Intussusception in a premature neonate: A rare and often misdiagnosed clinical entity

Intussusception is a very rare cause of intestinal obstruction in neonates. It is of extremely rare occurrence among premature neonates. We present a case of 11-day-old premature neonate who presented with abdominal distension, intolerance to feeds, vomiting, significant bilious aspirate and bleeding per rectum. The initial diagnosis of necrotizing enterocolitis (NEC) led to a delay in the diagnosis. On exploratory laparotomy, it turned out to be a case of ileo-colic intussusception with Meckel''s diverticulum as a lead point. This site of intussusception (ileo-colic) and presence of a lead point among premature neonate is of exceedingly rare occurrence and very few such cases have been reported.In this article, the published work about clinical features and management on intussusceptions in premature neonates has been reviewed. The authors intend to highlight the difficulty in distinguishing the NEC and intussusception. Subtle clinical and radiological features which can help in differentiating the two conditions have been emphasized. This can avoid the delay in diagnosis and management which can prove critical. High index of suspicion with timely intervention is the key for optimizing outcome. A diagnosis of intussusception should always be considered in any preterm infant with suspected NEC.     

Urethral ratio on voiding cystourethrogram: A comparative method to assess success of posterior urethral valve ablation

ObjectiveTo develop a simple, objective and reproducible quantitative measurement to assess success of posterior urethral valve ablation.MethodIn 30 patients with posterior urethral valves the diagnosis was confirmed by voiding cystourethrogram (VCUG). Our protocol was to perform valve ablation, and repeat VCUG at 12 weeks postoperatively. Urethral ratio was calculated by dividing the posterior urethral diameter by the anterior urethral diameter. Thirty males undergoing VCUG for urinary tract infections were evaluated as normative controls.ResultsMedian age of controls was 12 months (2 days–6 years) and of study group was 13 months (1 day–11 years). Mean urethral ratio in pre-fulguration group was 4.94 (±2.97) and in post-fulguration group was 2.134 (±1.19) (P < 0.001). The mean urethral ratio in the control group of 1.73 (±0.577) was significantly different from the pre-fulguration group result (P < 0.001), but not significantly different in comparison to the post-fulguration group (P = 0.104).ConclusionCalculation of urethral ratio on VCUG as a method of assessment of outcome of fulguration is objective, reproducible, and allows preoperative and postoperative VCUG from different facilities to be compared. A post-fulguration urethral ratio of 2.5–3 represents an acceptable result postoperatively.     

Electrically enhanced transdermal delivery of a macromolecule

The purpose of this study was to establish the delivery parameters for the enhanced transdermal delivery of dextran sulfate (MW 5000 Da). Full-thickness pig skin or epidermis separated from human cadaver skin was used. Silver-silver chloride electrodes were used to deliver the current (0.5 mA cm-2). For electroporation experiments, one or more pulses were given using an exponential decay pulse generator. The correct polarity for iontophoresis and pulsing was first established as cathode in the donor. The amount of drug delivered increased with increasing donor concentration up to a point, but not any further. The amount delivered also increased with pulse voltage, the delivery being twice as much as with iontophoresis alone (144.5+/-10.35 microg cm(-2)), when 6 pulses of 500 V were applied at time zero before iontophoresis (276+/-45.2 microg cm(-2)). It was observed that the amount delivered was a function of increasing pulse length when the apparent charge delivered was kept constant. Transport through pig skin (107.4+/-24.4 microg cm(-2)) was found to be comparable with that through human epidermis (84.9+/-18.4 microg cm(-2)). In conclusion, we have demonstrated the transdermal delivery of a 5000 Da molecular weight dextran sulfate using iontophoresis. It was also seen that iontophoretic delivery could be enhanced by simultaneous electroporation.     

Effect of Candida infection on outcome in patients with perforation peritonitis

Perforation peritonitis is treated with surgery and antibiotics. This study was conducted to identify bacterial and fungal microorganisms responsible for peritonitis in patients with hollow viscus perforation and to examine the influence of these microorganisms on the outcome. A prospective study was conducted from May 2005 to September 2006 involving 84 consecutive patients with spontaneous gastrointestinal perforation peritonitis, who were referred for surgery. Peritoneal fluid was analyzed by microbial culture and biochemical tests for bacteria and fungi. The Jabalpur Prognostic Score was calculated. Forty-two of the 84 patients had positive peritoneal fluid cultures. Escherichia coli was the most common bacterium (n=26) and Candida (n=13) the most common fungus isolated. Bacterial isolates were largely sensitive to amikacin while all the Candida isolates were sensitive to fluconazole. Mortality was significantly higher in patients with positive peritoneal cultures (15/42) compared with those with negative peritoneal cultures (0/42, p< 0.001), and in patients with mixed bacterial and fungal-positive cultures (10/13) compared with those with isolated bacterial cultures (5/29, p< 0.001). Using the Jabalpur Prognostic Score, positive fungal cultures were found to be associated with a significantly higher than expected mortality. Patients with gastrointestinal perforations and positive peritoneal cultures have a poor prognosis, which is significantly worsened by the association of positive fungal cultures. Early recognition and treatment of fungal infection is advisable.     

Laparoscopic management of persistent mullerian duct syndrome

Persistent mullerian duct syndrome (PMDS), characterized by the presence of mullerian structures in a virilized male, frequently presents as undescended testis, either intraabdominal or within a hernial sac. We describe a 10-month-old infant with PMDS successfully managed by the laparoscopic approach. At the age of 1.5 months, the patient presented with a left inguinal hernia and bilateral nonpalpable gonads in another center and underwent left inguinal exploration. The uterus and a gonadlike structure along with the hernia sac were found in the inguinal canal. Left inguinal herniotomy was performed after reduction of the uterus and gonadlike structure. No gonadal biopsy was obtained. The patient was further investigated in the same center. His karyotype was 46,XY. Magnetic resonance imaging of the abdomen and pelvis revealed a uterinelike structure posterior to the urinary bladder, but neither testis nor ovaries were visualized. At 10 months of age, he was referred to our department for further management. A laparoscopic single-stage orchiopexy was performed. Both testes were identified and brought to the scrotum by splitting the uterus in the midline and then bringing the testes with the vas and attached uterine tissue into the scrotum. The aim of placement of well-vascularized testes in the scrotum was achieved as confirmed on follow-up color Doppler ultrasound study 6 months postoperatively, which showed normal vascularity. Laparoscopic surgical techniques for this condition are also discussed.     

Transcending the skin barrier to deliver peptides and proteins using active technologies

Peptides and proteins have been investigated as promising therapeutic agents over the past decade. These macromolecules are conventionally administered by the parenteral route because oral delivery is associated with degradation in the gastrointestinal tract. Transdermal delivery presents a promising alternative route of drug delivery, avoiding pain associated with parenteral administration and degradation issues associated with oral delivery. However, the barrier properties of skin limit delivery to only small, moderately lipophilic molecules. Hence, hydrophilic macromolecules like peptides and proteins cannot passively permeate across skin. Active physical enhancement approaches such as iontophoresis electroporation, microneedles treatment, and sonophoresis have been developed to assist transdermal delivery of peptides and proteins. This review describes active physical transdermal enhancement approaches for transdermal delivery of peptides and proteins. The mechanisms associated with each technique and important parameters governing transdermal delivery of peptides and proteins are discussed in detail. Combinations of enhancement techniques for synergistic enhancement in protein and peptide delivery are also discussed.     

Ultrasonic rheology of a monoclonal antibody (IgG2) solution: implications for physical stability of proteins in high concentration formulations

The purpose of this work was to investigate if physical stability of a model monoclonal antibody (IgG(2)), as determined by extent of aggregation, was related to rheology of its solutions. Storage stability of the model protein was assessed at 25 degrees C and 37 degrees C for three months in solutions ranging from pH 4.0 to 9.0 and ionic strengths of 4 mM and 300 mM. The rheology of IgG(2) solutions has been characterized at 25 degrees C in our previous work and correlation of solution storage modulus (G') with protein-protein interactions established. The extent of aggregation was consistent with solution rheology as understood in terms of changes in G' with protein concentration. Thermodynamic stability of native IgG(2) conformation increased with increasing pH. The correlation between rheology and aggregation was also assessed at increased ionic strengths. The decrease in aggregation was consistent with change in solution rheology profile at pH 7.4 and 9.0. The results provide evidence of a relationship between solution rheology and extent of aggregation for the model protein studied. The implications of this relationship for formulation and physical stability assessment in high concentration protein solutions are discussed.     

Protein Structural Conformation and Not Second Virial Coefficient Relates to Long-Term Irreversible Aggregation of a Monoclonal Antibody and Ovalbumin in Solution

Purpose The purpose of the study was to investigate the relationship of the second virial coefficient, B₂₂, to the extent of irreversible protein aggregation upon storage. Methods A monoclonal antibody and ovalbumin were incubated at 37°C (3 months) under various solution conditions to monitor the extent of aggregation. The B₂₂ values of these proteins were determined under similar solution conditions by a modified method of flow-mode static light scattering. The conformation of these proteins was studied using circular dichroism (CD) spectroscopy and second-derivative Fourier transform infrared spectroscopy. Results Both proteins readily aggregated at pH 4.0 (no aggregation observed at pH 7.4); the extent of aggregation varied with the ionic strength and the presence of cosolutes (sucrose, glycine, and Tween 80). Debye plots of the monoclonal antibody showed moderate attractive interactions at pH 7.4, whereas, at pH 4.0, nonlinear plots were obtained, indicating self-association. CD studies showed partially unfolded structure of antibody at pH 4.0 compared with that at pH 7.4. In the case of ovalbumin, similar B₂₂ values were obtained in all solution conditions irrespective of whether the protein aggregated or not. CD studies of ovalbumin indicated the presence of a fraction of completely unfolded as well as partially unfolded species at pH 4.0 compared with that at pH 7.4. Conclusions The formation of a structurally altered state is a must for irreversible aggregation to proceed. Because this aggregation-prone species could be an unfolded species present in a small fraction compared with that of the native state or it could be a partially unfolded state whose net interactions are not significantly different compared with those of the native state, yet the structural changes are sufficient to lead to long-term aggregation, it is unlikely that B₂₂ will correlate with long-term aggregation.     

Imidazolopiperazines: hit to lead optimization of new antimalarial agents

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.     

Synthesis, X-ray analysis, and biological evaluation of a new class of stereopure lactam-based HIV-1 protease inhibitors

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 μM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).