Immunotherapy for Alzheimer's Disease: Current Scenario and Future Perspectives.

Alzheimer's disease (AD) is a global health concern owing to its complexity, which often poses a great challenge to the development of therapeutic approaches. No single theory has yet accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD. Therefore, treatment options targeting various molecules involved in the pathogenesis of the disease have been unsuccessful. However, the exploration of various immunotherapeutic avenues revitalizes hope after decades of disappointment. The hallmark of a good immunotherapeutic candidate is not only to remove amyloid plaques but also to slow cognitive decline. In line with this, both active and passive immunotherapy have shown success and limitations. Recent approval of aducanumab for the treatment of AD demonstrates how close passive immunotherapy is to being successful. However, several major bottlenecks still need to be resolved. This review outlines recent successes and challenges in the pursuit of an AD vaccine.

Optimization of the thrombin generation test components to measure potency of factor VIII concentrates.

INTRODUCTION: The thrombin generation test (TGT) is used both as a global haemostasis assay, and to compare activities of coagulation factor concentrates that have been spiked into patient plasma. However, TGT has not been systematically optimized to evaluate factor VIII (FVIII) product potency. AIMS: To improve the sensitivity of TGT to FVIII and allow a comparative analysis of the thrombin generating capacities of FVIII concentrates against reference preparations with known FVIII activity. METHODS: Concentrations of TGT components (analytical variables) were assessed to maximize the linearity and range of responses to the concentration of FVIII. RESULTS: We optimized the range and sensitivity of the TGT assay with respect to FVIII through the addition of FXIa to the assay. Other parameters that were adjusted, i.e. tissue factor (TF), procoagulant lipids and plasma concentrations, did not improve the ability of the assay to measure both high and very low levels of FVIII. In the optimized TF/FXIa-activated TGT assay, all thrombin generation curve parameters were suitable for FVIII quantification, but thrombin peak height and maximal velocity demonstrated better linearity in the desired FVIII range. We found that the optimized TF/FXIa-activated TGT has a wider range of sensitivity to FVIII than a commercially available TGT. Additionally, we demonstrated that the TF/FXIa-activated assay performs adequately by comparing potency measurements of five commercially available FVIII products using TGT and traditional chromogenic and one-stage clotting assays. CONCLUSIONS: The optimized TGT assay can be used to quantify and compare the thrombin generating capacities of FVIII concentrates.

Retained intracardiac spring: an unusual foreign body.

A rare case of a penetrating intracardiac injury due to a ball-point pen in an adult male is reported. The patient presented with a retained metal spring embedded in the interventricular septum without any cardiac defects. A small metal tip of the pen was also present in the left lung. The patient was asymptomatic and without any cardiovascular compromise. The cardiac injury was managed conservatively. At two years after the injury the patient is still asymptomatic.

Repair of parachute mitral valve with multiple ventricular septal defects: a case report and literature review.

A case of parachute mitral valve (PMV) associated with multiple muscular ventricular septal defects (VSDs) is reported in a 16-year-old girl who presented with dyspnea and a cardiac murmur. In addition, there were deformities of the right ear lobe and kyphoscoliosis of the thoracolumbar spine since birth. A preoperative diagnosis was made using two-dimensional and Doppler echocardiography, cardiac catheterization and angiocardiography. PMV was found to be stenotic and mildly regurgitant. At surgery, mitral valvuloplasty, preservation of the native valve apparatus and Dacron patch closure of multiple muscular VSDs was achieved. The latest available case reports in the literature pertaining to PMV and associated deformities have been reviewed.

Closed mitral valvotomy for mitral restenosis: experience in 113 consecutive cases.

The costs of heart operations and the problems related to anticoagulation after prosthetic valve replacement are among the limitations faced by patients in nonindustrialized countries with mitral stenosis caused by chronic rheumatic heart disease. The young age at which these patients are seen also compels the surgeon to preserve the native valve. The least costly and optimal way to achieve this objective is by closed mitral valvotomy. After closed mitral valvotomy, mitral restenosis is commonly encountered. We report here our 10-year experience with operation on 113 consecutive patients with mitral restenosis. Closed transventricular revalvotomy was performed with Tubbs dilator in 105 of 113 patients. Mean age was 343 years, with a male to female ratio of 1:1.5. Most patients were in New York Heart Association functional classes III and IV (74.3% and 19.4%, respectively). Mean interval between first and second valvotomy was 9.4 years, Hospital mortality rate was 2.8%, trivial postoperative mitral regurgitation occurred in 16.1%, and moderately severe regurgitation occurred in 1.9%. Early postoperative systemic embolism occurred in 3.8% of the cases. Moderate to excellent symptomatic improvement was noted in 89.4% of the cases and poor results were seen in 10.2%. Late follow-up of 76 patients ranged from 2 to 10 years (mean 3.8 years), with 39.4% patients in New York Heart Association class I and 50% in class II. Close mitral revalvotomy is thus an economical, simple, and safe palliative procedure that carries good long-term results.

Complete congenital sternal cleft in an adult: repair by autogenous tissues.

We are reporting here a rare case of congenital complete sternal cleft in an adult of 25 years of age, with absent anterior pericardium and "diastasis recti." Successful surgical repair was achieved along with the preservation of the already existing anatomic and mechanical sanctity of thoracic cage, sternal reconstruction, and protection of the underlying heart and great vessels with a good cosmetic result using autogenous tissue i.e., iliac bone and "V-Y" myoplasty of pectoralis major muscles with their functional preservation and correction of associated anomalies.

Triorganosilicon (IV) compounds: synthesis, structural study, and biological activity.

A few coordination compounds of silicon (IV) have been synthesized by the interaction of trimethyl- and triphenyl-chlorosilane with nitrogen-sulphur donor ligands. These compounds are monomeric, as indicated by molecular weight determination, and they behave as nonelectrolytes in dry DMF. From the electronic, infrared, 1H, and 13C NMR spectral results, it has been concluded that in these compounds, silicon is penta-coordinated in a trigonal bipyramidal environment. An assessment of biological activity of these compounds has shown that some of them are very active against P. mirabilis and others against S. viridans bacteria, while all of them show good fungicidal action against F. oxysporum, A. alternata, and A. niger.

Synthesis, characterization, and antitumor properties of some metal complexes of 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones).

Complexes of Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 2,6-diacetylpyridine bis(N4-azacyclic thiosemicarbazones), abbreviated as H2L, have been prepared and characterized by elemental analysis, molar conductance, magnetic moments (300-78 K) and spectral studies. On the basis of these studies, a distorted six-coordinate structure for Fe(L)Cl and a distorted five-coordinate structure for M(L) (M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), or Pt(II] are suggested. The ligands undergo deprotonation and appear to coordinate through the thione sulphur, the imine nitrogen and pyridyl nitrogen. All the ligands and metal complexes were screened for their antitumor activity against P 388 lymphocytic leukemia test system in mice, and it was found that a few of them possess significant activity at the dosages used.

Synthesis, spectroscopic, and antitumor activity of metal chelates of S-methyl-N-(l-isoquinolyl)-methylendithiocarbazate.

Complexes of Mn(III), Fe(III), Fe(II), Co(III), Ni(II), Cu(II), Zn(II), and Pt(II) with S-methyl-N-(l-isoquinolyl) methylendithiocarbazate (N-N-SH) were isolated and characterized by elemental analysis, conductance measurement, magnetic susceptibilities, and spectroscopic studies. On the basis of these studies, a highly distorted, high-spin, chloro-bridged, polymeric octahedral structure for [Mn(N-N-S)Cl2]; a distorted, low-spin, monomeric octahedral structure for [Fe(N-N-S)2]; a distorted, high-spin, octahedral structure for [Ni(N-N-S)2]; and a square-planar structure for [M(N-N-S)X] (M = Ni, Cu, Pt or Zn and X = Cl- or -OAc) are suggested. With Fe(III), the complex [Fe(N-N-S)2][FeCl4] was isolated while the Co(II) was oxidized to yield the Co(III) ion as [Co(N-N-S)2]2[CoCl4]. All these complexes were screened for their antitumor activity against P 388 lymphocytic leukemia test system in mice. Except for Mn(III), Fe(III), and Co(III) complexes, all were found to possess significant activity; the Cu(II) and Zn(II) complexes showed a T/C% value of 160 and 195, respectively, at their optimum dosages.

Synthesis, characterization, and antitumor activity of iron(II) and iron(III) complexes of alpha-N-heterocyclic carboxaldehyde thiosemicarbazones.

Complexes of iron(II) and iron(III) with 1-formylisoquinoline thiosemicarbazone (1-iqtsc-H), 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (4-Me-5-NH2-1-iqtsc-H) and 4-(m-aminophenyl)-2-formylpyridine thiosemicarbazone (4-m-NH2ph-2-pytsc-H) were synthesized and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature down to liquid N2 temperature), and Mössbauer, electronic, and infrared spectral studies. On the basis of these studies, a highly distorted, high-spin, five-coordinate structure for Fe(HL)SO4 (HL = 1-iqtsc-H, 4-Me-5-NH2-1-iqtsc-H or 4-m-NH2ph-2-pytsc-H) and a distorted, low-spin, octahedral structure for Fe(HL)Cl2 are suggested. The EPR spectra of iron(III) complexes show that all have dxy low-spin ground state. All these complexes have been screened for their antitumor activity against the P 388 lymphocytic leukemia test system in mice and have been found to possess significant activity at the dosages employed.

Synthesis, characterization and antitumor properties of some metal complexes of 3- and 5-substituted salicylaldehyde 2-pyridinylhydrazones.

Complexes of Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), and Pt(II) with 3- and 5-substituted salicylaldehyde 2-pyridinylhydrazones (XSPH, X = H, 3-NO2, 3-CH3O, 5-Br, 5-Cl, 5-CH3, or 5-NO2) have been prepared and characterized by elemental analysis, conductance measurements, magnetic moments (300-78 K), and spectral studies. On the basis of these studies a monomeric, high-spin, distorted octahedral structure for Mn(XSPH)2 and Fe(XSPH)2, a dimeric, high-spin, five-coordinate structure for Co(XSBH)Cl, a dimeric, low-spin, five-coordinate structure for Ni(XSPH)Cl and Zn(XSPH)(OAc), and a square-planar structure for M(XSPH)Cl.H2O (M = Cu(II) or Pt(II] complexes are suggested. The polycrystalline ESR spectra of Cu(II) complexes are isotropic and suggest dx2-y2 ground state in square-planar stereochemistry. Mössbauer spectral results indicate distorted octahedral structure for iron(II) complexes. All the metal(II) complexes have been screened for their antitumor activity against P388 lymphocytic leukemia test system in mice and have been found to possess no significant activity at the dosages used.