemaker implantation were of similar age and had similar comorbidities. Mean procedure- (48.9 ± 21.0 min) and fluoroscopy times (7.7 ± 7.8 minutes, both p <0.01) were shorter compared to the femoral approach. Electrical parameters were similar between the two approaches. There were only two complications during jugular veinous implantations (1 pericardial effusion and 1 dislocation), compared to 16 complications using the femoral approach (1 pericardial effusion, 2 femoral artery injuries and 13 major groin hematomas). CONCLUSION: The jugular approach may represent a safe and efficient alternative to the femoral implantation method for implantation of the Micra leadless pacemaker.

The Use of Dog Collars Offers Significant Benefits to Rabies Vaccination Campaigns: The Case of Zanzibar, Tanzania.

Tools and resources that could increase dog vaccination coverage have become increasingly critical towards progressing the goal to eliminate dog-mediated human rabies by 2030. In this regard, dog collars that are fitted during vaccination campaigns could potentially enhance owner participation. The use of dog collars will, however, increase the cost per dog vaccinated and the impact and benefit of this practice should be elucidated. This study evaluated the impact of dog collars by testing the perception and related behavioural influences in communities in Zanzibar. In this cross-sectional investigation-conducted approximately two months after the implementation of a mass dog vaccination (MDV) where dog collars were provided to vaccinated dogs-data were collected from 600 respondents in 56 municipal wards in Zanzibar. Descriptive analyses and logistic regressions were undertaken to determine the impact the collars had on respondents with regards to (i) engaging with the community dogs, (ii) health seeking behaviour after exposure, and (iii) overall participation during dog vaccination campaigns. From the data, it was evident that the collars had a positive impact on the community's perception of dogs, with 57% of the respondents feeling safer around a dog with a collar, while 66% of the respondents felt less safe around a dog without a collar. Furthermore, the collars had a positive impact on participation during dog vaccination campaigns. Of the 142 respondents who owned dogs, 64% reported that the collars made them more likely to take their dogs for vaccination, and 95% felt that the collar was an important sign of the dog's vaccination status. This study demonstrated that dog collars could not only improve participation during dog vaccination campaigns, but that they could also play a significant role in the community's perception of rabies vaccination campaigns and vaccinated dogs in general.

Noise-induced hormonal & morphological malformations in breeding pigeons.

Environmental pollution has the potential to have a significant impact on animal's health especially on birds due to daily exposure and habitat. This experimental study was carried out for a 60 days period in which, a total of 24 pigeon birds with suitable weight (80-100 g) were kept in Animal house with suitable environmental conditions viz, controlled temperature, humidity & light source to minimize any other stress. Out of twenty-four, eighteen birds were divided into three treatment groups (6 birds in each group). Whole experiment was run in triplicate manner in breeding season. One served as Control (Group 1) and remaining three were experimental groups including Road traffic noise (Group 2), Military noise (Group 3) & Human activities noise (Group 4). Noise was applied as recorded high intensity music (1125 Hz/ 90 dB) through speakers for 5-6 hrs. daily. Blood sampling was done after 20, 40 and 60 days by sacrificing treatment birds. Noise stress significantly (p<0.05) increase the serum levels of corticosterone and thyroid stimulating hormone (TSH) in Group 2 while significantly (p<0.05) decrease the serum levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) of Group 3 birds. Moreover, major fault bars formation was seen both in Group 2 and Group 3. It was concluded as that Noise stress caused rise in serum levels of Corticosterone and TSH but fall in LH and FSH. Along with fault bars formation was also prominent in all treatment groups due to stress hormone.

Identification PMS1 and PMS2 as potential meiotic substrates of CDK2 activity.

Cyclin dependent-kinase 2 (CDK2) plays important functions during the mitotic cell cycle and also facilitates several key events during germ cell development. The majority of CDK2's known meiotic functions occur during prophase of the first meiotic division. Here, CDK2 is involved in the regulation of meiotic transcription, the pairing of homologous chromosomes, and the maturation of meiotic crossover sites. Despite that some of the CDK2 substrates are known, few of them display functions in meiosis. Here, we investigate potential meiotic CDK2 substrates using in silico and in vitro approaches. We find that CDK2 phosphorylates PMS2 at Thr337, PMS1 at Thr331, and MLH1 in vitro. Phosphorylation of PMS2 affects its interaction with MLH1 to some degree. In testis extracts from mice lacking Cdk2, there are changes in expression of PMS2, MSH2, and HEI10, which may be reflective of the loss of CDK2 phosphorylation. Our work has uncovered a few CDK2 substrates with meiotic functions, which will have to be verified in vivo. A better understanding of the CDK2 substrates will help us to gain deeper insight into the functions of this universal kinase.

A novel function for CDK2 activity at meiotic crossover sites.

Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1-2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called "late recombination nodules" (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain. Here, we describe the phenotype of 2 Cdk2 point mutants with elevated or decreased activity, respectively. Elevated CDK2 activity was associated with increased numbers of LRN-associated proteins, including CDK2 itself and the MutL homolog 1 (MLH1) component of the MutLγ complex, but did not lead to increased numbers of COs. In contrast, reduced CDK2 activity leads to the complete absence of CO formation during meiotic prophase I. Our data suggest an important role for CDK2 in regulating MLH1 focus numbers and that the activity of this kinase is a key regulatory factor in the formation of meiotic COs.

Discovery of a chemical probe for PRDM9.

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

Diverse roles for CDK-associated activity during spermatogenesis.

The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly, several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins, suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.

CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I.

Meiosis generates four genetically distinct haploid gametes over the course of two reductional cell divisions. Meiotic divisions are characterized by the coordinated deposition and removal of various epigenetic marks. Here we propose that nuclear respiratory factor 1 (NRF1) regulates transcription of euchromatic histone methyltransferase 1 (EHMT1) to ensure normal patterns of H3K9 methylation during meiotic prophase I. We demonstrate that cyclin-dependent kinase (CDK2) can bind to the promoters of a number of genes in male germ cells including that of Ehmt1 through interaction with the NRF1 transcription factor. Our data indicate that CDK2-mediated phosphorylation of NRF1 can occur at two distinct serine residues and negatively regulates NRF1 DNA binding activity in vitro. Furthermore, induced deletion of Cdk2 in spermatocytes results in increased expression of many NRF1 target genes including Ehmt1 We hypothesize that the regulation of NRF1 transcriptional activity by CDK2 may allow the modulation of Ehmt1 expression, therefore controlling the dynamic methylation of H3K9 during meiotic prophase.

Metabolic Remodeling during Liver Regeneration.

Liver disease is linked to a decreased capacity of hepatocytes to divide. In addition, cellular metabolism is important for tissue homeostasis and regeneration. Since metabolic changes are a hallmark of liver disease, we investigated the connections between metabolism and cell division. We determined global metabolic changes at different stages of liver regeneration using a combination of integrated transcriptomic and metabolomic analyses with advanced functional redox in vivo imaging. Our data indicate that blocking hepatocyte division during regeneration leads to mitochondrial dysfunction and downregulation of oxidative pathways. This resulted in an increased redox ratio and hyperactivity of alanine transaminase allowing the production of alanine and α-ketoglutarate from pyruvate when mitochondrial functions are impaired. Our data suggests that during liver regeneration, cell division leads to hepatic metabolic remodeling. Moreover, we demonstrate that hepatocytes are equipped with a flexible metabolic machinery able to adapt dynamically to changes during tissue regeneration.

Nerve Conduction Abnormalities in Pre-Diabetics and Asymptomatic Diabetics.

Aim: To determine the electrophysiological abnormalities in pre-diabetics and/ or asymptomatic diabetics and analyse the role of nerve conduction for recognizing distal symmetric polyneuropathy. Material and Methods: A total of 180 subjects were categorized as: Group A: healthy Subjects (n=60), Group B Pre-diabetics (IFG +IGT, n=60) and Group C: Asymptomatic type 2 diabetics (n=60). Results: Electrophysiological studies revealed that amplitude of B/L Sural SNAP and tibial CMAP was significantly lower in affected pre-diabetics and asymptomatic diabetics. The presence of significant f wave latency was also noted in both these groups, more among asymptomatic diabetics. The observations on distal latency and nerve conduction velocity of sensory and motor nerves were statistically nonsignificant. Conclusion: Sensory nerve abnormality was more obvious than motor nerve abnormality in the pre-diabetic subjects. The changes in amplitude of motor nerve abnormality was observed late in course of disease i.e. in asymptomatic diabetic group than pre-diabetics. The amplitude of sensory nerve action potential and F wave latency parameters were the most sensitive measures of peripheral neuropathy in early diabetics in our study.

Theoretical design of metal-phthalocyanine dye-sensitized solar cells with improved efficiency.

The present work carried out a theoretical study of the electronic structures, absorption spectra, and photovoltaic performance of two series of transition metal-phthalocyanine derived from nonperipheral electron-donating substituents, either (2-phenyl) phenoxy(M-PC1) or quinoleinoxy(M-PC2). The DFT and TD-DFT were employed for this study. The effect of modifying the central metal atoms and the substitution on cell performance were investigated in terms of polarizability (α), hyper-polarizability (ß), chemical potential (µ), chemical hardness (η), electrophilicity power (ω), FMOs, energy gaps, UV/vis absorption spectra and injected driving force (ΔGinject), light harvesting efficiencies (LHE), total reorganization energy (λtot), open circuit photovoltage (Voc), and life time of the excited state (τ). The results obtained by using these parameters showed that the replacement of (2-phenyl) phenoxy by a proposed substituent such as quinoleinoxy would increase the hyper-polarizability, light harvesting efficiency, and open circuit photovoltage, while on the other hand the reorganization energy and the injection driving force are decreased. Modifying central metal atoms, such as Zn, Cd, Pd, and Pt, exhibited good performance in terms of the driving force of electron injection, charge transfer characteristics, and dye reorganization as compared with the Cu reference dye. The findings provided a useful prediction and perspective for the promising future for high-efficiency dye-sensitized solar cells (DSSCs) with dyes based on phthalocyanine. Graphical abstract Photovoltaic performance of Metallo-phthalocyanine contening (2-phenyl) phenoxy and quinoleinoxy.

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays.

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.

The Indispensable Role of Cyclin-Dependent Kinase 1 in Skeletal Development.

Skeletal development is tightly regulated through the processes of chondrocyte proliferation and differentiation. Although the involvement of transcription and growth factors on the regulation of skeletal development has been extensively studied, the role of cell cycle regulatory proteins in this process remains elusive. To date, through cell-specific loss-of-function experiments in vivo, no cell cycle regulatory proteins have yet been conclusively shown to regulate skeletal development. Here, we demonstrate that cyclin-dependent kinase 1 (Cdk1) regulates skeletal development based on chondrocyte-specific loss-of-function experiments performed in a mouse model. Cdk1 is highly expressed in columnar proliferative chondrocytes and is greatly downregulated upon differentiation into hypertrophic chondrocytes. Cdk1 is essential for proper chondrocyte proliferation and deletion of Cdk1 resulted in accelerated differentiation of chondrocytes. In vitro and ex vivo analyses revealed that Cdk1 is an essential cell cycle regulatory protein for parathyroid hormone-related peptide (PTHrP) signaling pathway, which is critical to chondrocyte proliferation and differentiation. These results demonstrate that Cdk1 functions as a molecular switch from proliferation to hypertrophic differentiation of chondrocytes and thus is indispensable for skeletal development. Given the availability of inhibitors of Cdk1 activity, our results could provide insight for the treatment of diseases involving abnormal chondrocyte proliferation, such as osteoarthritis.

Frequency of abdominal aortic calcification in a group of Iraqi hemodialysis patients.

Cardiovascular complications including abdominal aortic calcification significantly affect the mortality and morbidity in patients on a hemodialysis (HD) program. The objective of this study is to find the frequency of abdominal aortic calcification in patients on regular HD and to evaluate the effect of parameters on frequency and severity of abdominal aortic calcification. Fifty-four patients with end-stage renal disease on regular HD were studied from January 2011 to December 2011 to evaluate abdominal aortic calcification by plain abdominal X-ray. The study showed that 10 (18.5%) patients had abdominal aortic calcification. Only one (1.9%) had grade 3 calcification and among the remaining, five (9.3%) patients had grade 1 and four (7.4%), grade 2. There was a statistically significant difference (P <0.05) in the means of serum cholesterol among those with and without abdominal aortic calcification. Hypertension was noticed in most patients with abdominal aortic calcification. The frequency of abdominal aortic calcification is directly related to age and duration of dialysis. The only biochemical parameter with a statistically significant effect was serum cholesterol.

Systemic Wegener's granulomatosis with severe oculo-otological manifestations.

A case of Granulomatosis with Polyangiitis (Wegener's) is described in which the common presenting symptoms were hoarseness, deafness and ocular manifestations including marked redness and congestion of both eyes. The case findings and other systemic involvements are reviewed briefly along with histological and immunological discussions.

Occurrence of thermophilic Campylobacter spp. contamination on vegetable farms in Malaysia.

The aim of the present study was to examine the prevalence of thermophilic Campylobacter spp. (Campylobacter jejuni and Campylobacter coli) in soil, poultry manure, irrigation water, and freshly harvested vegetables from vegetable farms in Malaysia. C. jejuni was detected in 30.4% and 2.7% of the soil samples, 57.1% and 0% of the manure samples, and 18.8% and 3% of the vegetable samples from farm A and farm B, respectively, when using the MPNPCR method. Campylobacter spp. was not found in any of the irrigation water samples tested. Therefore, the present results indicate that the aged manure used by farm A was more contaminated than the composted manure used by farm B. Mostly, the leafy and root vegetables were contaminated. C. coli was not detected in any of the samples tested in the current study. Both farms tested in this study were found to be contaminated by campylobacters, thereby posing a potential risk for raw vegetable consumption in Malaysia. The present results also provide baseline data on Campylobacter contamination at the farm level.

Model concept for nitrate and nitrite utilization during anoxic transformation in the bulk water phase of municipal wastewater under sewer conditions.

A two-stage anoxic transformation process, involving growth of biomass utilizing two types of different electron acceptors, namely nitrate and nitrite, has been observed. The present water quality modules established for sewer processes cannot account for the two-stage process. This paper outlines the development of a model concept that enables the two-stage anoxic transformation process to be simulated. The proposed model is formulated in a matrix form that is similar to the Activated Sludge Models and Sewer Process Model matrices. The model was successfully applied to simulate changes in nitrate and nitrite concentrations during anoxic transformations in the bulkwater phase of municipal wastewater.

Utility of intrapleural streptokinase in management of chronic empyemas.

BACKGROUND: The nonsurgical medical approach with use of fibrinolytic agent is an alternative modality in management of chronic empyemas. With the introduction of purer forms of streptokinase, there has been renewed interest generated in the use of intrapleural thrombolytics with documented successful drainage of difficult to drain chronic empyemas. To evaluate the utility of streptokinase in the management of chronic difficult to drain empyemas in a single blind randomized case control study. MATERIAL AND METHODS: Twenty four cases of chronic/multiloculated empyema were included which had cases preferred having loculations or multiloculations and failure of drainage via thoracostomies for less than 100 ml during last 24 hours. Cases were randomized into two groups as 12 cases of streptokinases group and 12 cases of placebo group. Streptokinase given as 2.5 lac units in 100 ml of normal saline instilled intrapleurally for 6 consecutive days. In control group, 100 ml of normal saline without streptokinase was instilled intrapleurally through intercostal drain for 6 days. They were assessed by amount of drainage through intercostal drain for six days after instillation of streptokinase/placebo, duration of intercostal drainage in situ, and radiological improvement by standard x-ray chest. RESULTS: The study revealed increased drainage through intercostal drain in streptokinase group compared to control group. The mean duration of intercostal drainage in situ was shorter in streptokinase group compared to control group. Radiologically, streptokinase group revealed score 3 improvement in eight out of twelve cases and score 2 improvement in rest of the four cases. In control group, score 1 improvement was seen in two out of twelve cases and no improvement was seen in rest of the 10 cases. The observation difference is found to be highly significant statistically (p <0.001). No major adverse effects were noted in the streptokinase group. CONCLUSION: The study concludes the safety, efficacy, reduced hospital stay and decreased morbidity in patients treated with intrapleural streptokinase as compared to control group.

Integrated design of sewers and wastewater treatment plants.

Sewer system design must be integrated with wastewater treatment plant design when moving towards a more sustainable urban wastewater management. This integration allows an optimization of the design of both systems to achieve a better and more cost-effective wastewater management. Hitherto integrated process design has not been an option because the tools to predict in-sewer wastewater transformations have been inadequate. In this study the WATS model--being a new and validated tool for in-sewer microbial process simulations--is presented and its application for integrated sewer and treatment plant design is exemplified. A case study on a Malaysian catchment illustrates this integration. The effects of centralization of wastewater treatment and the subsequently longer transport distances are addressed. The layout of the intercepting sewer is optimized to meet the requirements of different treatment scenarios.

Half saturation constants for nitrate and nitrite by in-sewer anoxic transformations of wastewater organic matter.

A significant breakthrough and progress have been made in the study of the kinetics of microbial transformation in sewers under aerobic and under changing aerobic/anaerobic conditions. Fundamental knowledge on anoxic kinetics of wastewater is still lacking, so it is not now possible to apply an integrated approach to municipal wastewater treatment incorporating sewer networks as a bio-chemical reactor. This paper presents the results of studies on determining half saturation constants for nitrate, KNO3, and nitrite, KNO2, in raw wastewater. The average values of KNO3 and KNO2, determined from experiments conducted on 7 different wastewater samples were found to be 0.76 gNO3-N/m3 and 0.33 gNO2-N/m3 respectively.