Onset of small intestinal atrophy is associated with reduced intestinal blood flow in TPN-fed neonatal piglets

Our aim was to determine the speed of onset of total parenteral nutrition (TPN)-induced mucosal atrophy, and whether this is associated with changes in intestinal blood flow and tissue metabolism in neonatal piglets. Piglets were implanted with jugular venous and duodenal catheters and either a portal venous or superior mesenteric artery (SMA) blood flow probe. At 3 wk of age, piglets were randomly assigned to receive continuous enteral formula feeding (n = 8) or TPN (n = 17) for 24 or 48 h. Blood flow was recorded continuously and piglets were given an i.v. bolus of bromodeoxyuridine and (13)C-phenylalanine to measure crypt cell proliferation and protein synthesis, respectively. After 8 h of TPN, portal and SMA blood flow decreased 30% compared with enteral feeding (P < 0.01), and remained near levels of food-deprived piglets for the remaining 48 h of TPN. After 24 h, TPN reduced jejunal inducible nitric oxide synthase (iNOS) activity and protein abundance (P < 0.05), small intestinal weight, and villous height (P < 0.01) compared with enterally fed piglets. Cell proliferation and DNA mass were decreased (P < 0.05) and apoptosis increased (P < 0.05) after 48 h of TPN. Protein synthesis was lower (P < 0.05) after 24 h of TPN, and protein mass was lower (P < 0.05) after 48 h of TPN, compared with enteral feeding. These data indicate that the transition from enteral to parenteral nutrition induced a rapid (<8 h) decrease in intestinal blood flow, and this likely precedes villous atrophy and the suppression of protein synthesis at 24 h, and of cell proliferation and survival at 48 h.     

Congenital thoracic cord segmental amyelia: a rare manifestation of segmental spinal dysgenesis

Segmental spinal dysgenesis (SSD) is a rare congenital abnormality in which a segment of the spine and spinal cord fails to develop properly. We report a case of a 4-year-old female child who was born prematurely with a permanent neurological deficit in the lower limbs and sphincter incontinence. Radiological investigations revealed segmental agenesis of the thoracic spinal cord (D8-D11 vertebral levels) with an associated vertebral bony anomaly. The pathogenesis of this rare form of SSD syndrome is discussed and the relevant literature is briefly reviewed.     

MRI-guided frameless stereotactic percutaneous cordotomy

BACKGROUND: Use of intraoperative myelography as a radiologic guidance for percutaneous cervical cordotomy (PCC) has been superseded by more modern imaging. The only significant advancement in cordotomy techniques over the last 30 years has been CT-guided PCC. The goal of this study was to demonstrate the feasibility of an MRI-guided frameless technique in high cervical cordotomy. METHODS: We describe 6 patients with intractable pain treated using a frameless, MRI-guided, stereotactic, PCC technique in combination with standard physiological localization procedures. Results were compared with those from 32 patients who underwent PCC in the last 5 years using physiological localizing techniques only. RESULTS: Six patients (100%) who underwent the frameless technique had excellent pain relief postoperatively. Patients in the non-stereotactic group, on average, required a higher number of lesions (2.5 vs. 1.2, p < 0.005), and 7 (22%) of these patients had unsatisfactory pain relief following PCC (p = 0.21). Five patients in the non-stereotactic group had weakness postoperatively and 1 had changes in bladder function. Postoperative weakness occurred in 1 patient undergoing the frameless technique. At an average of 6 months of follow-up (range 5-11), excellent pain relief was achieved in 83% (5/6) of MRI frameless PCC patients and 55% (16/29) of standard PCC patients (p = 0.20). CONCLUSIONS: Intraoperative frameless stereotaxy provides surgeons with accurate information that helps to guide the operative approach and precisely tailor the trajectory and depth of the electrode, potentially increasing the safety and efficacy of the operation.     

Major components of the insulin-like growth factor axis are expressed early in chicken embryogenesis,with IGF binding protein ( IGFBP) -5 expression subject to regulation by Sonic Hedgehog

Using whole-mount in situ hybridisation techniques, we have examined the expression of major components of the insulin-like growth factor (IGF) axis in early development of the chicken embryo, including both IGF-I and -II, the type 1 IGF receptor ( IGFR), and two of the IGF binding proteins, ( IGFBP) -2 and -5. We report that these genes fall into two distinct groups with respect to expression pattern, with IGFBP-2 displaying broad overlap of mRNA expression with IGFR and IGF-I during early development, whereas the expression profile of IGFBP-5 most closely resembled that of IGF-II. Comparison between different stages revealed IGFBP-2 mRNA was detected as early as stage 3, whereas IGFBP-5 was first seen at stage 4. In addition, we detected expression domains of IGFBP-5, and to a lesser extent IGFBP-2, which did not overlap with either IGFR or IGF expression patterns. This could indicate IGF independent actions of the IGFBPs during early embryonic development. A striking observation concerning the expression profiles of both IGF-II and IGFBP-5 at early stages of chick embryogenesis is that both these genes are expressed asymmetrically in a pattern similar to that of Sonic Hedgehog (Shh). Furthermore, using cyclopamine, we have demonstrated that IGFBP-5 expression in the early embryo is regulated by Shh. Taken together, these results describe an important role for the IGF system in the very early stages of the developing chicken embryo, and imply that IGFBP-2 and -5 are fundamental developmental factors, with the latter involved in Shh signalling pathways.     

Product-Specific Impact of Viscosity Modulating Formulation Excipients During Ultra-High Concentration Biotherapeutics Drug Product Development

Developing ultra-high concentration biotherapeutics drug products can be challenging due to increased viscosity, processing, and stability issues. Excipients used to alleviate these concerns are traditionally evaluated at lower protein concentrations. This study investigates whether classically known modulators of stability and viscosity at low (<50 mg/mL) to high (>50 – 150 mg/mL) protein concentrations are beneficial in ultra-high (>150 mg/mL) concentration protein formulations and drug products. This study evaluates the effect of arginine monohydrochloride, proline, and lysine monohydrochloride on viscosity and concentratability at different high and ultra-high protein concentrations using a monoclonal antibody, mAbN, formulation as a candidate protein system. The effect of excipients on the viscosity and concentratability (rate and extent) was different at high versus ultra-high protein concentrations. These results highlight that classical excipients in literature known to modulate protein interactions at low protein concentrations and reduce viscosity at high protein concentrations may need to be evaluated at target protein concentrations in a product-specific manner while developing ultra-high concentration biologics drug products.     

Neutrophil Gelatinase–Associated Lipocalin Acts as a Robust Early Diagnostic Marker for Renal Replacement Therapy in Patients with Russell’s Viper Bite–Induced Acute Kidney Injuries

Snakebite-induced acute kidney injury (AKI) is frequently observed in patients following bites from vipers such as Russell’s viper (Daboia russelii) in India. Currently, the levels of serum creatinine are mainly used as a marker to determine the necessity for renal replacement therapy (RRT) (haemodialysis) in severe cases of AKI. However, it takes up to 48 h to ascertain a distinct change in creatinine levels compared to its baseline level upon admission. The time lost between admission and the 48 h timepoint significantly affects the clinical management of snakebite victims. Moreover, early diagnosis of AKI and decision on the necessity for RRT in snakebite victims is critical in saving lives, reducing long-term complications, and minimising treatment costs arising from expensive haemodialysis. Neutrophil gelatinase–associated lipocalin (NGAL) has been recently studied as a robust early marker for AKI in non-snakebite patients. However, its suitability for clinical use in snakebite victims has not been rigorously established. Here, we demonstrate the clinical significance of plasma NGAL as a robust marker for RRT following AKI using a large cohort (309) of Russell’s viper victims without any pre-existing health conditions. NGAL levels upon admission are positively correlated with creatinine levels at 48 h in different stages of AKI. Overall, NGAL acts as a robust early marker to ascertain the need for RRT following Russell’s viper bites. The quantification of NGAL can be recommended as a routine test in hospitals that treat snakebites to decide on RRT at early time points instead of waiting for 48 h to confirm the increase in creatinine levels. The diagnostic use of NGAL in Russell’s viper victims with pre-existing comorbidities and for other vipers should be evaluated in future studies.     

COVID-19 mortality and its risk factors: A single-center observational study

Objectives: To determine COVID-19 mortality and its risk factors in hospitalized patients at of a tertiary care center in north India. Methods: A retrospective observational study was conducted of patients who were hospitalized from May 2020 to January 2021. The in-hospital mortality was assessed, and demographic variables and comorbidities between COVID-19 deaths and survivors were compared. Results: A total of 24000 patients were admitted during the study period, among which 17000 had shown positive results of the RT-PCR test for COVID-19. The total mortality was 329 patients (1.37％), among which 232 (70.52％) succumbed due to COVID-19, and 97 (29.48％) died due to other illnesses. The mean age of the patients was (64.09±16.99) years. The mean age was significantly higher in COVID-19 related deaths [(67.63±13.78) years] as compared to that of the survivors [(60.52±19.5) years] (P<0.001). Compared to COVID-19 survivors, there were more males (72.41％ v.s. 61.5％) and less females (27.59％ v.s. 38.5％) in COVID-19 related deaths (P=0.001). Comorbidities such as hypertension, diabetes mellitus, and chronic kidney disease showed a significant correlation with COVID-19 mortality with an adjusted odds ratio of 2.389 (95％ CI: 1.465-2.982), 3.891 (95％ CI: 2.059-5.392), and 6.358 (95％ CI: 5.675-10.564), respectively. Conclusions: Elderly males with comorbidities have higher risk for mortality related to COVID-19. Ongoing vaccination drive is rightfully prioritised to serve the high-risk category first.     

Real-world assessment of a metered-dose inhaler with integrated dose counter.

Currently available metered dose inhalers (MDIs) do not track the remaining number of doses, indicating the need for a device that accurately monitors medication use. In an open-label study at 37 outpatient centers, patients > or =4 years old with asthma or chronic obstructive pulmonary disease requiring short-acting 32-agonists received two actuations of albuterol hydrofluoroalkane (HFA) [Ventolin HFA: GlaxoSmithKline], 90 microg twice daily, via a novel MDI with an integrated dose counter until all 200 actuations were completed. Concordance between counter readings, diary card-recorded actuations, and canister weights were measured in patients who completed > or =90% of the labeled actuations (n = 224). Adverse events and patient satisfaction were assessed in the intent-to-treat population (n = 268). In 43,865 recorded actuations, 333 counter versus diary discrepancies occurred (discrepancy rate of 0.76%), and 88% of discrepancies were by one to two actuations. Forty-seven percent of patients had no discrepancies. Incidence of the device firing without changes in counter readings was very low (0.09%). Mean expected actuations based on canister weights (184) were slightly lower than mean counter and diary-reported actuations (200 each). At baseline, 62% of patients reported anxiety about not knowing the quantity of medication remaining in their inhaler. On study completion, 92% expressed satisfaction with the dose counter and 92% agreed it would help prevent them from running out of medication. The adverse event profile showed that albuterol HFA was well tolerated. Integrated MDI counters are a useful and reliable tool for tracking a patient's medication supply.