Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome

Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include the heart and the kidneys which produce a wide range of pro-inflammatory cytokines in response to neurohormones and sympathetic activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and release of pro-inflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular, and renal functions that may negatively impact patients’ outcome. Anti-inflammatory treatment strategies aimed at attenuating end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF and CKD. It may also include specific (short-term) anti-inflammatory treatments that counteract inflammation during the unsettled phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant source of systemic inflammation in the cardiorenal syndrome.     

Cultural adaptation and validation of the “Kidney Disease and Quality of Life - Short Form (KDQOL-SF™) version 1.3” questionnaire in Egypt

Background

Health Related Quality of Life (HRQOL) instruments need disease and country specific validation. In Arab countries, there is no specific validated questionnaire for assessment of HRQOL in chronic kidney disease (CKD) patients. The aim of this study was to present an Arabic translation, adaptation, and the subsequent validation of the kidney disease quality of life-short form (KDQOL-SF^TM) version 1.3 questionnaire in a representative series of Egyptian CKD patients.

Methods

KDQOL-SF^TM version 1.3 was translated into Arabic by two independent translators, and then subsequently translated back into English. After translation disparities were reconciled, the final Arabic questionnaire was tested by interviewing 100 pre-dialysis CKD (stage 1-4) patients randomly selected from outpatients attending the Nephrology clinic at the Main Alexandria University Hospital. Test re-test reliability was performed, with a subsample of 50 consecutive CKD patients, by two interviews 7 days apart and internal consistency estimated by Cronbach’s α. Discriminant, concept, and construct validity were assessed.

Results

All items of SF-36 met the criterion for internal consistency and were reproducible. Of the 10 kidney disease targeted scales, only three had Cronbach’s α <0.7: quality of social interaction (0.23), work status (0.28), and cognitive function (0.60). All disease specific scales were reproducible. Results from discriminant validity showed that the study questionnaire could discriminate between patients’ subgroups. As for concept validity, the correlation between all domains of the questionnaire with overall health ratewas significant for all domains except for the work status, sexual function, emotional wellbeing, and role emotional. Furthermore, the correlation between the disease specific domains and the two composite summaries of SF-36 (physical and mental composite summaries) was significant for all domains except for sexual function with mental composite summary. Construct validity was indicated by the observation that the majority of the domains of the kidney disease targeted scale of KDQOL-SF^TM 1.3 were significantly inter-correlated. Finally, principal component analysis of the kidney disease targeted scale indicated that this part of the questionnaire could be summarized into 10 factors that together explained 70.9% of the variance.

Conclusion

The results suggest that this Arabic version of the KDQOL-SF^TM 1.3 questionnaire is a valid and reliable tool for use in Egyptian patients with CKD.

     

Neglected neck femur fractures in adolescents and young adults: factors predicting the surgical outcome

Background

Neglected femoral neck fracture in young adults is an intriguing problem. This retrospective study tried to solve that challenge through open reduction, cannulated screw internal fixation, autogenous iliac bone and bone marrow grafting.

Methods

Thirty-six cases were studied; they were classified according to Sandhu et al.'s classification. Twenty cases were type I and 16 cases were type II fractures; the mean age was 26.8 years; fracture neglect averaged 44.6 days. Twenty cases had posterior comminution and 16 cases had anterior comminution. All cases had open reduction, cannulated screw internal fixation, autogenous iliac bone and bone marrow grafting. The Harris hip score and Matta et al. grading system were applied for functional and radiological evaluation, respectively.

Results

The average postoperative follow-up was 25.3 months; 94.4 % of the cases had solid union in a mean of 19.6 weeks. Functionally, the Harris hip score averaged 87.8 points. Nonunion, avascular necrosis and coxa vara complicated two, two and four cases, respectively. Fair and poor radiological results were related to coxa vara and avascular necrosis, respectively. Nonunion was significantly related to posterior comminution, type II neglected fracture, and a neglect of more than 45 days. Age groups more than 30 years old and postoperative neck-shaft angles <140° were significantly associated with late-onset radiological healing and nonunion.

Conclusions

Cannulated screw osteosynthesis augmented by autogenous bone and bone marrow grafting is a simple, easy-to-perform surgical procedure with encouraging clinical outcomes for selected patients complaining of that difficult problem.     

Increased median nerve latency at the carpal tunnel of patients with "trigger finger": Comparison of 62 patients and 13 controls

An association between symptomatic compression neuropathy of the median nerve at the carpal tunnel and "trigger finger" has been reported in endocrine and metabolic disorders. We assessed the incidence of increased median nerve latency in subjects with "trigger finger". 62 consecutive patients with "trigger finger" and no signs or symptoms of median nerve compression underwent nerve conduction studies of the median nerve. 13 healthy adults served as controls. 39/62 patients had increased distal motor latency in the median nerve. Only 1 of 13 subjects in the control group had a borderline value of distal motor latency.     

The role of neuroimaging in the evaluation process of children with isolated sixth nerve palsy

Purpose

The purpose of this study was to assess the role of neuroimaging in identifying the etiology of pediatric isolated sixth nerve palsy (SNP).

Methods

A retrospective cohort study was conducted of all patients younger than 18 years of age with an isolated SNP seen at our medical center between 2003 and 2011.

Results

Sixteen children (nine girls; mean age, 4.5 years) with isolated SNP were identified during an 8-year period. Only cases with normal optic disk appearance and otherwise normal neurological examination were included into this study. Thus, 12 other children with SNP were excluded: ten children with papilledema, one child who developed a SNP following a resection of a brain tumor, and one with hydrocephalus and a shunt malfunction. All cases of isolated SNP were unilateral (ten left eyes). The most common cause for the SNP in these children was a tumor that was found in five patients. Other etiologies encountered in decreasing frequencies were: benign recurrent SNP (in four children), postviral or vaccination (in three children), and one case each of post trauma, Chiari malformation, congenital, and undetermined. Children who were found to have a tumor (9.9?±?5.5 years) were significantly older (P?=?0.019) than children who did not have a tumor (2.1?±?1.8 years).

Conclusions

Isolated SNP can be the presentation of a brain tumor in children, and therefore, early neuroimaging of the brain is recommended, especially in older children.     

Dosimetric and radiobiological investigation of permanent implant prostate brachytherapy based on Monte Carlo calculations

PurposePermanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort.Methods and MaterialsA cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose–volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated.ResultsFor the target, D₉₀ (V₁₀₀) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D₉₀ is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D_1cc = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D_1cc = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43.ConclusionsDVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.     

Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development,in-vitro and in-vivo clinical evaluation

Objective: To formulate solid lipid microparticles (SLMs) encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) for the treatment of periodontal diseases.

Methods: SLMs were prepared applying hot homogenization method, using different types of lipids and stabilized with various types and concentrations of surfactants. The optimized formula was subjected to freeze-drying followed by incorporation into poloxamer gel. Microbiological and clinical evaluation of the selected SLMs on patients suffering from periodontal diseases was performed.

Results: SLMs could entrap high percentage of both drugs (81.14% and 68.75 % for doxycycline hydrochloride and metronidazole respectively). Transmission electron microscopy images of SLMs showed nearly spherical particles. Freeze-dried SLMs showed satisfactory stability for three months. Combined drugs were molecularly dispersed in SLMs. Incorporation of the freeze-dried SLMs powder in poloxamer gel could control the drugs release for 72 h. In-vivo study revealed effective and safe use of SLMs gel for periodontitis treatment. Significant improvement in both microbiological and clinical parameters was observed as compared to scaling and root planing alone.

Conclusion: The formulated SLMs gel offers an applicable dosage form that can be injected directly into the periodontal pocket as adjunctive to scaling and root planing.     

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype‐4 chronic hepatitis C patients

The therapeutic effect of pegylated interferon (peg‐IFN) alfa‐2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa‐2a plus ribavirin) for 12 weeks, (n = 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa‐2a (160 μg) subcutaneous once weekly and oral weight‐based ribavirin (1000–1200 mg/day). Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs. 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs. 42/60 (70%); P < 0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. J. Med. Virol. 88:2170–2178, 2016. © 2016 Wiley Periodicals, Inc.

     

Disrupted muscarinic M1 receptor signaling correlates with loss of protein kinase C activity and glutamatergic deficit in Alzheimer's disease

There are few studies on the clinical and neurochemical correlates of postsynaptic cholinergic dysfunction in Alzheimer's disease (AD). We have previously found that attenuation of guanine nucleotide-binding (G-) protein coupling to muscarinic M(1) receptors in the neocortex was associated with dementia severity. The present study aims to study whether this loss of M(1)/G-protein coupling is related to alterations in signaling kinases and NMDA receptors. Postmortem frontal cortices of 22 AD subjects and 12 elderly controls were obtained to measure M(1) receptors, M(1)/G-protein coupling, NMDA receptors as well as protein kinase C (PKC) and Src kinase activities. We found that the extent of M(1)/G-protein coupling loss was correlated with reductions in PKC activity and NMDA receptor density. In contrast, Src kinase activity was neither altered nor associated with M(1)/G-protein coupling. Given the well established roles of neuronal PKC signaling and NMDA receptor function in cognitive processes, our results lend further insight into the mechanisms by which postsynaptic cholinergic dysfunction may underlie the cognitive features of AD, and suggest alternative therapeutic targets to cholinergic replacement.