Congenital methemoglobinemia due to NADH-methemoglobin reductase deficiency in three Indian families

Congenital methemoglobinemia is a relatively rare clinical disorder characterized by life-long cyanosis, caused by either an inherited mutant hemoglobin (Hb-M) or deficiency of physiologically active NADH-dependent methemoglobin reductase (NADH-MR). NADH-MR deficiency leads to two different types of recessive congenital methemoglobinemia. In type I, cyanosis is the only major symptom and NADH-MR deficiency is restricted only to the red blood cells. In type II, cyanosis is associated with severe mental retardation and neurological impairment. The objective of this study is to establish the cause of cyanosis in our cases of congenital methaemoglobinemia. Erythrocyte NADH-MR activity was assayed spectrophotometrically. Spectral analysis of the hemolysate treated with potassium ferricyanide was recorded between 400-700 nm and Hb electrophoresis on starch gel at pH 7.0 was done to rule out the presence of Hb-M. NADH-MR deficiency was detected in 3 families. There was a history of consanguinity in one of these cases. The three propositi presented with breathlessness, fever and peripheral cyanosis. There was no history of cardiac illness or exposure to drugs and chemicals. There were no signs and symptoms of mental retardation. The presence of Hb-M was ruled out. Hb-A2, Hb-F, G6PD activity and reduced glutathione levels were normal. NADH-MR activity in all the cases ranged from 4.1 to 9.2 IU/g Hb (normal range 7.0-24.0 IU/g Hb). We describe NADH-MR deficiency in three unrelated cases (age 4 months to 6 years) where the activity of the enzyme was 30-40% of normal. These three cases of congenital methemoglobinemia are due to type-I NADH-MR deficiency without mental retardation.     

Meiotic differentiation during colony maturation in Saccharomyces cerevisiae

As yeast colonies ceased growth, cells at the edge of these colonies transited from the cell division cycle into meiosis at high efficiency. This transition occurred remarkably synchronously and only at late stages of colony maturation. The transition occurred on medium containing acetate or low concentrations of glucose, but not on medium containing high glucose. The repression by high glucose was overcome when IME1 was overexpressed from a plasmid. Experiments with different growth media imply that meiosis in colonies is triggered by changes in the nutrient environment as colonies mature. HAP2 is required to sporulate in any carbon source, whereas GRR1 is required for glucose repression of sporulation. CLN3 is required to repress meiosis in colonies but not in liquid cultures, indicating that the regulators that mediate the transition to meiosis in colonies are not identical to the regulators that mediate this transition in liquid cultures.     

Targeted Delivery of Doxorubicin via Sterically Stabilized Immunoliposomes: Pharmacokinetics and Biodistribution in Tumor-bearing Mice

Purpose. To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice. Methods. DOX-loaded liposomes were prepared with (i) specific monoclonal IgG₃ antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG₃ (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 etc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma. Results. (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing, (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2–4 times more drug into the tumor, (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 >> D-SSL >> D-SSIL-IgG, suggesting that DOX delivered as D-SSIL-32/2 is most available to tumor cells. Conclusions. The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.     

Effect of postoperative chemotherapy and radiotherapy, on the survival of subcutaneously implanted Furth Wilms' tumor

The effect of surgery, postoperative combination chemotherapy and postoperative radiotherapy was evaluated in subcutaneously implanted Wistar/Furth rat Wilms' tumor. Four groups were studied. Group A (controls, no treatment given) had a median survival of 44 days. Group B (surgical excision of the primary tumor on day 14 after implantation) showed a median survival of 77 days, with 40% tumor-free long-term survivors (sacrificed on day 175). Group C (excision followed by chemotherapy consisting of vincristine, actinomycin D and adriamycin) had a median survival of 61 days with 35% tumor-free long-term survivors. Group D received the same postoperative chemotherapy as well as radiotherapy and had 55% tumor-free long-term survivors. This tumor may serve as a treatment model for some human Wilms' tumor cases who do not respond well to current therapies.     

PRIMARY INTRACRANIAL GERM CELL TUMORS: Clinicopathologic Review of 32 Cases

Primary intracranial germ cell neoplasms are rare tumors and constitute a heterogeneous group. We have reviewed 32 cases, over a 21-year period, from the University of Florida. The cases include 22 germinomas, 6 mixed germ cell tumors, and 4 teratomas. The clinical presentations in these cases were more closely related to the location of the tumor, that is, pineal or suprasellar, rather than the histologic subtype. Neuroimaging evaluation was useful in distinguishing between germinomas, teratomas, and other mixed germ cell tumors (MGCTs), primarily by evaluation of cystic versus solid lesions (teratoma versus germinoma), contents of cysts (teratoma versus MGCT), and infiltrative nature of the tumors (MGCT), although cytologic-histopathologic confirmation remains necessary. Germinomas responded favorably to radiation therapy with survival periods of over 16 years; MGCTs were treated with combination chemotherapy and radiation, with a markedly poorer prognosis. This study underlines the critical significance of histopathologic evaluation of the tumor in determining therapeutic interventions as well as prognosis.     

MRI evaluation of fatty liver in day to day practice: Quantitative and qualitative methods

Intracellular fat accumulation is a common feature of liver disease. Steatosis is the histological hallmark of non-alcoholic fatty liver disease (NAFLD) but also may occur with alcohol abuse, viral hepatitis, HIV and genetic lipodystrophies, and chemotherapy. This condition is common in the Western population and is typically associated with obesity and the metabolic syndrome. Early diagnosis and early treatment of NAFLD are important to prevent the development of end-stage liver disease and cancer. In addition, liver fat is a risk factor for postoperative complications after liver resection and transplantation. MRI has become a primary modality to assess hepatic steatosis, both qualitatively and quantitatively. In this article we discuss various MRI methods for evaluation of hepatic steatosis.     

Congenital methemoglobinemia caused by Hb-MRatnagiri (beta-63CAT-->TAT, His-->Tyr) in an Indian family

Hb-M is a very rare hemoglobinopathy in the Indian subcontinent. We report a family with Hb-M with lifelong cyanosis from the Ratnagiri district in western India. The propositus was a 11-year-old female child with a history of increasing cyanosis exacerbated by fever and weakness. Similar complaints were also noted in her mother and five maternal family members. There was no history of cardiac illness or exposure to drugs and chemicals. The methemoglobin level was 39.3% in the propositus and 21.1% in her mother with normal NADH-methemoglobin reductase activity. Abnormal absorption peaks by spectroscopic analysis, presence of hemoglobin instability, and a slow-moving band on starch gel electrophoresis supported the presence of Hb-M. Automated DNA sequence analysis of the beta globin gene showed a C-->T substitution at codon 63. This leads to a substitution of histidine (CAT) by tyrosine (TAT) at the beta 63 (E7) position, similar to Hb-M Saskatoon. We have named this variant as Hb-M(Ratnagiri).     

Pharmacy based surveillance for identifying missing tuberculosis cases: A mixed methods study from South India

BackgroundNo Indian studies have assessed the implementation of recent policy on pharmacy based surveillance and its contribution in TB notification. So, this study was conducted with objectives to describe: a) pharmacy based TB surveillance and TB notification, and b) experiences of pharmacy based surveillance implementation from the programme managers and pharmacists perspective.MethodsA mixed methods study—quantitative (cross-sectional) and qualitative (in-depth interviews) in two selected districts Dharmapuri and Salem districts of Tamil Nadu State, India.ResultsIn 2018, 45 (11%) of 397 pharmacies in Dharmapuri and 90 (6%) of 1457 pharmacies in Salem districts reported sale of anti-TB drugs to 1307 and 1673 persons respectively. Upon validation through direct patient contact 942 (72%) persons in Dharmapuri and 863 (52%) persons were identified as previously ‘un-notified’ TB patients. These patients constituted 20% and 29% of the total TB cases notified in Dharmapuri and Salem respectively. The enablers for implementing this activity were: understanding the importance of notification, availability of resources (manpower, computers) to record, report and validate the patient data, repeated trainings and partnerships. The barriers were: patients' hesitancy to share their details to pharmacists (confidentiality), cumbersome recording and reporting process, difficulties in recording patient details during high workload busy business hours.ConclusionThis process contributed about one-fourth of the TB patients notified in these districts. Its implementation needs to be strengthened and should be scaled up in other parts of the country.