Is hippocampal atrophy a future drug target?

Hippocampus is the brain structure, vital for episodic and declarative memory. Atrophy of the human hippocampus is seen in a variety of psychiatric and neurological disorders e.g. recurrent depression, schizophrenia, bipolar disorder, post-traumatic stress disorder, epilepsy, head injury, and Alzheimer's disease (AD). Importantly, aging hippocampus also undergoes atrophy. In many instances, for example, AD, the atrophy precedes the development of symptoms while in others, there is a temporal relationship between atrophy and symptomatology. The presence of atrophied hippocampus is one of the most consistent features of many common psychiatric disorders. Several factors contribute to this atrophy. Stress is one of the most profound factors implicated and the mechanisms involve glucocorticoids, serotonin, excitatory amino acids etc. Hippocampal formation as a whole can undergo atrophy or its individual structural components e.g. apical dendrities can exhibit atrophy. Several drugs of unrelated classes have been shown to prevent atrophy indicating heterogenous manner in which hippocampal atrophy is produced. These include, tianeptine (affects structural plasticity in hippocampus and is an effective antidepressant); phenytoin (antiseizure and neuroprotective); fluoxetine (downregulates neurodegenerative enzyme and increases neuroprotective hippocampal S100 beta); lithium (neuroprotective and antiapoptotic); tricyclic antidepressants (increase hippocampal neurogenesis); antipsychotics (reduce hippocampal neuronal suppression); sodium valproate (increases neurogenesis) and mifepristone (antioxidant, neuroprotective and anti-glucocorticoid). Now the most important question is: to what extent does the hippocampal atrophy play a role in the genesis of symptoms of diseases or their progression? And if it does, can we achieve the same degree of prevention or reversal seen in experimental animals, in humans also. An even more important question is: whether the prevention of atrophy would be clinically useful in affecting disease, viz slowing its progression, reducing morbidity, complications or positively affecting the outcome of one or more of its clinically important aspects. If the answer to this is yes, we would have to know at what stage of the disease we use the drugs, dose, duration, follow-up and efficacy. The use of these drugs in the above mentioned conditions can not only test the potential of atrophy as a future drug target, but could also help in learning more about the hippocampus in both health and diseases.     

Mitigation of Oxidation in Therapeutic Antibody Formulations: a Biochemical Efficacy and Safety Evaluation of <Emphasis Type="Italic">N</Emphasis>-Acetyl-Tryptophan and L-Methionine

Purpose

Biotherapeutics can be susceptible to oxidation during manufacturing and storage. Free L-methionine is known to protect methionine residues in proteins from oxidation. Similarly, free tryptophan and other indole derivatives have been shown to protect tryptophan residues from oxidation. N-acetyl-DL-tryptophan was previously identified as a potentially superior antioxidant to tryptophan as it has a lower oxidation potential and produces less peroxide upon light exposure. This study sought to confirm the antioxidant efficacy and safety of N-acetyl-DL-tryptophan and L-methionine as formulation components for biotherapeutic drugs.

Methods

Antibodies were subjected to AAPH and light exposure in the presence of N-acetyl-DL-tryptophan and L-methionine. Oxidation in relevant CDR and Fc residues was quantified by peptide map. In silico, in vitro, and in vivo studies were performed to evaluate the safety of N-acetyl-DL-tryptophan and L-methionine.

Results

Peptide mapping demonstrated that N-acetyl-DL-tryptophan was effective at protecting tryptophans from AAPH stress, and that the combination of N-acetyl-DL-tryptophan and L-methionine protected both tryptophan and methionine from AAPH stress. The safety assessment suggested an acceptable safety profile for both excipients.

Conclusions

N-acetyl-tryptophan and L-methionine effectively reduce the oxidation of susceptible tryptophan and methionine residues in antibodies and are safe for use in parenteral biotherapeutic formulations.

     

MYD88 L265P mutation in intraocular lymphoma: A potential diagnostic marker

Purpose:Vitreoretinal lymphoma (VRL) is the most common intraocular lymphoma (IOL). This can be either primary or secondary to the central nervous system lymphoma. The diagnosis of primary intraocular lymphoma (PIOL) currently relies on clinical diagnosis and cytological analysis of the vitreous or subretinal biopsy. Although most cases are diagnosed without much issue, the limited amount of vitreous fluid, subjectivity in cytological reporting, and special expertise in ocular pathology make the diagnosis challenging. MYD88 L265P mutation has been implicated to have diagnostic utility in PIOL. In this study, we screened consecutive vitreous biopsies for the presence of MYD88 L265P mutation to understand its diagnostic utility compared to conventional cytological analysis.Methods:Cytological analysis and MYD88 L265P mutation by PCR-based sequencing and restriction fragment length polymorphism (RFLP) were carried out on consecutive vitreous and subretinal biopsies collected from 21 patients. The diagnostic utility of the cytology and MYD88 L265P mutation analysis were compared.Results:Out of the 21 patients, 15 had clinical suspicion of having PIOL. Out of these suspected cases of PIOL, nine were confirmed on follow-up, while six were diagnosed as other intraocular pathologies. Diagnostic utility of MYD88 L265P mutation analysis revealed a sensitivity of 88.9%, specificity of 91.6%, positive and negative predictive value of 88.9% and 91.7%, respectively. Diagnostic accuracy of 90.5% was achieved with the mutation analysis that shows the superiority of MYD88 in both ruling in and ruling out PIOL. The diagnostic utility of MYD88 L265P mutation was superior to conventional cytological analysis.Conclusion:The analysis of MYD88 L265P mutation is reliable and efficient in the diagnosis of PIOL.     

Congenital right coronary artery aneurysm with fistula to right ventricle associated with isolated pulmonary valvular stenosis

Congenital aneurysmal dilatation of coronary artery with coronary cameral fistula is rare in childhood. We report an even rarer association of congenital right coronary artery aneurysm and right coronary artery to right ventricle fistula with bicuspid pulmonary valve stenosis and an intact ventricular septum in a 3-year-old child.     

Synthesis and biological evaluation of pyrrole-2-carboxamide derivatives: oroidin analogues

The reaction of pyrrole or dibromopyrrole-2-trichloroacetone with various amines results in the series of novel pyrrole-2-carboxamide bearing aromatic heterocycle or aryl or alkyl groups. Synthesized molecules were evaluated for their in vitro antibacterial activities. Most of the compounds exhibited potent activity against both Gram-positive and negative pathogens.