Endoscopic pituitary surgery - a. beginner’s guide

Endonasal endoscopic surgery is now the preferred technique to tackle pituitary tumours. Our paper describes the stepwise endoscopic approach for surgeons embarking on pituitary surgery. It also highlights the common pitfalls encountered during surgery and the ways to avoid them. One must proceed in a gradual step- wise manner starting from simple exposure of the sphenoid sinus to complete endoscopic tumour removal so us to gain the neurosurgeon’s confidence as well as develop our own skills, confidence and ability to tackle complications. We use the endonasal paraseptal trans- sphenoidal approach. Surgery begins with gentle packing between the middle turbinate and septum to expose the anterior sphenoid wall and expose the sphenoid astium. The ostitum is then widened inferiorly and onto the opposite side to expose both sphenoid sinuses. The inter- sphenoid sinus and necessary mucosa is removed to expose the sella. We then use a bone flap technique or punches to open the sella. After incising the dura, tumour is removed with a suction curette. An endoscope holder facilitates the operation. The bone flap is replaced at the end of surgery to reconstruct the sella. This is especially important if a CSF leak is present. Nasal packing is usually not required.     

Two Different Presentations of Sinus of Valsalva Aneurysm

Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly that can be congenital or acquired. We report 2 cases of SVA. The first case involves a 59‐year‐old male presenting with frequent syncope. Echocardiogram revealed a large right SVA obstructing the right ventricular outflow tract (RVOT). The second case involves a 21‐year‐old female presenting with sudden onset chest pain and a continuous machinery murmur. Echocardiogram revealed a ruptured right SVA into the right atrium. Although advanced percutaneous techniques have been implemented in the correction of this anomaly, open‐heart surgery with or without aortic valve replacement remains the treatment of choice.     

Population analyses of sustained-release verapamil in patients: effects of sex,race, and smoking

OBJECTIVE: Our objective was to determine the effects of age, sex, and sustained-release formulation on apparent oral clearance of sustained-release racemic verapamil in patient populations. METHODS: Population pharmacokinetic analyses were performed on data from 186 patients with hypertension, coronary artery disease, or supraventricular arrhythmias who were receiving long-term sustained-release oral racemic verapamil (Covera SR in 105 patients, Calan SR in 67 patients, and other formulations in 14 patients; mean +/- SD dose, 280 +/- 139 mg) for clinical care or as a part of phase III efficacy studies. Of those 186 patients, 135 were men (age, 63 +/- 12 years; ideal body weight, 70.7 +/- 6.6 kg) and 51 were women (age, 60 +/- 17 years; ideal body weight, 53.7 +/- 7.2 kg). Verapamil was measured by HPLC, and population analyses were performed by use of NONMEM software. Sex, age, and formulation were the covariates considered in the population model building. Subgroup analyses of race, smoking, and alcohol consumption were also performed. Significance of covariates was determined by likelihood ratio tests. RESULTS: Sex significantly affected steady-state clearance of oral sustained-release racemic verapamil. Apparent oral clearance of sustained-release verapamil was 23.8 +/- 2.3 mL/min per kilogram in women compared with 18.6 +/- 3.4 mL/min per kilogram in men. Clearance estimates were faster in black subjects compared with white subjects, as well as in smokers compared with nonsmokers. Effects of age, formulation, and alcohol consumption were not detected. CONCLUSIONS: In middle-aged and older patients, apparent oral clearance of sustained-release racemic verapamil was affected by sex (faster in women compared with men), race (faster in black subjects compared with white subjects), and smoking (faster in smokers compared with nonsmokers) but not by age, alcohol, or formulation.     

Comparative Studies of Lamivudine-zidovudine Nanoparticles for the Selective Uptake by Macrophages

The present study investigates the specific drug targeting of anti retroviral drugs, such as lamivudine and zidovudine, after intraperitoneal (i.p) injection by incorporation into polymeric nanoparticles (PNs) and solid lipid nanoparticles (SLNs). Our results showed that Glyceryl Monosterate-Poloxamer 188 SLNs (average diameter of 522.466 nm) showed slow drug release rates (63.18% of lamivudine and 62.37% of zidovudine were released in 12 hrs) among all the SLN formulations. For Poly lactic-co-glycolic acid (PLGA)-Poloxamer 188 PNs (average diameter of 70.348 nm), there were faster release rates of both lamivudine and zidovudine (97% and 94.06%, respectively, in 12 hrs). Tissue distribution studies were carried out in mice and concentrations of drugs in different organs were determined using high performance liquid chromatography (HPLC) after i.p. administration. Glyceryl Monosterate-Poloxamer 188 SLNs and PLGAPoloxamer 188 PNs showed increase in the distribution of lamivudine and zidovudine to liver and spleen when compared to the drugs in solution. Also, Glyceryl Monosterate-P 188 SLNs showed higher concentration of drugs in RES organs than PLGA-P 188 PNs.     

Heme impairs the ball-and-chain inactivation of potassium channels

Fine-tuned regulation of K⁺ channel inactivation enables excitable cells to adjust action potential firing. Fast inactivation present in some K⁺ channels is mediated by the distal N-terminal structure (ball) occluding the ion permeation pathway. Here we show that Kv1.4 K⁺ channels are potently regulated by intracellular free heme; heme binds to the N-terminal inactivation domain and thereby impairs the inactivation process, thus enhancing the K⁺ current with an apparent EC₅₀ value of ∼20 nM. Functional studies on channel mutants and structural investigations on recombinant inactivation ball domain peptides encompassing the first 61 residues of Kv1.4 revealed a heme-responsive binding motif involving Cys13:His16 and a secondary histidine at position 35. Heme binding to the N-terminal inactivation domain induces a conformational constraint that prevents it from reaching its receptor site at the vestibule of the channel pore.A-type K⁺ channels, a family of voltage-gated K⁺ (Kv) channels, play a vital role in the control of neuronal excitability, regulation of presynaptic spike duration, Ca²⁺ entry, and neurotransmitter release (1). One of the prominent features of A-type K⁺ channels is their inactivation, which is mediated by two structurally distinct processes (2, 3). The fast inactivation is initiated by the N-terminal protein structure, thereby termed N-type inactivation, whereas the slow C-type inactivation is related to the pore structure (2, 3). N-type inactivation proceeds according to a “ball-and-chain” mechanism; the positive charges of the N-terminal ball domains bring the structures to the pore domain of the channel and the distal segment of one of the four intrinsically disordered N-terminal ball domains enters the hydrophobic central cavity/vestibule of the inner pore of the channel thus obstructing the flow of K⁺ (2–5).Acute enzymatic or mutational removal of the distal N terminus eliminates N-type inactivation, and in such inactivation-removed channels, intracellular application of peptides corresponding to the N-terminal sequence restores inactivation (4, 6, 7). Structural analysis suggests that the N-terminal inactivation structure needs to be flexible or even intrinsically disordered to reach the receptor in the channel’s cavity (8, 9).“Tuning” of rapid N-type inactivation is an effective way of adapting cells to specific needs. For example, molecular processes affecting the speed and degree of N-type inactivation in Kv1.4 (KCNA4) channels include redox regulation of a cysteine residue in the N-terminal ball structure (C13) (10), protonation of histidine at position 16 (11), interaction with membrane lipids (12), and Ca²⁺-dependent phosphorylation (13). Furthermore, low-molecular-weight compounds affecting N-type inactivation (N-type disinactivators) have been discussed as potential drugs regulating cellular excitability (14).Heme [Fe(II) protoporphyrin-IX] is well known as a protein cofactor, often conferring gas sensitivity as exemplified in hemoglobin, cytochromes, myoglobin, and soluble guanylyl cyclase. In many heme proteins including soluble guanylyl cyclase, heme is bound or coordinated in part by an amino acid sequence typically containing a histidine or cysteine residue, which acts as an axial fifth ligand (in addition to the four bonds provided by the nitrogen atoms of the protoporphyrin-IX ring to the iron center) to the redox-sensitive iron center, and water or a bound gas molecule acts as the sixth ligand (15). However, recent advances revealed a novel role of heme as a nongenomic modulator of ion channel functions, first exemplified for the large-conductance voltage- and Ca²⁺-dependent K⁺ channel (Slo1 BK) (16) and later for the epithelial Na⁺ channel (17). Detailed analysis of the biophysical action of heme [ferrous iron (Fe²⁺)] or hemin [ferric iron (Fe³⁺)] on the Slo1 BK channel demonstrated that hemin is a potent modulator of the allosteric gating mechanism of the channel (18), and mutagenesis studies have indicated the sequence CKACH located in the cytoplasmic C terminus of the channel plays a critical role (16, 19). However, neither for Slo1 BK channels nor for epithelial Na⁺ channels, the interaction of heme with the ion channel protein is structurally resolved. In this study, we found that the fast N-type inactivation of Kv1.4 A-type K⁺ channels is potently modulated by heme/hemin. Furthermore, we provide structural insight into heme interaction with a channel explaining how heme prevents A-type channels from entering an inactivated state.