Mucormycosis: An opportunistic pathogen during COVID-19.

The pandemic of coronavirus disease 2019 (COVID-19) still remains on an upsurge trend. The second wave of this disease has led to panic in many countries, including India and some parts of the world suffering from the third wave. As there are no proper treatment options or remedies available for this deadly infection, supportive care equipment's such as oxygen cylinders, ventilators and heavy use of steroids play a vital role in the management of COVID-19. In the midst of this pandemic, the COVID-19 patients are acquiring secondary infections such as mucormycosis also known as black fungus disease. Mucormycosis is a serious, but rare opportunistic fungal infection that spreads rapidly, and hence prompt diagnosis and treatment are necessary to avoid high rate of mortality and morbidity rates. Mucormycosis is caused by the inhalation of its filamentous (hyphal form) fungi especially in the patients who are immunosuppressed. Recent studies have documented alarming number of COVID-19 patients with mucormycosis infection. Most of these patients had diabetes and were administered steroids for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and were consequently more prone to mucormycosis. Hence, the present review emphasizes mucormycosis and its related conditions, its mechanism in normal and COVID-19 affected individuals, influencing factors and challenges to overcome this black mold infection. Early identification and further investigation of this fungus will significantly reduce the severity of the disease and mortality rate in COVID-19 affected patients.

Functional characterization of the alpha adrenergic receptor modulating the hydroosmotic effect of vasopressin on the rabbit cortical collecting tubule.

To characterize the type of alpha adrenergic receptor, the effects of specific alpha adrenergic agonists and antagonists on antidiuretic hormone [( Arg8]-vasopressin [AVP])-induced water absorption were evaluated in cortical collecting tubules isolated from the rabbit kidney and perfused in vitro. In the presence of AVP (100 microU/ml), net fluid volume absorption (Jv, nanoliters per minute per millimeter) was 1.39 +/- 0.09 and osmotic water permeability coefficient (Pf, X 10(-4) centimeters per second) was 150.2 +/- 15.0. The addition of 10(-6) M phenylephrine (PE), an alpha adrenergic agonist, resulted in a significant decrease in Jv and Pf to 0.72 +/- 0.11 (P less than 0.005) and 69.9 +/- 10.9 (P less than 0.005). The addition of 10(-4) M prazosin (PZ), an alpha adrenergic antagonist, did not cause any significant change in Jv and Pf, which were 0.71 +/- 0.09 (P = NS vs. AVP + PE) and 67.8 +/- 9.5 (P = NS vs. AVP + PE), respectively. In a separate group of tubules, in the presence of AVP (100 microU/ml) and PE (10(-6) M), Jv and Pf were 0.78 +/- 0.17 and 76.1 +/- 18.0, respectively. The addition of 10(-6) M yohimbine (Y), an alpha 2 adrenergic antagonist, resulted in a significant increase in Jv to 1.46 +/- 0.14 (P less than 0.01) and Pf to 157.5 +/- 22.3 (P less than 0.005). Y (10(-4) M) or PZ (10(-4) M) alone did not significantly affect Jv and Pf in the presence of AVP )100 microU/ml). The effect of the natural endogenous catecholamine norepinephrine (NE) on Jv and Pf in the presence of AVP and propranolol (PR) was next examined. Jv and Pf were 1.53 +/- 0.07 and 176.3 +/- 5.2, respectively, in the presence of AVP (100 microU/ml) and PR (10(-4) M). The addition of NE (10(-8) M) resulted in a significant decrease in Jv to 1.19 +/- 0.11 (P less than 0.05) and Pf to 127.0 +/- 11.3 (P less than 0.02). Increasing the concentration of NE to 10(-6) M resulted in a further decrease in Jv and Pf to 0.70 +/- 0.10 (P less than 0.01 vs. NE 10(-8) M) and 68.5 +/- 10.6 (P less than 0.01 vs. NE 10(-8) M), respectively. The inhibitory effect of NE on AVP-induced water absorption was blocked by Y, but not by PZ. The effect of the alpha 2 adrenergic agonist clonidine (CD) on Jv and Pf was also examined. In the presence of AVP (10 microU/ml) Jv and Pf were 1.65 +/- 0.04 and 175.1 +/- 13.1, respectively. The addition of CD (10(-6) M) resulted in a significant decrease in Jv to 1.08 +/- 0.12 (P < 0.01) and Pf to 108.1 +/- 15.4 (P < 0.01). Increasing the concentration of CD to 10(-4) M resulted in a further significant decrease in Jv and Pf to 0.57 +/- 0.13 (P < 0.02 vs. CD 10(-6) M) and 54.7 +/- 13.8 (P < 0.01 vs. CD 10(-6) M), respectively. Similar results were obtained in the presence of AVP (100 microU/ml). The inhibitory effect of CD on AVP-induced water absorption was blocked by Y. CD did not significantly affect Jv and Pf in the presence of 8-bromo adenosine 3',5'-cyclic monophosphate. These studies indicate that alpha adrenergic agonists directly inhibit AVP-mediated water absorption at the level of renal tubule, an effect that can be blocked by specific alpha2 adrenergic antagonists, but not by specific alpha1 adrenergic antagonists. Alpha2 adrenergic stimulation directly inhibits AVP-mediate water absorption at the level of the tubule, an effect that can be blocked by a specific alpha2 adrenergic antagonist. This effect appears to be exerted at the level of activation of adenylate cyclase, since it is absent in the present of cyclic AMP.

Modulation of the hydro-osmotic effect of vasopressin on the rabbit cortical collecting tubule by adrenergic agents.

The effects of catecholamines on antidiuretic hormone ([Arg(8)]-vasopressin [AVP])-induced water absorption were evaluated in cortical collecting tubules isolated from the rabbit kidney and perfused in vitro. In the presence of AVP (100 muU/ml), net fluid volume absorption (J(v), nanoliters per minute per millimeter) was 1.14+/-0.12 and osmotic water permeability coefficient (P(f), X 10(-4) centimeters per second) was 217.3+/-39.9. The addition of the alpha-adrenergic agonist, phenylephrine (PE), in a concentration of 10(-6) M resulted in a significant decrease in J(v) and P(f) to 0.83+/-0.13 (P < 0.001) and 148.8+/-41.8 (P < 0.02), respectively. Increasing the concentration of PE to 10(-5) M resulted in a further decrease in J(v) and P(f) to 0.53+/-0.05 (P < 0.05 vs. PE 10(-6) M) and 88.5+/-9.0 (P 0.05 vs. PE 10(-6) M), respectively. In a separate group of tubules, in the presence of AVP (100 muU/ml) and PE (10(-5) M), J(v) and P(f) were 0.35+/-0.07 and 66.0+/-17.3, respectively. The addition of the alpha-adrenergic antagonist, phentolamine (PH), in a concentration of 10(-6) M resulted in a significant increase in J(v) to 1.07+/-0.19 (P < 0.001) and P(f) to 193.3+/-35.9 (P < 0.005). PH (10(-5) M) alone did not significantly affect J(v) and P(f) in the presence of AVP (100 muU/ml) nor in the presence of 8-bromo adenosine 3',5' cyclic monophosphate (8-BrcAMP). J(v) and P(f) were 1.20+/-0.21 and 174.0+/-25.8, respectively, in the presence of 8-BrcAMP (10(-4) M). We next examined the effect of the beta-adrenergic agonist, isoproterenol (ISO), on J(v) and P(f) in the presence of AVP. J(v) and P(f) were 1.04+/-0.10 and 202.6+/-17.2, respectively, in the presence of AVP (100 muU/ml) and 1.06+/-0.18 and 193.4+/-27.7, respectively, in the presence of AVP (10muU/ml). However, in the presence of AVP in a concentration of 2.5 muU/ml, J(v) was 0.60+/-0.07 and P(f) was 100.7+/-24.7. ISO (10(-6) and 10(-5) M) did not have any significant effect in the presence of the above maximal and submaximal concentrations of AVP. In the absence of AVP, control J(v) was 0.01+/-0.12 and P(f) was 4.6+/-11.0. The addition of ISO at 25 or 37 degrees C did not result in any significant change in J(v) or P(f). These studies indicate that alpha-adrenergic agonists directly inhibit AVP-mediated water absorption at the level of the tubule, an effect that can be blocked by a specific alpha-adrenergic antagonist. This effect appears to be exerted at the level of activation of adenylate cyclase since it is absent in the presence of cAMP. The beta-adrenergic agonists do not directly inhibit or enhance AVP-mediated water absorption at the level of the renal tubule.

Cross-regulation of VPAC2 receptor internalization by m2 receptors via c-Src-mediated phosphorylation of GRK2.

The aim of the study was to examine the mechanisms by which ACh, acting via m2 receptors, regulates GRK2-mediated VPAC(2) receptor desensitization in gastric smooth muscle cells. VIP induced VPAC(2) receptor phosphorylation and internalization in freshly dispersed smooth muscle cells. Co-stimulation with acetylcholine (ACh), in the presence of m3 receptor antagonist, 4-DAMP, augmented VPAC(2) receptor phosphorylation and internalization. The m2 receptor antagonist methoctramine or the c-Src inhibitor PP2 blocked the effect of ACh, suggesting that the augmentation was mediated by c-Src, derived from m2 receptor activation. ACh induced activation of c-Src and phosphorylation of GRK2 and the effects of ACh were blocked by methoctramine, PP2, or by uncoupling of m2 receptors from G(i3) with pertussis toxin. In conclusion, we identified a novel mechanism of cross-regulation of GRK2-mediated phosphorylation and internalization of G(s)-coupled VPAC(2) receptors by G(i)-coupled m2 receptors via tyrosine phosphorylation of GRK2 and stimulation of GRK2 activity.

Low incidence of bovine leukocyte adhesion deficiency (BLAD) carriers in Indian cattle and buffalo breeds.

BLAD is an autosomal recessive genetic disease that affects Holstein-Friesian (HF) cattle worldwide. It is a disease characterized by a reduced expression of the adhesion molecules on neutrophils. The disease is caused by a mutation that replaces adenine at 383 with guanine, which causes an amino acid change from aspartic acid to glycine. Blood samples and a few semen samples were collected from 1250 phenotypically normal individuals, including HF (N=377), HF crossbred (N=334), Jersey (105), other breeds of cattle (N=160) and water buffalo Bubalus bubalis (N=274) belonging to various artificial insemination stations, bull mother farms (BMFs) and embryo transfer (ET) centres across the country. PCR-RFLP was performed to detect a point mutation in CD18, surface molecules of neutrophils. The results indicate that out of 1250 cattle and buffaloes tested for BLAD, 13 HF purebreds out of 377 and 10 HF crossbreds out of 334 appear to be BLAD carriers. In the HF and HF crossbred population, the percentage of BLAD carriers was estimated as 3.23%. The condition is alarming as the mutant gene has already entered the HF crossbred cattle population and therefore, the population of HF and its crossbreds needs regular screening to avoid the risk of spreading BLAD in the breeding cattle population of India.

Lack of carriers of citrullinaemia and DUMPS in Indian Holstein cattle.

The present study investigated the occurrence of 2 autosomal recessive genetic diseases, bovine citrullinaemia and deficiency of uridine monophosphate synthase (DUMPS), in Indian Holstein cattle. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed on a group of 642 animals, mainly HF and HF crossbred cattle, to identify carriers of these diseases. None of the animals were carriers of citrullinaemia or DUMPS. It is possible that with the mounting selection pressure, the international gene pool may diminish, and consequently the risk of dissemination of inherited defects will increase. It is therefore recommended to screen breeding bulls for their breed-specific genetic diseases before they are inducted in artificial insemination programmes, to minimize the risk.

Pseudomonas peritonitis and continuous ambulatory peritoneal dialysis.

In a population of 44 patients receiving continuous ambulatory peritoneal dialysis (CAPD) for a total of 591 patient months, there were 104 episodes of peritonitis. The organisms were gram-positive in 65.4%, gram-negative in 23.1%, and cultures of the dialysate were sterile in 11.5%. Pseudomonas aeruginosa was the most frequently encountered gram-negative organism, accounting for 38.5% of the gram-negative infections or 9.6% of all infections. In all cases of P aeruginosa peritonitis, aminoglycoside antibiotic therapy for up to four weeks failed to eradicate the infection, and all patients required removal of the Tenckhoff catheter because of the presence of a sinus tract infection. We conclude that P aeruginosa is the most frequent cause of gram-negative peritonitis in patients receiving CAPD. The presence of a sinus tract infection should be suspected in all patients in whom peritonitis secondary to this organism develops. Removal of the Tenckhoff catheter will be required to cure the peritoneal infection.

Efficacy of intravenous vancomycin in the treatment of gram-positive peritonitis in long-term peritoneal dialysis.

Peritonitis is the major complication of long-term peritoneal dialysis. Gram-positive bacteria are responsible for two thirds of the total number of peritonitis episodes. Conventional therapy consists of daily administration of antibiotics, either parenterally or intraperitoneally. Vancomycin, an antibiotic with a prolonged half-life in renal failure, has a wide spectrum of activity against gram-positive bacteria and diffuses readily across the peritoneal membrane. In the present study, 82 percent of gram-positive peritonitis episodes were cured following the intravenous administration of vancomycin at weekly intervals. This cure rate compares favorably with that obtained following conventional therapy of peritonitis. It is concluded that intravenous vancomycin is an effective treatment for gram-positive peritonitis in patients undergoing long-term peritoneal dialysis. This form of therapy is convenient, reduces hospitalization, minimizes cost, and avoids possible contamination of the peritoneal dialysate used during the intraperitoneal administration of antibiotics.

Changing concepts in treatment of severe symptomatic hyponatremia. Rapid correction and possible relation to central pontine myelinolysis.

Severe symptomatic hyponatremia (serum sodium level below 120 meq/liter) is often a life-threatening emergency that can result in permanent neurologic damage or death if left untreated. Early recognition and rapid correction to mildly hyponatremic levels by the administration of hypertonic saline are important in order to reduce the potential mortality and morbidity. If the serum sodium level is more than 105 meq/liter, it can be corrected to a value of 125 to 130 meq/liter. However, if the serum sodium level is less than 105 meq/liter, it may be safe to raise the value by only 20 meq/liter. Care should be taken to avoid acute correction to normonatremia or hypernatremia. Moreover, it is also of equal importance to avoid development of hypernatremia in the subsequent days following the correction to mild hyponatremia.

The mechanism of hypercalciuria in streptozotocin-induced diabetic rats.

Metabolic studies were performed in streptozotocin-induced diabetic (D) rats and normal control (C) rats to assess the role of hyperphagia in the hypercalciuria of diabetes. Urinary calcium excretion (UCaV) was significantly higher in D v C rats fed ad libitum. When D rats were pair-fed (calorie and mineral restriction) with C rats, UCaV declined but remained significantly higher than in C rats. When D rats were allowed their usual increased calorie intake but restricted to C rat mineral consumption, UCaV remained elevated. These findings suggested a tubular reabsorptive defect. In vivo microinjection studies were then performed to identify the site(s) of the tubular reabsorptive defect. Using 1.0 mmol/L Ca in the injectate, 45Ca recovery in the urine (CaR%) was significantly higher in D rats after intratubular injections into early and late proximal tubules and late distal but not early distal tubules. An additional load-dependent defect was revealed in the terminal nephron when the Ca concentration of the injectate was increased to 1.8 mmol/L. After early distal injection, CaR% was significantly increased in D v C rats. Infusion of PTH into thyroparathyroidectomized C and D rats enhanced Ca absorption to a similar degree but did not correct the reabsorptive defect in D rats. These results argue against a lack of end-organ responsiveness to PTH in diabetes or a low serum PTH level as the cause of the hypercalciuria. We conclude that hyperphagia contributes to the hypercalciuria of diabetes in the absence of increased Ca intake. Also, two tubular reabsorptive defects exist: one in the loop of Henle; the other, load-dependent in the terminal nephron.(ABSTRACT TRUNCATED AT 250 WORDS)

IgA nephropathy in a patient with ankylosing spondylitis and a solitary kidney.

We describe a patient with ankylosing spondylitis and psoriasis who was found to have IgA nephropathy in a solitary kidney. Renal biopsy demonstrated mesangial proliferation and interstitial nephritis with mesangial deposition of IgA. Although the renal disease and the rheumatic disease could have been present together by chance association, evidence is presented to suggest a possible common pathogenesis.

Rapid correction of severe hyponatremia in the rat: histopathological changes in the brain.

The purpose of the present studies was to examine the effects of rapid correction of severe hyponatremia (serum sodium less than 120 meq/liter) either to mildly hyponatremic levels (serum sodium = 130 meq/liter) or to normonatremic levels (serum sodium = 150 meq/liter) on the brain histology of rats. In group I, 13% of the rats revealed brain lesions following correction to mildly hyponatremic levels by the administration of 855 mM NaCl. All the rats (100%) in group II had brain lesions following correction to normonatremic levels by 24 h of water restriction. Similarly, all the rats in group III showed brain lesions following correction to normonatremic levels by the administration of 855 mM NaCl. Severe hyponatremia by itself did not cause any brain lesions in another group. We conclude that rapid correction of severe hyponatremia to mildly hyponatremic levels by the administration of 855 mM NaCl does not cause significant brain lesions. On the other hand, rapid correction to normonatremic levels either by water restriction or by the administration of 855 mM NaCl results in significant brain lesions.

Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study.

We studied the effects of replacement therapy in two groups of patients with symptomatic hyponatremia. Thirty-three patients, who were studied prospectively, had no evidence of cerebral demyelinating lesions. Their hyponatremia (mean serum sodium concentration [+/- SE], 108 +/- 1 mmol per liter) was increased to 126 +/- 1 mmol per liter with hypertonic saline (856 mM) delivered at a rate of 1.3 +/- 0.2 mmol per liter per hour. The serum sodium concentration did not rise to normal or hypernatremic levels in the first 48 hours of therapy, and none of these patients had a respiratory arrest or other hypoxic episode. Twelve patients, evaluated retrospectively, had evidence of cerebral demyelinating lesions at autopsy or on computerized axial tomography. The rate of correction of hyponatremia (1 +/- 0.2 mmol per liter per hour) was similar to the rate in the patients in Group I. However, at least one of four characteristics was present: an increase in serum sodium to normal or hypernatremic levels in the first 48 hours, a change in the serum sodium concentration of more than 25 mmol per liter in the first 48 hours, a hypoxic-anoxic episode, and an elevation of serum sodium to hypernatremic levels in patients with hepatic encephalopathy. Although these four features were associated with demyelination, our observations suggest that this complication does not depend on the rate of correction of hyponatremia.

Absorption and disposition of ibuprofen in hemodialyzed uremic patients.

The absorption and disposition of ibuprofen was investigated in seven hemodialyzed uremic patients. Ibuprofen (400 mg) was orally administered to each patient 1 hr or 4 hr prior to hemodialysis. Uremic patients appeared to absorb ibuprofen at a slower rate as compared to normal subjects. The hemodialysis systems used in this study yielded a mean extraction efficiency of 16.7% for ibuprofen, with a mean dialysis plasma clearance of 22.7 ml/min. The drug recovery resulting from hemodialysis represented a small fraction of the ingested dose of ibuprofen (less than 4%). The half-life of ibuprofen (1.3-1.9 hr) was not significantly altered by hemodialysis. Observations of extraction efficiency, drug recovery and half-life during dialysis suggested nondialyzability of ibuprofen, probably due to its extensive protein binding (approximately 90%). Uremic patients may require a comparatively longer time to achieve the therapeutic concentration attained in normal volunteers. However, dosage adjustment is not required once a regimen is implemented in uremia.

Symptomatic hyponatremia in rats: effect of treatment on mortality and brain lesions.

Hyponatremia was induced in rats over 3 days with dextrose in water and vasopressin. Eighty-five percent of the rats survived for 5 mo after spontaneous correction of mild hyponatremia. However, spontaneous correction of symptomatic hyponatremia (serum sodium less than 120 meq/l) resulted in 32% survival. Rapid correction of symptomatic hyponatremia by hypertonic saline with an absolute change in serum sodium of greater than 14 and less than 25 meq/l in the first 24 h allowed 100% of the rats to survive for 5 mo without brain lesions. On the other hand, correction of symptomatic hyponatremia with an absolute change in serum sodium of greater than 25 meq/l in the first 24 h resulted in 12% survival and development of brain lesions. We conclude that rapid correction of symptomatic hyponatremia improves survival and is safe if the absolute change in serum sodium is between 14 and 25 meq/l in the first 24 h. Increased mortality and brain lesions are associated with an absolute change in serum sodium of greater than 25 meq/l in the first 24 h.

Microinjection study of renal calcium absorption in the phosphate-depleted rat.

Tracer microinjection studies were performed in chronically phosphate-depleted (CPD) and phosphate-supplemented (PS) rats in order to determine the site of the defect in calcium absorption which developed in CPD. Calcium recovery in the final urine was significantly higher in CPD than in PS rats after microinjections into the early and the late proximal tubules. However, there was no significant difference in the urinary recovery between the two groups after injection into the early and late distal convoluted tubules. The difference in calcium recovery in late proximal studies persisted during PTH infusion. This indicates that there is a defect in calcium absorption in phosphate-depleted rats between late proximal and early distal tubules, which is not correctable with PTH infusion.

Factor XI deficiency in Indian Bos taurus, Bos indicus, Bos taurus x Bos indicus crossbreds and Bubalus bubalis

We investigated the occurrence of Factor XI (FXI) deficiency syndrome in the following Indian dairy animals: Bos taurus Holstein-Friesian and Jersey cattle, Bos indicus Indian cattle breeds, B. taurus x B. indicus crossbreds and the river buffalo Bubalus bubalis. Factor XI deficiency is an autosomal recessive bleeding disorder known to affect Holstein cattle worldwide. A total of 1001 dairy animals, mainly bulls, were genotyped to detect the mutation within exon 12 of the gene encoding for factor XI. Two Holstein bulls were detected as heterozygous (carrier) for FXI deficiency, giving a carrier frequency of 0.6 percent in Indian Holstein cattle. None of the other cattle or buffalo breeds was found to be a carrier for FXI. Sequence comparison between normal and heterozygous animals revealed that there is a 77 base pair insertion fragment (AT (A)29 TAAAG (A)27 GAATTATTAATTCT) within exon 12 of the FXI gene. Both sequences were submitted to the National Center for Biotechnology Information (NCBI) GenBank and assigned the accession numbers DQ438908 for normal Holstein Friesian animals and DQ438909 for heterozygous Holstein Friesian animals.