Hemoglobin solution: Is a normal [Hb] or P50 more important?

Although stroma-free hemoglobin solution (SFH) supports normal levels of oxygen consumption in baboons exchange transfused to zero hematocrit, a significant decrease occurs in the mixed venous oxygen tension ($\text{P}\text{v}\text{O}{}_2$). The hemoglobin concentration (6–8 g%) and P₅₀ (12–17 Torr) are both low in the current SFH preparations, and it is likely that they contribute to the low $\text{P}\text{v}\text{O}{}_2$ values. A multiple linear regression analysis was used to quantitate the contribution of simultaneous changes in [Hb] and P₅₀ to the observed change in $\text{P}\text{v}\text{O}{}_2$ during total exchange transfusion with SFH. During the study the average $\text{P}\text{v}\text{O}{}_2$ decreased from 51.4 to 22.4 Torr; the [Hb] fell from 11.6 to 5.1 g%; and the P₅₀ decreased from 31 to 19.5 Torr. The resulting equation was $\text{P}\text{v}\text{O}{}_2\text{= 4.0[}\text{Hb}\text{] + 0.33 P}{}_{50}\text{- 4.2}$. The equation calculates that the 6.5 g% decrease in [Hb] was responsible for a fall in $\text{P}\text{v}\text{O}{}_2$ of 26 Torr, while the fall in P₅₀ of 11.5 Torr decreased the $\text{P}\text{v}\text{O}{}_2$ only 3.8 Torr. The data suggest that an increased [Hb] should be more effective in raising $\text{P}\text{v}\text{O}{}_2$ than a higher P₅₀. Since a low $\text{P}\text{v}\text{O}{}_2$ is an indication of a reduced oxygen reserve, future efforts should attempt to achieve a hemoglobin solution with a normal [Hb].     

Acid–base physiology: new concepts

The traditional approach to acid–base physiology is based on the Henderson–Hasselbalch equation which is derived from the CO₂/HCO₃⁻${\text{CO}}_2/{{\text{HCO}}_3}^{-}$ buffer system. However, it is becoming increasingly recognized that this is an incomplete analysis as it focuses on only one of the six reactions involving H⁺ and can lead to the incorrect assumption that CO₂ and HCO₃⁻${{\text{HCO}}_3}^{-}$ are independently adjusted factors that ultimately determine pH. In 1983, Stewart, a Canadian physiologist, proposed that a fuller understanding of acid–base physiology required consideration of biological fluids as a complex dynamic system, taking into account the interactions of all the chemical species involved. He showed that the true independent variables controlling the pH of any given fluid compartment are: the difference in the concentration of ‘strong ions’, the total concentration of ‘weak acid’, and the PCO₂. Importantly, H⁺ and HCO₃⁻${{\text{HCO}}_3}^{-}$ are dependent variables and it is incorrect to think of them as being specifically regulated to manipulate pH. This review will discuss the importance of pH homeostasis and highlight the implications of the Stewart approach in our understanding of acid–base control mechanisms and disorders. In particular, the true mechanisms by which the kidney regulates plasma pH will be discussed, emphasizing key misconceptions that have been propagated as a result of the traditional approach.     

Ablation of Osteopontin Improves the Skeletal Phenotype of Phospho1−/− Mice

PHOSPHO1 and tissue‐nonspecific alkaline phosphatase (TNAP) have nonredundant functions during skeletal mineralization. Although TNAP deficiency (Alpl^?/? mice) leads to hypophosphatasia, caused by accumulation of the mineralization inhibitor inorganic pyrophosphate (PP_i), comparably elevated levels of PP_i in Phospho1^?/? mice do not explain their stunted growth, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis. We have previously shown that elevated PP_i in Alpl^?/? mice is accompanied by elevated osteopontin (OPN), another potent mineralization inhibitor, and that the amount of OPN correlates with the severity of hypophosphatasia in mice. Here we demonstrate that plasma OPN is elevated and OPN expression is upregulated in the skeleton, particularly in the vertebrae, of Phospho1^?/? mice. Liquid chromatography/tandem mass spectrometry showed an increased proportion of phosphorylated OPN (p‐OPN) peptides in Phospho1^?/? mice, suggesting that accumulation of p‐OPN causes the skeletal abnormalities in Phospho1^?/? mice. We also show that ablation of the OPN gene, Spp1, leads to improvements in the skeletal phenotype in Phospho1^?/? as they age. In particular, their scoliosis is ameliorated at 1 month of age and is completely rescued at 3 months of age. There is also improvement in the long bone defects characteristic of Phospho1^?/? mice at 3 months of age. Mineralization assays comparing [Phospho1^?/?; Spp1^?/?], Phospho1^?/?, and Spp1^?/? chondrocytes display corrected mineralization by the double knockout cells. Expression of chondrocyte differentiation markers was also normalized in the [Phospho1^?/?; Spp1^?/?] mice. Thus, although Alpl and Phospho1 deficiencies lead to similar skeletal phenotypes and comparable changes in the expression levels of PP_i and OPN, there is a clear dissociation in the hierarchical roles of these potent inhibitors of mineralization, with elevated PP_i and elevated p‐OPN levels causing the respective skeletal phenotypes in Alpl^?/? and Phospho1^?/? mice. © 2014 American Society for Bone and Mineral Research.     

Computation of nash equilibrium pairs of a stochastic differential game

Consider the random motion of two points M_e and M_p in an open and bounded domain D₀ in the plane. Each of the velocities, u = (u₁ u₂)^T of M_e and v = (v₁, v₂)^T of M_p, are perturbed by a corresponding R²-valued Gaussian white noise. Let A and D_c be two disjoint closed subsets of D₀. Suppose that at t = 0, M_e is in A and M_p is anywhere in D₀. Denote by ?₁ and ?₂ the following events: ?₁ = {M_p intercepts M_e in A before M_e reaches the set D_c and before either M_e or M_p has left D₀}, and ?₂ = {M_e reaches the set D_c before being intercepted by M_p, while M_p is in A, and before either M_p or M_e has left D₀}. The problem dealt with here is to find a pair of velocity strategies (u*, v*) such that, in the sense of a Nash equilibrium point, the probabilities Prob(?¹) and Prob(?₂) will both be maximized on a given class of velocity strategies (u, v). Sufficient conditions on (u*, v*) are derived which require the existence of a smooth solution (V,Q) to a pair of coupled non-linear partial differential equations. A finite-difference scheme for solving these equations is suggested, and two examples are treated in detail.     

Relationship Among Radiological Measurements of Anterior Mediastinal Fat and Outcomes of Lung Transplantation in Fibrotic Patients

ObjectiveLung transplantation (LT) for pulmonary fibrosis is related to higher mortality than other transplant indications. We aim to assess whether the amount of anterior mediastinal fat (AMF) was associated to early and long-term outcomes in fibrotic patients undergoing LT.MethodsRetrospective analysis of 92 consecutive single lung transplants (SLT) for pulmonary fibrosis over a 10-year period. AMF dimensions were measured on preoperative CT-scan: anteroposterior axis (AP), transverse axis (T), and height (H). AMF volumes (V) were calculated by the formula: AP × T × H × 3.14/6.According to the radiological AMF dimensions, patients were distributed into two groups: low-AMF (V < 20 cm³) and high-AMF (V > 20 cm³), and early and long-term outcomes were compared by univariable and multivariable analyses.ResultsThere were 92 SLT: 73M/19F, 53 ± 11 [14–68] years old. 30-Day mortality (low-AMF vs. high-AMF): 5 (5.4%) vs. 15 (16.3%), p = 0.014. Patients developing primary graft dysfunction within 72 h post-transplant, and those dying within 30 days post-transplant presented higher AMF volumes: 21.1 ± 19.8 vs. 43.3 ± 24.7 cm³ (p = 0.03) and 24.4 ± 24.2 vs. 56.9 ± 63.6 cm³ (p < 0.01) respectively. Overall survival (low-AMF vs. high-AMF) (1, 3, and 5 years): 85%, 81%, 78% vs. 55%, 40%, 33% (p < 0.001).Factors predicting 30-day mortality were: BMI (HR = 0.77, p = 0.011), AMF volume (HR = 1.04, p = 0.018), CPB (HR = 1.42, p = 0.002), ischaemic time (HR = 1.01, p = 0.009).Factors predicting survival were: AMF volume (HR = 1.02, p < 0.001), CPB (HR = 3.17, p = 0.003), ischaemic time (HR = 1.01, p = 0.001).ConclusionPreoperative radiological assessment of mediastinal fat dimensions and volumes may be a useful tool to identify fibrotic patients at higher risk of mortality after single lung transplantation.     

Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease

Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1–3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1 ^lacZ/+ mice, that expressed β-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1 ^lacZ/lacZ knockout mice. Heterozygous Pkhd1 ^lacZ/+ mice expressed β-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1 ^lacZ/lacZ mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1 ^lacZ/lacZ mice, with pancreatic cysts arising less frequently. The expression of β-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1 ^lacZ/lacZ mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1–3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1 ^lacZ/lacZ mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.     

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Clinical relevance of diffusion tensor imaging parameters in lumbar disco-radicular conflict

PurposeTo measure the fractional anisotropy (FA) and the mean diffusivity (MD) values of L4, L5 and S1 nerve roots using diffusion tensor imaging (DTI) and to correlate them with four different clinical patterns.Patients and methodsFifty-six human participants were prospectively included and divided between four groups: healthy subjects, patients with clinical symptomatic nerve root pain with and without anatomical discoradicular conflict and patients with incidental anatomical discoradicular conflict seen on magnetic resonance imaging (MRI). MRI protocol included anatomical sequences (sagittal T1- and T2-weighted, axial T2-weighted) and a 25 directions DTI sequence. FA and MD values were measured in consensus by two readers and compared between the four groups.ResultsMean FA and MD values were significantly different for patients with clinically symptomatic nerve root pain (n = 27) both with (n = 16) (FA = 0.187 ± 0.015; MD = 510 ± 40) and without (n = 11) (FA = 0.193 ± 0.011; MD = 490 ± 30.5) anatomical discoradicular conflict compared to healthy subjects (n = 29) (FA = 0.221 ± 0.011; MD = 460.9 ± 35.5) including 2 subjects with incidental anatomical discoradicular conflict (FA = 0.211 ± 0.013; MD = 450.8 ± 41.2) on MRI (P = 0.003).ConclusionMeasurement of FA and MD values of L4, L5 and S1 nerve roots using DTI could be useful in lumbar nerve root pain assessment. Further studies with different image processing methods are needed.     

Adjuvant alpha adrenergic blockers: Are they equally efficient for renal and upper ureteral calculi disintegrated by shock wave lithotripsy?

ObjectivesTo evaluate the effects of tamsulosin on stone clearance and analgesic requirements after shock wave lithotripsy (SWL) for solitary renal and upper ureteral calculi.Patients and methodsA prospective randomized placebo controlled study was carried out on 126 patients who underwent SWL for solitary radio-opaque renal or upper ureteral calculi ≤20 mm. Patients were randomized into two groups receiving either 0.4 mg of tamsulosin (GT) or placebo (GP). SWL was performed 3-weekly until patients became stone-free or for a maximum of 3 months. Analgesics were used on demand and pain was evaluated by a visual pain scale.ResultsRenal stones represented 55.6% and 66.7% for GT and GP, respectively (p = 0.27). Mean renal and ureteral stone size were (12.3 ± 1.8 mm vs. 11.5 ± 2.3 mm, p = 0.14) and (9.7 ± 2.6 mm vs. 8.6 ± 1.7 mm, p = 0.1) for the GT and GP, respectively. GT required fewer SWL sessions for ureteral (1.2 vs. 1.6, p = 0.02) and renal stones (1.8 vs. 2.3, p = 0.08). Stone-free rate (SFR) was higher in GT for upper ureteral stones (96.4% vs. 66.7%, p = 0.01) and renal pelvis stones at a cutoff size >10 mm (p = 0.01). The mean time of stone clearance was significantly lower in GT (4.2 ± 1.9 weeks vs. 7.5 ± 2.3 weeks, p = 0.001) for ureteral stones. Attacks of renal colic were more frequent in GP (82.5% vs. 44.4%, p = 0.04) with increased demand for analgesia (p = 0.04). Steinstrasse was recorded in 3 and 7 patients of the GT and GP, respectively (p = 0.32).ConclusionTamsulosin facilitates clearance of upper ureteral stone fragments after SWL and decreases the analgesic requirements. These effects were not similarly evident for renal stones.     

Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection

Multiple morphological abnormalities of the sperm flagella (MMAF) are a rare type of male infertility. Mutations in DNAH1, CFAP43 and CFAP44 are the main aetiology of the disorder. Previously, good intracytoplasmic sperm injection (ICSI) outcomes were reported for MMAF patients with DNAH1 mutations. However, the ICSI prognosis for MMAF patients with CFAP43 or CFAP44 mutations was not known. We designed a retrospective cohort study. Molecular genetic testing identified six MMAF patients with biallelic CFAP44 (CFAP44⁺ group) or CFAP43 mutations and 12 patients with homozygous or compound heterozygous DNAH1 mutations (DNAH1⁺ group). A control group consisted of age‐matched, non‐MMAF men. For MMAF patients carrying CFAP44 mutations, the recorded rates of fertilisation, transferable embryos, pregnancy and delivery after ICSI were 76.47%, 88.46%, 50.0% and 50.0% respectively. The fertilisation rate was significantly higher in the CFAP44⁺ group than in the DNAH1⁺ group (76.47% vs. 54.5%, p = 0.0196). There were no statistically significant differences in the rates of transferable embryos, implantation, clinical pregnancy and miscarriage between the CFAP44⁺ group and either the DNAH1⁺ group or the age‐matched control group. Our results support a good ICSI prognosis for MMAF patients carrying CFAP44 or CFAP43 mutations.     

Intraabdominal Pressure and Gastric Intramucosal pH: Is There an Association?

p = 0.009), sepsis (χ ² = 3.7; p = 0.06), renal impairment (χ ² = 28.3; p = 0.0000001), relaparotomy (χ ² = 4.1; p = 0.04), and death (χ ² = 9.7; p = 0.002). This study demonstrated a significant clinical association between increased IAP and abnormal pHi. An abnormally low pHi was associated with poor outcome.     

An optimal control model for COVID-19, zika,dengue, and chikungunya co-dynamics with reinfection

The co-circulation of different emerging viral diseases is a big challenge from an epidemiological point of view. The similarity of symptoms, cases of virus co-infection, and cross-reaction can mislead in the diagnosis of the disease. In this article, a new mathematical model for COVID-19, zika, chikungunya, and dengue co-dynamics is developed and studied to assess the impact of COVID-19 on zika, dengue, and chikungunya dynamics and vice-versa. The local and global stability analyses are carried out. The model is shown to undergo a backward bifurcation under a certain condition. Global sensitivity analysis is also performed on the parameters of the model to determine the most dominant parameters. If the zika-related reproduction number ${ℛ}_{\text{0Z}}$ is used as the response function, then important parameters are: the effective contact rate for vector-to-human transmission of zika (${\beta }_2^h$, which is positively correlated), the human natural death rate (${\vartheta }^h$, positively correlated), and the vector recruitment rate (${\mathrm{\Psi }}^v$, also positively correlated). In addition, using the class of individuals co-infected with COVID-19 and zika (${ℐ}_{\text{CZ}}^h$) as response function, the most dominant parameters are: the effective contact rate for COVID-19 transmission (${\beta }_1$, positively correlated), the effective contact rate for vector-to-human transmission of zika (${\beta }_2^h$, positively correlated). To control the co-circulation of all the diseases adequately under an endemic setting, time dependent controls in the form of COVID-19, zika, dengue, and chikungunya preventions are incorporated into the model and analyzed using the Pontryagin's principle. The model is fitted to real COVID-19, zika, dengue, and chikungunya datasets for Espirito Santo (a city with the co-circulation of all the diseases), in Brazil and projections made for the cumulative cases of each of the diseases. Through simulations, it is shown that COVID-19 prevention could greatly reduce the burden of co-infections with zika, dengue, and chikungunya. The negative impact of the COVID-19 pandemic on the control of the arbovirus diseases is also highlighted. Furthermore, it is observed that prevention controls for zika, dengue, and chikungunya can significantly reduce the burden of co-infections with COVID-19.     

Morphological imaging and CT histogram analysis to differentiate pancreatic neuroendocrine tumor grade 3 from neuroendocrine carcinoma

PurposeTo compare morphological imaging features and CT texture histogram parameters between grade 3 pancreatic neuroendocrine tumors (G3-NET) and neuroendocrine carcinomas (NEC).Materials and methodsPatients with pathologically proven G3-NET and NEC, according to the 2017 World Health Organization classification who had CT and MRI examinations between 2006-2017 were retrospectively included. CT and MRI examinations were reviewed by two radiologists in consensus and analyzed with respect to tumor size, enhancement patterns, hemorrhagic content, liver metastases and lymphadenopathies. Texture histogram analysis of tumors was performed on arterial and portal phase CT images. images. Morphological imaging features and CT texture histogram parameters of G3-NETs and NECs were compared.ResultsThirty-seven patients (21 men, 16 women; mean age, 56 ± 13 [SD] years [range: 28-82 years]) with 37 tumors (mean diameter, 60 ± 46 [SD] mm) were included (CT available for all, MRI for 16/37, 43%). Twenty-three patients (23/37; 62%) had NEC and 14 patients (14/37; 38%) had G3-NET. NECs were larger than G3-NETs (mean, 70 ± 51 [SD] mm [range: 18 - 196 mm] vs. 42 ± 24 [SD] mm [range: 8 - 94 mm], respectively; P = 0.039), with more tumor necrosis (75% vs. 33%, respectively; P = 0.030) and lower attenuation on precontrast (30 ± 4 [SD] HU [range: 25-39 HU] vs. 37 ± 6 [SD] [range: 25-45 HU], respectively; P = 0.002) and on portal venous phase CT images (75 ± 18 [SD] HU [range: 43 - 108 HU] vs. 92 ± 19 [SD] HU [range: 46 - 117 HU], respectively; P = 0.014). Hemorrhagic content on MRI was only observed in NEC (P = 0.007). The mean ADC value was lower in NEC ([1.1 ± 0.1 (SD)] × 10⁻³ mm²/s [range: (0.91 - 1.3) × 10⁻³ mm²/s] vs. [1.4 ± 0.2 (SD)] × 10⁻³ mm²/s [range: (1.1 - 1.6) × 10⁻³ mm²/s]; P = 0.005). CT histogram analysis showed that NEC were more heterogeneous on portal venous phase images (Entropy-0: 4.7 ± 0.2 [SD] [range: 4.2-5.1] vs. 4.5 ± 0.4 [SD] [range: 3.7-4.9]; P = 0.023).ConclusionPancreatic NECs are larger, more frequently hypoattenuating and more heterogeneous with hemorrhagic content than G3-NET on CT and MRI.     

Joint effect of glutathione S‐transferase genotypes and cigarette smoking on idiopathic male infertility

Inconsistent results of association studies investigated the role of glutathione S–transferase genes in idiopathic male infertility may be explained by ethnical differences in gene–gene and gene–environment interactions. In this study, we investigated a joint contribution of GSTM1, GSTT1 and GSTP1 gene polymorphisms and cigarette smoking to the risk of idiopathic infertility in Russian men. DNA samples from 203 infertile and 227 fertile men were genotyped by a multiplex polymerase chain reaction (GSTM1 and GSTT1 deletions) and PCR‐restriction fragment length polymorphism (GSTP1 I105V) methods. The GSTP1 genotype 105IV was associated with increased risk of male infertility (OR = 1.50 95% CI 1.02–2.20 P = 0.04). Genotype combinations GSTP1 105II/GSTT1 del (G1), GSTM1 del/GSTT1 del (G2) and GSTM1 + /GSTT1 del (G3) were associated with decreased risk of male infertility (P ≤ 0.003), whereas a genotype combination GSTP1 105IV/GSTT1 + (G4) was associated with increased disease risk (P = 0.001). The genotype combinations G3 and G4 showed a significant association with infertility in smokers; however, nonsmokers carriers did show the disease risk. In conclusion, GSTM1, GSTT1 and GSTP1 genes are collectively involved in the development of idiopathic male infertility and their phenotypic effects on the disease risk are potentiated by cigarette smoking.