A mathematical model for three-phase-lag dipolar thermoelastic bodies.

In this study we approach a mixed initial-boundary value problem to modeling a three-phase-lag dipolar thermoelastic body. The constitutive laws in this context are given. We establish a uniqueness result and prove a reciprocal theorem. The variational principle obtained in this context is a generalization of the known Gurtin's principle for classical elasticity.

In vivo CT study of carpal axial alignment.

Axial rotation of the carpal bones forms an important component of all wrist movements; however, carpal alignment in the axial plane has somehow not attracted attention. The present study comprised computed tomography (CT) imaging of the wrist joint in 53 asymptomatic volunteers lying prone with the shoulder abducted, elbow flexed and the palm facing down. Axial axes of various carpal bones and the distal radius were drawn and measured. The scaphoid axis was found to be in neutral position in 11%, and supinated in 89% of wrists, with mean of 16 degrees (SD 9 degrees ) while the lunate axis was in neutral position in 17% and supinated in 83% of the wrists with mean of 13 degrees (SD 9 degrees ). The axis for the triquetrohamate joint was found to be 9 degrees pronated (SD 13 degrees ) and 6 degrees supinated (SD 7 degrees ) for the capitohamate joint. Mean values for various carpal angles were 24 degrees, 21 degrees, 3 degrees, 22 degrees and 7 degrees for the radioscaphoid, radiolunate, scapholunate, lunotriquetral and lunocapitate angle, respectively. Examination was repeated in ten volunteers and showed statistically similar values for the various measurements, except the lunotriquetral angle. The present study provides a reference database of normal anatomy for carpal axial alignment. Its potential applications include identifying abnormal axial alignment of the carpal bones that may occur in various pathological conditions affecting the wrist joint, and also quantification of normal and abnormal axial motion of the carpal bones.

Sodium valproate in the management of painful neuropathy in type 2 diabetes - a randomized placebo controlled study.

OBJECTIVE: To study the effectiveness and safety aspects of sodium valproate in the management of painful neuropathy in patients of type 2 diabetes mellitus. MATERIAL AND METHODS: A randomized double-blind placebo controlled trial of sodium valproate was done in type 2 diabetic patients to assess its efficacy and safety in the management of painful neuropathy. We screened 60 patients but eight patients could not complete the study; hence, the present study was done on 52 patients. Each patient was assessed by clinical examination, pain score by short form of the McGill pain questionnaire (SF-MPQ) and electrophysiological examination, which included motor and sensory nerve conduction velocity, amplitude and H-reflex initially and at the end of 1 month of treatment. RESULTS: Significant improvement was noticed in the pain score of patients receiving sodium valproate in comparison to patients receiving placebo at the end of 1 month (P < 0.05). The changes in electrophysiological data were not significant. The drug was well tolerated by all patients except one who developed a raised aspartate transaminase (AST)/alanine transaminase (ALT) level after 15 days of treatment. CONCLUSION: Sodium valproate is a well-tolerated drug and provides significant subjective improvement in painful diabetic neuropathy. These data provide a basis for future trials of longer duration in a larger group of patients.

Pilomatrixoma of the head and neck in children.

OBJECTIVE: Pilomatrixomas are benign skin neoplasms of hair follicle origin. They are one of the most common superficial masses of the head and neck excised in children. Although the entity has been well studied in the literature, few studies have been undertaken to evaluate the clinical characteristics of head and neck pilomatrixomas specifically in children. The purpose of this study was to review the clinical characteristics and management of children presenting with pilomatrixomas of the head and neck at a large tertiary care pediatric hospital. STUDY DESIGN: A retrospective chart review was performed of all patients with histologically confirmed pilomatrixoma of the head and neck excised during a 6-year period (1992-1997) at the Children's Hospital of Philadelphia. RESULTS: Ninety-one cases of pilomatrixoma were confirmed in 86 patients. The age range was 5 months to 17 years. The median age at time of excision was 6.0 years. The most common sites of occurrence were the cheek (36%), neck (20%), periorbital region (14%), and scalp (9%). The male to female ratio was 1:1.5. Multiple lesions were found in 8.2% of patients. Surgical excision was curative in all cases. CONCLUSION: Pilomatrixoma is a cutaneous neoplasm that is one of most common causes of superficial head and neck masses in children. Although the presurgical diagnosis may be difficult in some cases, pilomatrixoma must be kept in the differential of superficial head and neck masses in children. Surgical excision is almost always curative.

Reduced cellular transport and activation of fluoropyrimidine nucleosides and resistance in human lymphocytic cell lines selected for arabinosylcytosine resistance.

Arabinofuranosylcytosine (araC) resistant H9-araC0.05 and H9-araC0.5 sublines were obtained following in vitro exposure of H9 cells to 0. 05 and 0.5 microM araC, respectively. These cell lines were 83.3- and 266.7-fold, 21- and 80-fold, and 2.4- and 4.0-fold more resistant to 5-fluorouridine (FUR), 5-fluoro-2'-deoxyuridine (FdUR), and 5-fluorouracil (FU), respectively. Compared with H9 cells, the cellular accumulation of FUR was 2.2 and 0.2%, FdUR 15.6 and 0.9%, and FU 56.9 and 66.5% in H9-araC0.05 and H9-araC0.5 cells, respectively. An araC resistant HL60 cell line (promyelocytic cell line) was 5.0- and 1.7-fold resistant to FUR and FdUR, respectively, but displayed no resistance to FU. The lower FUR and FdUR nucleotide levels in the resistant cells were a result of reduced cellular transport and uridine kinase (UR kinase) and thymidine kinase (TK) activities. Compared with the parental cell line, the p-nitrobenzyl thioinosine (an inhibitor of nucleoside transport) binding sites also were lower in the araC resistant cells. There was no difference in the expression of multidrug-resistant protein and thymidylate synthase mRNA in the parental and the resistant cell lines. Data presented here suggest that araC exposure of H9 cells, in addition to araC resistance, induced/selected cells that were resistant to FUR and FdUR. These cells had altered cellular drug transport and lower TK and UR kinase activities. Further studies to understand molecular mechanisms of this phenomenon are warranted.

Azidothymidine and interferon-alpha induce apoptosis in herpesvirus-associated lymphomas.

Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human herpesvirus type 8 required IFN-alpha to potentiate AZT-induced apoptosis. IFN-alpha did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated significantly higher intracellular AZT monophosphate than did resistant lymphomas. Our data demonstrated distinct apoptotic responses to AZT and IFN-alpha in herpesvirus-associated lymphomas. EBV-positive BL cells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN-alpha to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfected with BCL-2 became resistant. Susceptibility to antivirus-mediated apoptosis may be exploited to improve the therapy of certain herpesvirus-associated lymphomas.

Cross-resistance of dideoxycytidine-resistant cell lines to azidothymidine.

2',3'-Dideoxycytidine (ddC) and azidothymidine (AZT) inhibit HIV-1 replication and currently are used in AIDS therapy. Long-term use of the drugs is associated with the selection of drug-resistant HIV strains, thus limiting their effectiveness. Another mechanism, associated with their altered metabolism in host cells, also can cause "cellular" drug resistance. Human lymphocytic H9 cell lines (H9-ddC0.5w and H9-ddC5.0w) selected for ddC resistance by exposure to 0.5 and 5.0 microM ddC were found to be cross-resistant to AZT. Compared with controls, the thymidine kinase (TK) activities in H9-ddC0.5w and H9-ddC5.0w cells were 56.7 and 51.4% (with thymidine as a substrate) and 50.3 and 42% (with AZT as a substrate). Consequently the cellular incorporation of AZT and thymidine (24-hr incubation) also was reduced to 51.3 and 70.0% in H9-ddC0.5w cells and to 12.1 and 17.3% in H9-ddC5.0w cells. A 3-hr incubation with 25 microM AZT and ddC decreased their cellular incorporation to 50.5 and 76.15% in H9-ddC0.5w cells and to 12.95 and 47.8% in H9-ddC5.0w cells compared with H9 cells. Thus, the change in AZT accumulation did not correlate exactly with the decrease in TK activity and far exceeded the effect on ddC accumulation. Evidence is presented that ddC, in addition to deoxycytidine kinase, affected TK1 activity. The involvement of multidrug resistance proteins in the mechanism of the resistance was ruled out by the failure of trifluoperazine and verapamil to alter cellular accumulations of AZT, ddC, daunorubicin, and rhodamine-123. Development of cellular ddC and AZT cross-resistance may affect the therapeutic efficacy of these antiviral agents.

Collateral resistance of a dideoxycytidine-resistant cell line to 5-fluoro-2'-deoxyuridine.

Exposure of a human lymphocytic cell line, H9 cells, to 0.5 microM and 5.0 microM dideoxycytidine (ddC) resulted in isolation of ddC-resistant H9-ddC0.5w and H9-ddC5.0w cell lines. In addition, these cell lines were also resistant to azidothymidine and had reduced deoxycytidine kinase and thymidine kinase activities. We now show that these cell lines are 4-fold and 2000-fold collaterally resistant to 5-fluoro-2'-deoxyuridine (FdUR), respectively, but not to 5-fluorouracil (FU). Biochemical evaluations show that, compared to the parental cells, the FdUR phosphorylation was reduced to 36.3% and 9.2% and the FdUMP levels were decreased to 48.1% and 1.2% in these cell lines. Taken together, the data suggest that ddC, an antiviral agent, is capable of inducing resistance to FdUR-a drug that is not its analog and which has a different metabolism, target site, and mechanism of action.

Decreased parotid saliva gustin/carbonic anhydrase VI secretion: an enzyme disorder manifested by gustatory and olfactory dysfunction.

BACKGROUND: Taste and smell dysfunction has been reported to occur in patients with a variety of clinical problems. We wanted to investigate a specific group of patients in whom taste and smell dysfunction occurred putatively related to a specific biochemical abnormality in a salivary growth factor [gustin/carbonic anhydrase (CA) VI] considered responsible for maintenance of taste bud function. METHODS: Eighteen patients developed loss and/or distortion of taste and smell after an acute influenza-type illness. They were evaluated clinically, by psychophysical tests of taste and smell function, by measurement of parotid salivary gustin/CAVI by a radioimmunoassay and by measurement of serum, urine, and salivary zinc. Biopsies of circumvallate papillae were obtained in 6 patients and examined by transmission electron microscopy. Similar studies were performed in 55 asymptomatic volunteers with biopsies of circumvallate papillae performed in 4. RESULTS: Taste and smell acuity were impaired in patients compared with healthy volunteers and parotid gustin/CAVI, salivary, and serum zinc concentrations were lower in patients than in healthy volunteers. Taste buds in circumvallate papillae of patients exhibited severe vacuolization, cellular degeneration, and absence of dense extracellular material. CONCLUSIONS: These results describe a clinical disorder formulated as a syndrome of hyposmia (decreased smell acuity), hypogeusia (decreased taste acuity), dysosmia (distorted smell function), dysgeusia (distorted taste function), and decreased secretion of parotid saliva gustin/CAVI with associated pathological changes in taste bud anatomy. Because gustin/CAVI is found in humans only in parotid saliva and has been associated with taste bud growth and development these results suggest that inhibition of synthesis of gustin/CAVI is associated with development of taste bud abnormalities and thereby loss of taste function.

Efficacy of exogenous oral zinc in treatment of patients with carbonic anhydrase VI deficiency.

BACKGROUND: We previously described a disorder in 18 patients with decreased parotid saliva gustin/carbonic anhydrase (CA) VI secretion associated with loss of taste (hypogeusia) and smell (hyposmia) and distorted taste (dysgeusia) and smell (dysosmia). Because gustin/CAVI is a zinc-dependent enzyme we instituted a study of treatment with exogenous zinc to attempt to stimulate synthesis/secretion of gustin/CAVI and thereby attempt to correct the symptoms of this disorder. METHODS: Fourteen of the 18 patients with this disorder completed the study. They were treated with 100 mg of exogenous zinc daily for 4 to 6 months, in an open clinical trial. Both before and after treatment, measurements were obtained of parotid saliva gustin/CAVI, parotid saliva, serum and urine zinc, taste and smell function, and, in some patients, examination of circumvallate taste buds by electron microscopy. RESULTS: Treatment success was predicated upon significant increases in parotid saliva gustin/CAVI. This occurred in 10 of the 14 patients who were labeled responders; they also exhibited improvement in taste and smell acuity, a diminution in dysgeusia and dysosmia and increased zinc concentrations in parotid saliva, serum, and urine. Taste bud morphology returned to normal in each responder in whom it was measured. No increase in gustin/CAVI occurred in 4 patients who were labeled nonresponders; they exhibited no improvement in taste or smell acuity and no increases in parotid saliva zinc. However, serum and urine zinc increased to levels similar to those measured in the 10 responders. Two of 4 nonresponders reported diminution in dysgeusia and dysosmia. Taste bud morphology did not change from the abnormal state in the 1 nonresponder in whom it was measured. CONCLUSIONS: Zinc treatment is effective in patients in whom this trace metal increases synthesis/secretion of gustin/CAVI and ineffective in those in whom it does not. Increased gustin/CAVI in this disorder is probably associated with zinc stimulation of the gene responsible for the synthesis/secretion of gustin/CAVI. Among nonresponders, zinc was ineffective for several possible reasons, including resistance to zinc and possible sialylation of gustin/CAVI, which may render it functionally ineffective. Results suggest the hypothesis that gustin/CAVI is a trophic factor that promotes growth and development of taste buds through its action on taste bud stem cells.

Effects of basic fibroblast growth factor on irradiated porcine skin flaps.

OBJECTIVE: To determine the vascular and collagen effects of supplemental basic fibroblast growth factor (bFGF) in irradiated porcine skin flaps. INTERVENTION: Animals were subjected to 2 fractions of 650 cGy orthovoltage radiation. Following this, the skin flaps were administered bFGF intracuticularly for 6 days before and after surgery. The animals were sacrificed 3 weeks after the start of bFGF administration. Tissues were analyzed for vascularity, collagen content, wound-breaking strength, and histopathological analysis. RESULTS: The bFGF-treated flaps showed a 62% increase in vascularity compared with controls (10.4%+/-2.4% vs 6.43%+/-2.27%; P<.05). The bFGF flaps had a significantly lower collagen concentration compared with control flaps when measured by hydroxyproline content (0.0619+/-0.0211 nm/microg vs 0.0784+/-0.0150 nm/microg). Wound-breaking strength was not significantly different, although the bFGF flaps had a trend toward lower breaking strength. Histologically, the bFGF-treated flaps showed increased cellularity, fibroblasts, and extracellular mucopolysaccharides compared with controls. CONCLUSIONS: This study provides evidence that supplemental bFGF can increase vascularity to skin flaps in previously irradiated porcine skin tissue. Histologically, radiation did not prevent the angiogenic effect of bFGF.

Herpes zoster and post-herpetic neuralgia--a clinical trial of aspirin in chloroform for anodyne.

Pain associated with Herpes Zoster (HZ) and Post-herpetic Neuralgia (PHN) has been a challenging task to manage with ease. Topical aspirin dissolved in chloroform is an effective means of reducing pain due to HZ and PHN in most patients. The locus of pain origin and analgesia induced by topical aspirin is supposed to be at cutaneous free nerve ending pain receptors. The present study was conduced in fifty two patients of HZ and PHN. Pain intensity before and after the application of drug was measured with help of Sort Form McGill Pain Questionnaire (SE-MPQ). Most of the patients experienced relief of pain within 1-5 minutes after the aspirin-chloroform application. Maximum relief was achieved in about 30-40 minutes and persisted for 5-6 hrs. In the beginning 3-4 applications were required but frequency decreased gradually as the pain abated.

Effect of enalapril therapy on ventilatory pulmonary function tests in hypertensive patients.

Fifty newly diagnosed nonsmoker patients suffering from mild to moderate hypertension (diastolic BP 90 to 114 mmHg), randomly selected and not having respiratory or other systemic diseases which may affect pulmonary functions were subjected to thorough interrogation and clinical examination. Twenty five normal age and sex matched healthy volunteers served as control. All patients and controls were subjected to ventilatory pulmonary function tests (VPFT), done by computerized spirometer. Hypertensive patients were put on oral enalapril, doses were titrated and maintained on 2.5 to 10 mg once daily. Twenty percent of the total hypertensive patients reported mild to moderate dry cough and was more frequently observed among females (27%). Significant decline was observed in MEF 50% and MEF 25% of vital capacity values (p 0.0204 and 0.0001) after 10 days of enalapril therapy. These two VPFT parameters showed significantly higher decline among patients who developed cough as compared to patients who did not develop cough. Decline in VPFT parameters were directly related to doses of enalapril.

Exercise induced proteinuria as an early indicator of diabetic nephropathy.

Diabetic nephropathy is a life threatening microvascular complication of diabetes characterized by presence of proteinuria and progressive impairment of renal function. This study was carried out on 25 patients of diabetes mellitus and 25 healthy individuals who served as controls. All the persons were asked to perform certain programmed amount of exercise and protein excretion rates were measured in urine collected over following three periods: just before exercise, just after exercise and one hour post exercise. It was observed that basal urinary protein excretion rate as well as exercise induced urinary protein levels were significantly higher in diabetics than in control (p < 0.001). Values were significantly higher in uncontrolled diabetes as compared to those with good metabolic control. Urinary protein values were also related to the duration of diabetes. Higher values were observed in patients having diabetes of more than 5 years as compared to those with less than 5 years duration. This test is good and easy to perform for early detection and management of diabetic nephropathy which is essential to reduce long term morbidity and mortality in diabetics.

Severe and complicated malaria in Bikaner (Rajasthan), western India.

Severe and complicated malaria is an important cause of mortality in Plasmodium falciparum infection. We describe in this study the details of 532 cases of such syndromes admitted to hospital during an outbreak of malaria between September-December 1994. Increase in the annual rain fall, collection of water around Indra Gandhi Canal, forestation of shrubs around it and migration of labor, adaptation of Anopheles stephensi to desert climate and favorable breeding of An. culicifacies in the areas under impact of irrigation were presumptive causes of the outbreak in this region. Cerebral malaria (25.75%), hepatic involvement (11.47%), spontaneous bleeding (9.58%), hemoglobinuria (7.89%), severe anemia (5.83%), algid malaria (5.26%), ARDS (3%) and renal failure (2.07%) were the important manifestations. The overall mortality was 11.09%, which was high because of infection in the non-immune population of this area. Ignorance about the severity of this disease and lack of transportation facility was another important factor. Morality was highest in ARDS (81.25%) followed by severe anemia (70.97%), algid malaria (46.43%), renal failure (45.45%), jaundice (36.06%) and cerebral malaria (33.57%). Pregnancy was an important determinant increasing the mortality in female patients. Mortality was very high (82.35%) in those persons who presented with more than 3 syndromes together.

Genotoxicity and mitochondrial damage in human lymphocytic cells chronically exposed to 3'-azido-2',3'-dideoxythymidine.

AZT (3'-azido-2',3'-dideoxythymidine), the first nucleoside analog approved for the treatment of AIDS (acquired immunodeficiency syndrome), induces significant toxic effects in humans exposed to therapeutic doses. As an inhibitor of the HIV-1 (human immunodeficiency virus 1) reverse transcriptase, AZT blocks the incorporation of nucleotides into the host's newly synthesized DNA. Incorporation of AZT into mammalian DNA as well as specific localization of the drug into telomeric DNA, has been previously documented by immunohistochemistry. As with other nucleoside analogs, AZT has affinity for polymerase-gamma, the enzyme responsible for the replication of mitochondrial DNA. In order to examine the mechanisms of toxic events induced by long-term AZT exposure, human T-lymphocytic H9 cells were cultured with 25 microM AZT for 7 months. In the resulting H9-AZT cells, incorporation of AZT into DNA was demonstrated by radioimmunoassay and immunohistochemistry, chromosomal aberrations and micronuclei were scored and intracellular lipid distribution was determined. Two pmol of AZT per microgram of DNA were detected by radioimmunoassay in H9-AZT cells. Control cells showed negative values in the radioimmunoassay. Cytogenetic observations on H9-AZT cells showed an increase in chromosomal aberrations and nuclear fragmentation when compared with unexposed H9 cells. Electron microscopy revealed mitochondrial damage and an elevated accumulation of neutral intracellular lipid deposits probably as a consequence of a distortion in the beta-oxidation of fatty acids normally carried out by this organelle. The toxicities explored here suggest that the mechanisms of AZT induced cytotoxicity in bone marrow of the patients chronically exposed to the drug in vivo may involve both chromosomal and mitochondrial DNA damage.

Association of cerebral palsy with epilepsy.

Fifty patients of various types of cerebral palsy were studied to find out an association between cerebral palsy, EEG abnormalities and development quotient. Seventy-six per cent patients had spastic cerebral palsy. Hypotonic cerebral palsy was the next common type (14%). Athetosis and ataxic forms were found to be rare (2% each). Epilepsy was associated with 56% patients. Clinical types of seizures observed were: Generalised tonic-clonic (43%), myoclonic (17.9%), generalised tonic (10.7%), partial simple (10.7%) and partial complex (17.9%). The incidence of seizures was highest in hypotonic type in which 85.7% had epilepsy. Mean developmental quotient of cerebral palsy patients was 34.9% with maximum retardation in hypotonic cerebral palsy (25.14%). Sixty per cent of patients had abnormal EEG, out of these hypotonic patients had maximum (70%) chances of EEG abnormality followed by spastic patients (55%). Developmental retardation was more severe statistically in the patients with abnormal EEG than normal EEG.

A hereditable combination of congenital anomalies.

A kindred of seven affected individuals in three generations is described with autosomal dominant inheritance of bilateral five-fingered hands, pedal polydactyly with syndactyly and agenesis of the tibia and of the lower end of the radius.