Hepatitis B surface protein docked vesicular carrier for site specific delivery to liver

The intrinsic liver tropism of liposomes can be augmented by the addition of targeting features such as the incorporation of hepatotropic elements of the hepatitis viruses. Hepatitis B virus is known to infect hepatocytes after viremia by asialoglycoprotein receptor mediated uptake. However, the specificity of hepatitis B virus surface protein (HBsAg) towards hepatocytes has confronting reports. In the present study, we evaluated the functional ability of HBsAg to be employed as a ligand for targeting hepatocytes. We prepared (14)C labeled small unilamellar vesicles (SUVs) composed of egg PC/Cholesterol/N-glutarylphosphatidylethanolamine (NGPE) in a 60:30:10 molar ratio. HBsAg was covalently linked to SUVs using a water-soluble carbodiimide (EDC) mediated conjugation with NGPE. In vitro cell binding and uptake studies revealed that bioprotein docked carrier system was efficiently taken up by HepG2 cells by the receptor mediated endocytosis. The biodistribution behaviour of plain and HBsAg coated liposomes was also examined followed by intravenous injection. The study revealed that almost 75% of the radioactivity was recovered in the liver after 4 h of injection that was nearly three-fold greater in magnitude than the plain liposomes. Further, fractionation of liver into liver parenchymal cells (PC) and non-parenchymal cells confirmed the preferential localization of the HBsAg coated liposomal carrier in the parenchymal cells.     

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers

Rationale N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience.Objective The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion.Methods Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation.Results At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels.Conclusion This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.     

Souter-Strathclyde total elbow arthroplasty in rheumatoid arthritis: medium-term results

We present the outcome of 47 Souter-Strathclyde replacements of the elbow with a mean follow-up of 82 months (12 to 129). The clinical results were assessed using a condition-specific outcome measure. The mean total score (maximum 100) before the operation was 47.21 and improved to 79.92 (p < 0.001). The mean pain score (maximum 50) improved from 21.41 to 46.70 (p < 0.001) and the mean functional component of the score (maximum 30) from 11.19 to 18.65 (p < 0.001). There was negligible change in the score for the range of movement although a significant improvement in mean flexion from 124 degrees to 136 degrees was noted (p < 0.001).Revision surgery was required in four patients, for dislocation, wound dehiscence and early infection in one, late infection in two and aseptic loosening in one. The cumulative survival was 75% at nine years for all causes of failure and 97% at ten years for aseptic loosening alone. Our study demonstrates the value of the Souter-Strathclyde total elbow arthroplasty in providing relief from pain and functional improvement in rheumatoid patients.     

An update on myasthenic crisis

Opinion statement Myasthenia gravis (MG) is the most common disorder of the neuromuscular junction. Myasthenia crisis, defined as respiratory failure requiring mechanical ventilation in MG, is a common life-threatening complication that occurs in approximately 15% to 20% of patients with MG during their life time. The advent of effective mechanical ventilation, specialized neurointensive care units and the widespread use of immunotherapies have substantially altered the prognosis of myasthenic crisis. Early intubation and mechanical ventilation is perhaps the most important step in the management of myasthenic crisis. The authors favor an orotracheal approach for intubation, and placement of small bore duodenal tubes that may help decrease the risk of aspiration and may be more comfortable than regular nasogastric tubes for the patient. Plasma exchange may be more effective than the intravenous immunoglobulin in the treatment of myasthenic crisis involving respiratory failure. A randomized trial is required to confirm the superior efficacy of plasma exchange compared with intravenous immunoglobulin. In the acute setting, the role of immunosuppression and intravenous/intramuscular pyridostigmine and the newer agents such as tacrolimus remains limited and at times controversial. The therapy should be tailored at an individual basis using best clinical judgment.     

Audiological features of GJB2 (connexin 26) deafness

OBJECTIVE: The aim of the present study was to characterize audiological profiles in patients with GJB2 deafness DESIGN: We screened DNA from 399 individuals with nonsyndromic deafness for mutations in the connexin 26 gene (GJB2) by sequence analysis. A total of 77 (19%) of these deaf individuals were biallelic GJB2 mutations (either homozygous or compound heterozygous mutations) (GJB2 deafness). Using the audiological classification criteria of genetic deafness proposed by the European Workshop on Genetic Hearing Loss, we analyzed audiograms of these patients to characterize audiological features of the GJB2 deafness. In addition, we reviewed audiological data of 411 deafness cases from the literature providing details of audiological data (including 157 with GJB2 deafness). RESULTS: All categories of hearing loss severity were found, with significant differences in the findings from GJB2 cases: 1 (4.5%) of 22 individuals with mild hearing loss, 10 (13.3%) of 75 with moderate loss, 14 (14.9%) of 94 with severe loss, and 52 (25%) of 208 with profound deafness (Chi-square test, 3 df, p = 0.016). 81.6% of patients with GJB2 mutations had severe to profound loss, 18.4% with mild to moderate loss (Chi-square test, p = 0.014). The 235delC mutation was always associated with profound deafness. The main audiogram shapes found were residual/sloping (72.7%) and flat (23.4%). There were no differences in the severity and audiogram shapes of the hearing impairment between homozygous and compound heterozygous GJB2 deafness (Chi-square test, p > 0.05). CONCLUSIONS: Our study shows that the probability of finding biallelic GJB2 mutations increases with the severity of hearing loss. Audiograms associated with GJB2 deafness were usually nonspecific. Patients with unknown causes of severe or profound hearing loss should be routinely tested for GJB2 mutations, but due to the variability in hearing loss, individuals with lesser degrees of hearing loss should not be precluded from testing.     

Therapeutic advances in interventional neurology

Rapid advances in the field of interventional neurology and the development of minimally invasive techniques have resulted in a great expansion of potential therapeutic applications. We discuss therapeutic interventional neurology as applied in clinical practice in one of the two possible ways: 1) embolization leading to occlusion of blood vessels; and 2) revascularization leading to reopening of blood vessels. These procedures can be applied to a broad range of cerebrovascular diseases. In the first section of this review, we will explore the evolution of these interventions to occlude aneurysms, arteriovenous malformations, neurovascular tumors, and injuries. In the second section, revascularization in acute ischemic stroke, stenosis, and dural venous thrombosis will be discussed.     

Molecular screening of unculturable bacteria present in men with reproductive failure

Objective  To determine the presence of unculturable bacteria using polymerase chain reaction (PCR) in infertile men with pyosperrmia. Design  Perspective clinical study. Setting  The study took place at the Department of Reproductive Medicine, Owaisi Hospital and Research Center; In vitro Fertilization Unit, Mahavir Hospital and Research Center; Center for Cellular and Molecular Biology; and Bharat Biotech Foundation, Hyderabad, India. Patients  A total of 68 infertile men and 15 donors, all with no symptoms of genito-urinary tract infections and sterile semen cultures were included in the study. Interventions  None. Main outcome measures  Screening bacteria using routine bacterial cultures and PCR based screening with universal eubarterial primers. Results  The statistical analysis of all the semen parameters in asthenazoospermic, azoospermic, ceyptazoospermic, severe oligospermic and mild oligospermic patients were found to be significant compared with the controls. All the groups were found to be significant compared with the controls (P < 0.05) except for volume and pus cells in the cryptozoospermia group. The Student’s t-test also was significant for the seminal parameters before and after treatment of 68 selected individuals with pyospermia and sterile cultures. A total of 44.11% (30/ 68) samples were collected from the negative culture of pyospermic infertile men have shown the presence of bacteria on amplification using PCR with universal eubacterial primers. The DNA was purified and sequenced. The sequences were checked for homology using DNASTAR and Ribosomal Data-Base Project II. A total of 90% of the samples have shown the nearest evolutionary relation to Pantoea P102 (AF394539) and 10% of samples have shown close relation with Burkholderia cepacia (AF042161). Conclusion  The routine bacteriological cultures were unable to detect certain bacterial species particularly with members of enterobacteriaceae family (Pantoea species). Polymerase chain reaction, when used for screening bacteria, can detect the unculturable form of bacteria in infertile men. No amplification for bacterial DNA was obtained in control samples (fertile men with sterile semen cultures.)     

Non-resection approaches for colorectal liver metastases

The field of in situ destruction of liver tumors has expanded rapidly with various institutions' results suggesting that these methods represent viable palliative options, primarily because of the low associated morbidity and mortality. Despite this enthusiasm, clinical trials are needed to determine the true nature and degree of palliation. Treating a systemic disease such as colorectal liver metastases with local therapy strategies alone is of dubious value. In fact, it has been shown by most reports that the limiting factor inpatient outcome is disease progression rather than technical failure. For optimal results, physicians performing in situ ablation of liver lesions should be familiar with tumor biology and the natural history of the malignancy, and possess expertise in proper integration of other therapeutic modalities (eg, systemic chemotherapy and hepatic artery chemotherapy). Patients with liver metastases from colorectal carcinoma should therefore be evaluated for curability by a surgical oncologist within the context of a multidisciplinary team, as surgical resection remains the best treatment to achieve long-term survival. Such an assessment offers the patient the opportunity of a tailored therapy that may consist of hepatic resection, intravenous or regional chemotherapy, and local ablative therapy. Furthermore, results of RF ablation should be reported in terms of well-established oncological outcomes (eg, overall survival, disease-free survival, progression-free survival) that are more meaningful to the patient, rather than lesion-oriented outcomes. Because most of the ablative techniques have not yet been validated, it is imperative that well-designed clinical trials are conducted under the auspices of national cooperative groups. To consider them standard independent therapies otherwise would be premature.